Search Results

Examining Why More Than Half of all Who Have Charcot-Marie-Tooth Disease are not Able to Obtain Genetic Confirmation of Their Disease There’s a rare and complex inheritable peripheral neuropathy with a confusing name. Called CMT, the disease is also a neuromuscular disease, and it is difficult to diagnose. Doctors rely on symptoms, family history, specialized testing that looks for abnormalities with how the peripheral nerves transmit their signals (nerve conduction study), and genetic testing. Genetic testing, however, often fails to identify the cause for an individual’s CMT, leaving doctors and patients frustrated. There are many different genetic tests available for CMT. With test names such as “Comprehensive CMT Panel,” Comprehensive Neuropathies Panel,” and “[CMT] Neuropathies Panel,” for example, one would think any of these would find the genetic cause when ordered. With such convincing genetic test names, how is it, then, that genetic testing often fails to reveal the cause of one’s CMT? Here, we will attempt to uncover and understand why this propensity exists and what, if anything, can be done to solve it. Discovering CMT Charcot-Marie-Tooth disease (CMT) is a complex heterogeneous rare inherited neuromuscular peripheral polyneuropathy. First described in 1886 by the three doctors whose names this disease bears, Jean-Martin Charcot (1825-1893), Pierre Marie (1853-1940), both from France, and Howard Henry Tooth (1856-1925) from England, the cause was not found for more than another 100 years, in 1991 (Raeymaekers, et al., 1991). Leading up to this monumental genetic discovery, scientists knew CMT was inheritable and therefore had a genetic component, and they predicted there might be four or five causes for CMT. The initial genetic discovery, however, was only the beginning. As of today, scientists have discovered CMT-causing mutations in 128 individual genes (Experts in CMT, 2023). Additionally, scientists have mapped four potential CMT causes to four chromosomal locations, but the exact gene remains elusive. Combined, these account for 162 individual CMT subtypes. Despite the enormity of the number of CMT-causal genes thus far discovered, scientists believe they could very well be only halfway to discovering all genetic causes for CMT (Shy, 2020). Clinically, CMT is divided into CMT1 and CMT2 according to nerve conduction study results (Dyck, Lambert, & Mulder, 1963). Statistically, approximately 95% of all individuals who have demyelinating CMT (CMT1 clinical diagnosis) can today obtain a genetic confirmation of their CMT. In sharp contrast, only about 50% of individuals who have an axonal CMT (CMT2 clinical diagnosis) can obtain a genetic confirmation, and some believe this might be as low as only 30% (Züchner, 2021) (Shy, 2020). Combined, less than half of all who have CMT can today obtain genetic confirmation of their clinical diagnosis. Current data modeling depicts that 1 out of every 2,500 people in the world have CMT (Inherited Neuropathies Consortium (INC), 2021). This modeling accounts for both diagnosed and undiagnosed cases. The model predicts that 0.04% of the global population has CMT, even if they’re not yet diagnosed. We can use this model to estimate how many CMTers can obtain genetic confirmation versus how many cannot. The Likelihood of Obtaining Genetic Confirmation There are approximately 8 billion people in the world today (United States Census Bureau, 2023). This means approximately 3.2 million people have CMT, even if they don’t yet know it. Using the probability of obtaining genetic confirmation statistics previously discussed, approximately 28.5% to approximately 47.5% of CMTers can obtain genetic confirmation, equating to between approximately 912 thousand and 1.5 million CMTers while between 1.7 million and 2.28 million CMTers are not able to obtain confirmation, globally. In the US, which has a population of approximately 334 million, there are about 134,000 CMTers. Between approximately 38,000 and 63,000 can obtain genetic confirmation while between 71,000 and 95,000 cannot. Statistically, a CMT genetic test is more likely to fail at identifying a genetic cause for one’s CMT than the test is to genetically confirm CMT, and this is due to the limitations of CMT genetic testing. These limitations are predicated, in part, on the statistical variables we’ve thus far discussed. Additionally, the genes that make up the chosen test panel is another variable to account for. The Variability of Commercially Available CMT Genetic Test Panels CMT genetic testing has long been commercially available. There are many laboratories offering various gene panels for CMT. A gene panel is a genetic test that looks at more than one specific gene as part of the test. Everything from a basic three or four gene panel up to and including a panel with 153 genes are readily available. Some of the smaller panels, for example having four genes to as many as 60 genes, include genes in which every gene on the panel has linkage to CMT. Getting into the larger ones, panels having more than eighty genes, for example, often include genes that have no CMT linkage. This is another part of the problem CMTers face for obtaining genetic confirmation of their disease. The most popular and/or largest CMT genetic test panels commercially available are compiled with an impressive list of genes on their respective panels. However, a review of these panels reveal each is limited insofar as they exclude sometimes dozens of CMT-related genes. Also, each respective panel has genes the others do not. Laboratories, regardless of which genetically caused disease they are offering testing for, have the ability to add genes to their panels that meet the needs of the patient community. The genetic testing industry in the US is largely unregulated though (NIH, 2022). There isn’t a standard that genetic testing companies must adhere to for gene inclusion on their respective panels. Genetic testing companies are able to make the decisions for themselves, and understandably so. According to Carly Siskind, MS, CGC, who is a certified genetic counselor at Stanford University Department of Neurogenetics and Neurogenomics, and who is a leading CMT genetics expert, there isn’t a commercial laboratory that offers a gene panel that includes all known CMT-related genes. The specific test ordered plays a large role in testing outcomes—not all panels are created equally. Says Siskind, “this is one of the toughest hurdles I have when trying to obtain a genetic diagnosis for my CMT patients.” Examining the Data The following tables provide an exhaustive list of all CMT-related genes discovered and published as of March 6, 2023, and an itemized breakdown of three CMT genetic test panels: Invitae’s Comprehensive Neuropathies Panel test 03200 (Invitae Comprehensive Neuropathies Panel, 2022), GeneDx’s Hereditary Neuropathies Panel test 737 (GeneDx Hereditary Neuropathies Panel Test Code: 737, 2022), and Blueprint Genetics’ Charcot-Marie-Tooth Neuropathies Panel test NE1301 (Blueprint Genetics, 2022). The gene list for each panel is given, and on each panel, the genes linked to CMT are marked in red and with an asterisk (*). Following the three panels are itemized analyses comparing each of the three panels to one another, and a datapoint for each that gives the CMT-related genes excluded by the panel. The Invitae Comprehensive Neuropathies panel has an option to add nine additional genes. The following data are based on the panel’s standard 102 genes without the optional add-ons. The exhaustive list of CMT-causal genes includes an “aka” in parenthesis for genes that appear on the subsequent panels with an older name. The HUGO Gene Nomenclature Committee is the governing body for curating gene names and their symbols. The exhaustive list of genes displays the currently approved HGNC gene symbol (abbreviation) for each gene. Not all genes on the following panels have been updated to the latest HGNC approved symbol by the respective laboratory, and any discrepancy is superficial based on this. Panel Statistics Invitae 03200: 85 genes with linkage to CMT** GeneDx 737: 82 genes with linkage to CMT Blueprint Genetics NE1301: 97 genes with linkage to CMT Comparison Invitae 03200 genes not on GeneDx 737 (11 genes): ATP1A1, DCTN1, DHTKD1, DRP2, FBLN5, MARS1, MCM3AP, PMP2, POLG, SURF1, UBA1 Invitae 03200 genes not on Blueprint Genetics NE1301 (4 genes): DRP2, SIGMAR1, SLC5A7, VRK1 GeneDx 737 genes not on Invitae 03200 (8 genes): ABHD12, CNTNAP1, KARS1, MPV17, PNKP, SCO2, SETX, VCP GeneDx 737 genes not on Blueprint Genetics NE1301 (6 genes): ABHD12, CNTNAP1, SCO2, SIGMAR1, SLC5A7, VRK1 Blueprint Genetics NE1301 genes not on Invitae 03200 (15 genes): ARHGEF10**, ATP6, CCT5**, COA7, CTDP1, DCAF8, HADHB, HK1, KARS1, MPV17, MTRFR, PNKP, SCYL1, SETX, VCP Blueprint Genetics NE1301 genes not on GeneDx 737 (20 genes): ARHGEF10, ATP1A1, ATP6, CCT5, COA7, CTDP1, DCAF8, DCTN1, DHTKD1, FBLN5, HADHB, HK1, MARS1, MCM3AP, MTRFR, PMP2, POLG, SCYL1, SURF1, UBA1 Invitae 03200 genes not on either GeneDx 737 or Blueprint Genetics NE1301 (1 gene): DRP2 GeneDx 737 genes not on either Invitae 03200 or Blueprint Genetics NE1301 (3 genes): ABHD12, CNTNAP1, SCO2 Blueprint Genetics NE1301 genes not on either Invitae 03200 or GeneDx 737 (10 genes): ARHGEF10**, C12ORF65, CCT5**, COA7, CTDP1, DCAF8, HADHB, HK1, MT-ATP6, SCYL1 Genes on all three of these panels (721genes): AARS (aka AARS1), AIFM1, ATL1, ATL3, ATP7A, BAG3, BICD2, BSCL2, CHCHD10, COX6A1, DNAJB2, DNM2, DNMT1, DST, DYNC1H1, EGR2, ELP1, FBXO38, FGD4, FIG4, GAN, GARS (aka GARS1), GDAP1, GJB1, GNB4, HARS (aka HARS1), HINT1, HSPB1, HSPB8, IGHMBP2, INF2, KIF1A, KIF5A, LITAF, LMNA, LRSAM1, MFN2, MME, MORC2, MPZ, MTMR2, NDRG1, NEFH, NEFL, NGF, NTRK1, PDK3, PLEKHG5, PMP22, PRDM12, PRPS1, PRX, RAB7A, REEP1, RETREG1, SBF1, SBF2, SCN11A, SCN9A, SEPT9, SH3TC2, SLC12A6, SLC25A46, SPG11, SPTLC1, SPTLC2, TFG, TRIM2, TRPV4, WNK1, YARS (aka YARS1) Genes not on Invitae (43 genes): ABHD12, ARHGEF10**, ATP6 (aka MT-ATP6), C19ORF1, CADM3, CCT5**, CFAP267, CNTNAP1, COA7, CTDP1, DCAF8, DGAT2, FLVCR1, GBF1, Genomic Rearrangement Between 8q24.3 and Xq27.1, HADHB, HK1, HSPB3**, ITPR3, JAG1, KARS1, MPV17, MTRFR (aka C12ORF65), MYH14, MYO9B, NAGLU, NOTCH2NLC, PDXK, PHYH, PNKP, POLR3B, PSAT1, SCO2, SCYL1, SETX, SORD, SGPL1**, SYT2, TUBB3, UBE3C, VCP, VWA1, WARS1 Genes not on GeneDx (46 genes): ARHGEF10, ATP1A1, ATP6 (aka MT-ATP6), C19ORF12, CADM3, CCT5 CFAP276, COA7, CTDP1, DCAF8, DCTN1, DGAT2, DHTKD1, DRP2, FBLN5, FLVCR1, GBF1, Genomic Rearrangement Between 8q24.3 and Xq27.1, HADHB, HK1, HSPB3, ITPR3, JAG1, MARS (aka MARS1), MCM3AP, MTRFR, MYH14, MYO9B, NAGLU, NOTCH2NLC, PDXK, PHYH, PMP2, POLG, POLR3B, PSAT1, SCYL1, SGPL1, SORD, SURF1, SYT2, TUBB3, UBA1, UBE3C, VWA1, WARS1 Genes not on Blueprint (32 genes): ABHD12, C19ORF12, CADM3, CFAP276, CNTNAP1, DGAT2, DRP2, FLVCR1, GBF1, Genomic Rearrangement Between 8q24.3 and Xq27.1, HSPB3, ITPR3, JAG1, MYH14, MYO9B, NAGLU, NOTCH2NLC, PDXK, PHYH, POLR3B, PSAT1, SCO2, SGPL1, SIGMAR1, SLC5A7, SORD, SYT2, TUBB3, UBE3C, VRK1, VWA1, WARS1 Genes not on any of these 3 panels (23 genes): C19ORF12, CADM3, CFAP276, DGAT2, FLVCR1, GBF1, Genomic Rearrangement Between 8q24.3 and Xq27.1, ITPR3, JAG1, MYH14, MYO9B, NAGLU, NOTCH2NLC, PDXK, PHYH, POLR3B, PSAT1, SORD, SYT2, TUBB3, UBE3C, VWA1, WARS1 The three example panels and their differences perfectly illustrate the limitations inherent in conventional CMT genetic testing. These limitations are why a genetic test result that fails to provide a clear straightforward confirmation of the clinical CMT diagnosis means only that the gene with the responsible mutation has yet to be tested for and a result like this does not mean CMT is ruled out. **Invitae 03200 optional nine additional genes adds the CMT genes ARHGEF10, CCT5, HSPB3, and SGPL1 to the panel. Beyond The Conventional Panel Gene panels for CMT genetic testing are the standard go-to. A gene panel is a genetic test that looks at more than one gene during a test, but the genes being looked at are the specific genes listed on the panel and nothing beyond these, whether there are only two genes on the panel or hundreds. When a gene panel doesn’t reveal a clear straightforward genetic confirmation of the clinical CMT diagnosis there are more sophisticated genetic tests available as next-step options. When conventional genetic testing is exhausted and obtaining a genetic confirmation of the clinical CMT diagnosis didn’t happen, the next step is Whole Exome Sequencing (WES). WES is a sophisticated and expansive genetic test. WES sequences the entire genome—all 20,000+ genes, then attempts to look at all coding regions of every gene—the exons. Hence “exome.” A gene has two basic parts: the exon which holds all coding genetic material, and the intron which holds all non-coding genetic material. What is Whole Exome Sequencing (WES)? WES attempts to look at the coding material of all genes to identify disease-causing mutations. Coding, in this context, means the part of each gene that encodes something; and encode means instructs, controls, defines, builds, etc., something within a cell, whether that be an enzyme, a protein, etc. If we think of each gene as a recipe, the coding material is the ingredients, and the cooking instructions are how the gene “encodes.” For example, the SORD gene encodes (cooks, makes) the sorbitol dehydrogenase (dee-hydro-geh-nace) enzyme, and the gene makes this enzyme based on the ingredients (the coding material) of the gene. How the order of the SORD gene’s ingredients are listed (the sequence) determines how the recipe is cooked, (cooking instructions, encodes) and the sorbitol dehydrogenase enzyme is the result, just like following a recipe for chocolate chip cookies results in chocolate chip cookies. When a doctor orders a WES, they include symptom and condition information with the order. For example, this might look like “history of foot drop, sensory loss, muscle atrophy, suspected Charcot-Marie-Tooth disease.” Once the laboratory sequences the individual’s DNA, the sequenced data is captured by a computer program. Clinicians then input as keywords into the computer program the symptom and condition information provided with the doctor’s order. The computer program then compares this keyword information against genes that are known to have mutations that cause conditions that match the keywords and generates a list of matching genes. This list is referred to as the “primary gene list.” After the computer program renders the primary gene list, each gene on the list is analyzed for mutations. Any mutations that are identified are then verified by clinicians and genomic scientists at the laboratory. When identified mutations are either known causes (pathogenic) or potentially known causes for conditions matching the input keywords, the mutations are reported in the results. Mutations that are known to be benign and harmless generally are not reported. Although WES attempts to look at all genes rather than only certain genes listed on a panel, there are limitations to WES in the context of CMT. The Limits of WES A significant limitation of WES results is “coverage depth,” or how well each gene is reliably analyzed. Some laboratories have greater coverage depth than others, and this drives overall outcome potential. Another significant variable governing the limitations of WES’s ability to reveal an individual’s CMT cause is the symptom and condition information provided by the doctor with the order. If these are too vague, WES’s rendered primary gene list might not capture the gene with the CMT-causing mutation. As equally significant, if the laboratory doesn’t know that a gene has been discovered to have CMT-causing mutations (these discoveries are not reported to, tracked by, or recorded by any entity, agency, or organization), the gene will not be included in the primary gene list and then analyzed for potential CMT-causing mutations. When this happens, the results might not truly represent an individual’s genetic profile, and just like when conventional gene panels fail to reveal a cause of CMT, a WES result that fails to reveal the CMT cause means only that the gene with the CMT-causing mutation was not looked at, and the result means only this. When WES fails to reveal the CMT cause, another test, Whole Genome Sequencing (WGS), is the next and final option. WGS is performed just like WES, but WGS goes beyond only the coding regions of each gene and looks at all parts of the gene. WGS is used only for research purposes at the present time. In the context of CMT, WGS is also bound by the same limitations as WES. For diagnostic purposes, WGS, at the present time, doesn’t provide much of a diagnostic advantage over WES. This is likely to change, however, as technology grows, and as genomic science understandings evolve. Why test with so many limitations in CMT genetic testing and with results that are statistically more likely to be negative or inconclusive? To Test or Not to Test? CMT genetic testing is a personal choice. For some, the decision is based on treatment availability. “If I can’t treat it, why test for it?” is a common view in the CMT community. Many healthcare providers feel the same way. Additionally, if there is a higher likelihood for a negative genetic test result than there is for a positive test result, “why should I bother?” These are valid feelings about CMT genetic testing. Often, the decision to not test is based on prohibitive out-of-pocket costs whether the costs are from insurance coverage denials or from an absence of healthcare coverage. Other times, testing just isn’t convenient with having to go to an outpatient lab for a blood draw. Sometimes, these things result from a lack of healthcare provider awareness regarding available CMT genetic testing options. Modern testing is now performed with simple at-home saliva collection with a cheek swab, and this overcomes some of these issues. Many CMTers and their healthcare providers become frustrated by CMT genetic test results that fail to confirm the clinical diagnosis. For a healthcare provider, the lack of genetic confirmation means the diagnostic puzzle is that much more difficult to piece together. In a survey of 100 CMT patients who have a clinical diagnosis but have been unable to obtain genetic confirmation, 97% said they feel like they lack a “real diagnosis,” and 89% say their negative genetic test result is preventing them from attaining closure. These things are understandably frustrating. For some, seeing this frustration in the community fosters an unwillingness to attempt genetic testing, and rightfully so—in the survey, 37% said the chances of a negative test result is sufficient enough to not bother with testing. The reasons to forego CMT genetic testing are many and are as diverse as are the individual CMTers. The above examples from the CMT patient community, from the healthcare community, and from the survey results are just a few reasons that drive decisions to not test. Where CMT genetic testing might not reveal the genetic cause for the CMTer, there is still a chance it will reveal that cause. Obtaining genetic confirmation of one’s CMT means knowing the exact subtype. Knowing the exact subtype means knowing the subtype’s inheritance pattern—how CMT can be passed on and the chances that it will be passed onto the CMTer’s children. This is important for family planning, if not for the CMTer, then for the CMTer’s children when they’re ready to start their own family. Having genetic confirmation often means meeting criteria for clinical trials. CMT clinical trials are almost always subtype specific. Investigators trialing a drug, or a gene therapy, are targeting a specific genetic cause that applies only to the related subtype. For this reason, genetic confirmation is needed for trial participation (Record, et al., 2023). Much like the reasons to not test, the reasons to test are many and are as diverse as are the individual CMTers. The reasons to test, however, are not limited to only the prospect of a confirmatory test result. Results that fail to overtly identify a genetic cause for one’s CMT are as equally important as results that do confirm, and they are perhaps even more important. When Genetic Testing Fails So much in CMT relies on a genetic confirmation. In this context, confirmation means confirming the clinical CMT diagnosis. Genetic confirmation in CMT, however, is the exception, not the rule. If genetic confirmation is not possible for so many who have CMT, then how are they to know for certain they even have CMT? As it turns out, genetic testing is not needed to diagnose CMT. Richard A. Lewis, MD is a Professor of Neurology at Cedars-Sinai Medical Center and is the Director of the Charcot-Marie-Tooth Association’s (CMTA) Center of Excellence CMT Clinic at Cedars-Sinai. Dr. Lewis explains that genetic testing is but only one piece of the diagnostic picture doctors consider when diagnosing CMT (Raymond, 2021). According to Dr. Lewis, symptoms, family history, and nerve conduction study results all play an equal role when diagnosing CMT, and together, often inform the doctor's genetic testing decisions. To diagnose CMT, says Dr. Lewis, “one needs the appropriate clinical picture—numbness and weakness in the feet and usually in the hands occurring with reduced reflexes, plus a family history of the same problems that cannot be due to other causes such as diabetes. Also, the nerve conduction studies should show evidence of neuropathy—nerve conduction velocities that are very slow fit a diagnosis of CMT1 [clinical CMT1 diagnosis], and if not very slow, CMT2 [clinical CMT2 diagnosis].” Dr. Lewis continues, “having pes cavus (high arches) since early in life is supportive evidence of a CMT diagnosis. But other neuropathies can give a similar clinical picture and similar nerve conduction study findings.” Dr. Lewis also explains that “an abnormal genetic test with the right mutation in the right gene would be proof it’s CMT. However, genetic testing doesn’t always detect a problem and that doesn’t mean that a genetic disorder such as CMT is not the cause.” “In addition,” Dr. Lewis says, “genetic testing results can be difficult to interpret and can be confusing to the patient.” A definitive diagnosis depends on a doctor putting all the diagnostic information together; and, it is important not to miss a treatable cause of neuropathy. With all of this complexity in mind, Dr. Lewis advises that it is best to get a good neurologic evaluation if you have neuropathy. The Significance of a Negative CMT Genetic Test Result A CMT genetic test result that comes up empty can be gut wrenching for the CMTer, especially when all genetic testing options have been exhausted. There’s no question about that. It’s an unfortunate reality for so many. At face value, this outcome might seem like testing was a waste of time. Nothing could be farther from the truth though. A negative test result is just as important as a positive result, and perhaps even more important. Laboratories store genetic test sequenced genome data. Data? Once the lab sequences a genome (genome = DNA), all the genetic information is input into a computer program. The computer program then renders this sequenced information into a structured data file that can be stored, analyzed, and compared against in the future. This is the important part in the context of CMT. The Distant Cousin Project CMT genetic discoveries happen, in part, because scientists can analyze and compare many different genomes from many different CMTers. The Genesis Project is one such organization that is actively engaged in identifying undiscovered genes that hold CMT-causing mutations. The work conducted by the Genesis Project has thus far resulted in more than 100 rare disease genetic discoveries (The Genesis Project, 2022). Some of these discoveries are genes with linkage to CMT, including the monumental SORD-deficiency CMT discovery (Cortese, et al., 2020). The Genesis Project Foundation was co-founded and is chaired by Stephan Züchner, MD PhD, who is a geneticist at the University of Miami. Dr. Züchner has dedicated his working life to identifying unknown genetic causes of rare diseases. Among his genetic discovery credits are dozens of genes with linkage to CMT. Dr. Züchner has many active research projects that are focused on finding undiscovered culprit genes for rare diseases. A culprit gene is a gene that has a disease-causing mutation. One such project focusing on CMT is the Distant Cousin Project. What is the Distant Cousin Project? The Distant Cousin Project, Dr. Züchner explains, is a genetic research project whose purpose is to identify CMT culprit genes by analyzing the genome of a CMTer and a distant cousin who also has CMT, then comparing the two genomes to find identical gene mutations that could potentially explain their CMT. Why a distant relative and not a parent or sibling? The answer might surprise you. Dr. Züchner explains, “Intuitively, it might seem that having one’s genome and the genomes of close family members with the same disease sequenced should lead to a discovery of the culprit. To some extent, that’s true.” This makes sense. This seems very straightforward and fairly simple. However, Dr. Züchner continues, “The problem is that researchers can readily identify hundreds of potential culprit variants (variations of unknown significance) in many genes in nearly every genome studied. One shares too much DNA with close relatives to narrow the genes down to just a few possibilities.” This is where the Distant Cousin Project comes in. The foundational basis of the Distant Cousin Project is to look at the CMTer’s genome and that of a distant cousin, perhaps a 3rd or 4th cousin, if the CMTer has or can locate such a distant relative, then compare the two. Unlike close relatives such as parents and siblings who share many of the same genetic mutations, “4th cousins share only about one-fifth of one percent of their DNA,” explains Dr. Züchner. “If two 4th cousins share the same culprit gene,” Dr. Züchner continues, “there is a very good chance that researchers could locate it.” Dr. Züchner also cautions that such distant relatives, who both have CMT, might have different genetic causes from each other. Dr. Züchner is conducting the Distant Cousin Project research study through his work at the University of Miami and the participant genomes will be analyzed by The Genesis Project. There has already been a successful outcome. Through this study, Dr. Züchner and his team of researchers have identified mutations in the ITPR3 gene that are causing a CMT1 subtype. Dr. Züchner explained that two large families, one family from Wisconsin and one from Sydney, Australia were the key for this discovery, and the discovery was made possible by their participation in the Distant Cousin Project. CMT1J has emerged as the subtype name for this discovery (Kniffin, 2022). Dr. Züchner’s study is limited to ten families, and the study is currently enrolling participants. To be considered, the CMTer, one of their parents, and the distant cousin must have a clinical CMT diagnosis preferably from a recognized CMT expert clinic and each must have unsuccessful genetic testing outcomes. Although a daunting task for many, the CMTer must have located the distant cousin prior to enrolling in the study. The study provides the related genomic analysis at no cost to the participants. If you’d like to be considered for the study, you can send an email to study coordinator, Yeisha Arcia, at y.arciadejesus@miami.edu. The Distant Cousin Project is just one example of how negative CMT genetic test results are intrinsically important to CMT research and this example perfectly illustrates the importance of undergoing genetic testing regardless of the outcome – study participants must first have failed CMT genetic testing before they are eligible for the study. The study might then lead to identifying the culprit gene and its responsible CMT-causing mutation, and the discovery might stand the CMT world on its head. One such discovery made possible by the genomic database work of Dr. Züchner and The Genesis Project, the SORD-deficiency CMT discovery, did just that. SORD-Deficiency CMT Combing heaps of genomic data curated by The Genesis Project, Dr. Züchner and his team of investigators at the University of Miami made a discovery that has changed the course of CMT treatment research. Analyzing a collection of genomes from CMTers who had undergone unsuccessful genetic testing, the investigators discovered mutations in the SORD gene in several of the genomes and were able to conclude these were a cause for CMT. Cortese et al., 2020 dubbed this new CMT subtype discovery “SORD-deficiency.” What makes this discovery so special? Very quickly, researchers learned that an estimated 3,000 CMTers in the US, 4,000 CMTers in Europe, and an estimated 60,000 CMTers worldwide have this CMT subtype (Shendelman, 2022). SORD-deficiency CMT is the most commonly occurring autosomal recessive axonal subtype. Prior to genetic confirmation, CMTers who have this subtype are/were clinically diagnosed with CMT2 or the CMT classification dHMN (Distal Hereditary Motor Neuropathy). This discovery wouldn’t have been possible if the many CMTers whose genomes led to the discovery hadn’t undergone genetic testing that resulted in a negative outcome. But why is this discovery so important. The SORD gene encodes an enzyme called sorbitol dehydrogenase. The mutations in the SORD gene that cause CMT cause this enzyme to be either nonfunctioning or absent altogether. The result is CMT. Due to the hard work of many scientists, researchers, and investigators, both from within CMT and outside of CMT, expertise with therapies targeting the sorbitol dehydrogenase enzyme was identified. With so many working together, this expertise, developed by a biopharma company named Applied Therapeutics, adapted an investigational sorbitol dehydrogenase targeting therapy to the needs of the newly found SORD-deficiency CMT community. Just two years after the SORD-deficiency discovery, there was a Phase III clinical trial underway investigating a treatment for this CMT subtype (Applied Therapeutics, 2022). Now, almost three years after discovery, preliminary data from this clinical trial released by Applied Therapeutics show very promising results as a potential viable treatment for this subtype (SORD-CMT INSPIRE Trial, February 2023 Preliminary Data Release, 2023). “Examples like SORD,” explains Dr. Züchner, “show how genomic discovery increasingly can result in direct pathways to treatment trials.” Solving the Unsolvable The reasons why so many CMTers are unable to obtain genetic confirmation of their CMT, are unable to obtain that coveted genetic diagnosis are many. A significant factor in testing outcomes is the specific test the doctor orders. A review of available data from the websites of the companies whose panels we analyzed shows striking differences between each, yet each has capabilities the others do not, meaning each can potentially result in a genetic confirmation that’s not possible with the others. Which is best? “That depends,” seems to be the best answer. The genetic test panels used in CMT are part of the problem because of so much variability between the panels and because of the panel names themselves. One such panel, titled, “Charcot-Marie-Tooth Disease Comprehensive Panel,” infers the test should yield the best possible test outcome. However, there are only 57 genes on the panel (Invitae Charcot-Marie-Tooth Disease Comprehensive Panel, 2022). The company offers an optional three genes to add to the test. Even at 60 genes, this is less than half of all known genes discovered to have CMT-causing mutations. While these panels are part of the problem, the respective companies who offer CMT genetic testing are also the solution. Companies offering CMT genetic testing have to do better with panel design. CMT genetic discoveries move fast. All data presented in this article are publicly available. When scientists make CMT genetic discoveries, they publish their findings in peer-reviewed journal articles. If the paper itself is not fully publicly available, the abstract is in the very least. Three years after the SORD discovery, the most common autosomal recessive axonal CMT, the gene is not on any CMT genetic testing panel. The ability for a testing company to learn of new discoveries is there. The companies must then adjust their CMT panels accordingly. The patient community, the healthcare community, the research community, and the biopharma community need this. Health and well-being depend on this. The patient community has a responsibility to the solution, also. A negative CMT genetic test result, as frustrating as it might be, is a significant part of the solution to the problem of less than half of all who have CMT not being able to obtain genetic confirmation of their disease. Closing this gap requires CMTers to participate in genetic testing. Researchers who are working to find unknown genetic causes need genomes from CMTers who have negative genetic test results. This means that, when genetic testing fails to reveal the cause, the patient needs to contact researchers like Dr. Züchner and have their genome (DNA) added to a database that researchers are continually analyzing. Patient advocacy groups are also part of the solution. Patient advocacy groups provide research funding that supports genetic discoveries in CMT. These groups, such as the HNF and the CMTA, for example, are authoritative bodies within the CMT space. These groups, and others, are perfectly positioned to generate the needed awareness among the patient and healthcare communities around the need for genetic testing, and especially the importance of a negative test result, and then who to contact with that result. The Hereditary Neuropathy Foundation (HNF) has a fantastic program called CMT Genie that leads CMTers to CMT genetic testing when they otherwise wouldn’t have access to testing, and this program is creating the needed awareness. As complex of a problem as CMT genetic testing is, the problem is solvable. Solving this problem will require everybody in the CMT community working together. The CMT community has many moving parts, and each are integral to overcoming the limitations of genetic testing that are inherent in CMT. In Closing Gene discovery in CMT continues to grow. Today, scientists have discovered 128 genes to have CMT-causing mutations. During the research for this article, we learned of two very recent gene discoveries in CMT that aren’t published yet (these are not part of the data analysis). Without publication, commercial labs don’t know to even consider the genes for inclusion on their panels. In a recent conference I attended, Steven S. Scherer, MD, PhD, a renowned CMT clinician and researcher who has many CMT gene discoveries to his credit, suggested [we’ll] cross the 200 genes mark by [2030]. With the rates of annual gene discovery in CMT, he’s spot on. If Dr. Shy is right, crossing the 200 gene mark doesn’t get us to the finish line, but is only another lap out of an undetermined number of needed laps in this race though. When first described in 1886 by Drs. Charcot, Marie, and Tooth, CMT was a simple disease affecting only the lower legs. CMT, however, has no doubt emerged as perhaps one of the most complex diseases the medical science community has on their plate. Unfortunately, this complexity results in many who have this disease begging for answers but finding only more questions. The need for CMT patients to undergo genetic testing has never been greater. Currently, there is no effective treatment nor a cure for the disease (Cipriani, et al., 2023). Genetic confirmation helps with identifying a patient population treatment researchers and biopharma researchers need for studying potential therapies. At the same time, negative results are even more important because these provide a crucial opportunity for researchers to obtain vital genomes from CMTers in hopes of discovering new causes of CMT. A single genome submission from a CMTer who had a negative genetic test result can potentially affect thousands if their DNA leads to researchers finding a new cause for CMT. This has happened with the SORD-CMT discovery, and it could very well happen again. About the Author Kenneth Raymond was first diagnosed clinically with CMT1 in late 2002, at the age of 29. He was genetically confirmed to have CMT1A a year later. Kenneth has since devoted his life to studying, researching, and learning all things CMT, with an emphasis on the genetics of CMT as they relate to everyday CMTers. Currently pursuing an MS in Genetics, Cell, and Developmental Biology at Arizona State University, Kenneth’s passion for understanding CMT and improving the lives of those who are living with CMT remains as strong as ever. Download your free copy of Error 404: Gene Not Found by clicking this link: https://www.expertsincmt.com/downloads-1/error-404%3A-gene-not-found CMT Gene Discovery, CMT Genetic Testing, Patient Resources, and Clinical Research The Genesis Project Foundation: https://www.tgp-foundation.org/ The Charcot-Marie-Tooth Association: https://cmtausa.org/ The CMTA's Patients as Partners Research Registry: https://www.cmtausa.org/our-research/for-patients-and-families/patients-as-partners/ References Applied Therapeutics. (2022). Applied Therapeutics: INSPIRE. Retrieved October 14, 2022, from Applied Therapeutics: https://www.appliedtherapeutics.com/inspire/ Applied Therapeutics Announces Positive Sorbitol Reduction Data From the Ongoing Phase 3 INSPIRE Trial in Sorbitol Dehydrogenase (SORD) Deficiency. (2023, February 16). Retrieved February 16, 2023, from Applied Therapeutics: https://ir.appliedtherapeutics.com/news-releases/news-release-details/applied-therapeutics-announces-positive-sorbitol-reduction-data Blueprint Genetics. (2022). Blueprint Genetics - Charcot-Marie-Tooth Neuropathy Panel test NE1301. Retrieved February 11, 2023, from Blueprint Genetics: https://blueprintgenetics.com/tests/panels/neurology/charcot-marie-tooth-neuropathy-panel/ Cortese, A., Zhu, Y., Rebelo, A. P., Negri, C., Courel, S., Abreu, L., . . . Züchner, S. (2020, May 4). Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes. Nature genetics, 52(5), 473–481. doi:https://doi.org/10.1038/s41588-020-0615-4 Cipriani, S., Guerrero-Valero, M., Tozza, S., Zhao, E., Vollmer, V., Beijer, D., . . . Bolino, A. (2023, February 1). Mutations in MYO9B are associated with Charcot-Marie-Tooth disease type 2 neuropathies and isolated optic atrophy. European journal of neurology, 511–526. doi:https://doi.org/10.1111/ene.15601 Dyck, P. J., Lambert, E. H., & Mulder, D. W. (1963, January 1). Charcot‐Marie‐Tooth disease nerve conduction and clinical studies of a large kinship. Neurology, 13(1). doi:https://doi.org/10.1212/WNL.13.1.1 Experts in CMT. (2023, March 6). CMT-Associated Genes and Their Related Subtypes Database. Retrieved April 7, 2023, from Experts in CMT: https://www.expertsincmt.com/cmt-geneticsdatabase GeneDx - Hereditary Neuropathy Panel. (2022). Retrieved May 24, 2023, from GeneDx | Sema4: https://www.genedx.com/tests/detail/hereditary-neuropathy-panel-800 Inherited Neuropathies Consortium (INC). (2021). CMT in Depth - What is CMT. Retrieved February 2023, from Rare Diseases Clinical Research Network: https://www.rarediseasesnetwork.org/cms/inc/Healthcare-Professionals/CMT Invitae Charcot-Marie-Tooth Disease Comprehensive Panel Test Code: 3201. (2022). Retrieved June 7 24, 2023, from Invitae: https://www.invitae.com/en/providers/test-catalog/test-03201 Invitae Comprehensive Neuropathies Panel Test Code: 3200. (2022). Retrieved May 24, 2023, from Invitae Corporation: https://www.invitae.com/en/physician/tests/03200/ Kniffin, C L;. (2022, November 3). #620111 Charcot-Marie-Tooth Disease, Demyelinating, Type 1J; CMT1J. Retrieved February 11, 2023, from OMIM - Online Mendelian Inheritance in Man: https://www.omim.org/entry/620111?search=cmt1j&highlight=cmt1j NIH. (2022, February 2). Regulation of Genetic Tests. Retrieved June 12, 2023, from National Human Genome Research Institute: https://www.genome.gov/about-genomics/policy-issues/Regulation-of-Genetic-Tests Raeymaekers, P., Timmerman, V., Nelis, E., De Jonghe, P., Hoogendijk, J. E., Baas, F., . . . Bolhuis, P. A. (1991). Duplication in chromosome 17p11.2 in Charcot-Marie-Tooth neuropathy type 1a (CMT 1a). The HMSN Collaborative Research Group. Neuromuscular disorders : NMD,, 1(2), 93–97. doi:https://doi.org/10.1016/0960-8966(91)90055-w Raymond, K. (2021, December 1). Pushing The Limits: Examining the Limitations of Genetic Testing in Charcot-Marie-Tooth Disease. (K. Raymond, Editor) Retrieved April 11, 2022, from Experts in CMT: https://www.expertsincmt.com/post/pushing-the-limits Record, C. J., Skorupinska, M., Laura, M., Rossor, A. M., Pareyson, D., Pisciotta, C., . . . Inherited Neuropathies Consortium, R. (2023, June 7). Genetic analysis and natural history of Charcot-Marie-Tooth disease CMTX1 due to GJB1 variants. Brain : a journal of neurology, Advance online publication. doi:https://doi.org/10.1093/brain/awad187 Shendelman, S. (2022, September 28). Founder and CEO, Applied Therapeutics. HNF Sord Webinar Part 2. (E. Lugo, Interviewer) Retrieved October 17, 2022, from https://www.youtube.com/watch?v=mWa7mAZb7kM&t=280s Shy, M. E. (2020, June 6). Director, Division of Neuromuscular Medicine-Neurology, University of Iowa give his presentation on Research and Clinical Trials in CMT. 2020 MDA Engage CMT Symposium: MDA Mission Spotlight. (N. Petrouski, Interviewer) Muscular Dystrophy Association. Retrieved July 2021, from https://www.youtube.com/watch?v=GWOOzQFWaYM&list=PLxofS4JHjGXXfMhWYiifLRSnHFflDJuv3 The Genesis Project. (2022). Retrieved February 11, 2023, from The Genesis Project Foundation: https://www.tgp-foundation.org/ United States Census Bureau. (2023). U.S. and World Population Clock. Retrieved February 10, 2023, from U.S. Census Population Clock: https://www.census.gov/popclock/world Züchner, S. (2021, October 27). Dr. Stephan Züchner: Exciting Genetic Discoveries Lead to Life-Changing CMT Therapies. CMT4Me Podcast. (C. Ouellette, & E. Ouellette, Interviewers) Charcot-Marie-Tooth Association. Retrieved November 2021, from https://cmt4me.buzzsprout.com/1849476/9429530-dr-stephan-zuchner-exciting-genetic-discoveries-lead-to-life-changing-cmt-therapies

Exploring What Makes SORD-Deficiency CMT So Different from Every Other CMT Subtype, and Discussing Why SORD-Deficiency is CMT "Everyone has high sorbitol. That's part of this disease. We do know that sorbitol level does drive the disease severity. Why is that important? Because, with AT-007 treatment, we're reducing sorbitol levels. So, it's important to know that sorbitol is driving this disease and how high or low your sorbitol levels are makes a difference in terms of how quickly and aggressively the disease will progress." --Shoshana Shendelman, PhD, Founder, Applied Therapeutics Charcot-Marie-Tooth disease, or what is CMT, is an inheritable peripheral nervous system disease with no current treatment or cure. The peripheral nervous system comprises all the nerves that lie outside of the brain and spinal cord except the optic nerves, and CMT can affect all of them (including the optic nerves for some). CMT is not an easy disease to describe. CMT is a heterogeneous multisystem disease (heterogeneous (het-eh-row-jeh-nay-us) = many different causes and the presentation can be different for everybody). CMT is a peripheral neuropathy (neuro- = nerve, -pathy = disease) that is actually a peripheral polyneuropathy because CMT affects more than one peripheral nerve at a time rather than just one nerve (poly- = many/more than one, mono- = one (polyneuropathy vs. mononeuropathy)). CMT is also a neuromuscular disease because the disease of the peripheral nerves causes symptoms to present in muscles (neuro- = nerve, -muscular = affects skeletal muscle). CMT, however, is not a muscle disease. If this isn’t confusing enough, the name doesn’t help. It gets easier, though, when we know the name’s origin. CMT gets its name from the three doctors who first described it in 1886: Jean-Martin Charcot (1825-1893), Pierre Marie (1853-1940), both from France, and Howard Henry Tooth (1856-1925) from England. Today, CMT as a disease name has evolved into an umbrella term that refers to many different sensory and/or motor neuropathies, axonopathies, myelinopathies, and neuronopathies (Pisciotta & Shy, 2018) (Bansagi, et al., 2017). In its infancy, however, CMT described a disease that causes only lower leg muscle weakness and atrophy, or what is aptly called, “peroneal muscle atrophy.” Over time, however, CMT has revealed itself to be profoundly more diverse with reaches far beyond the lower legs (multisystem). The Age of Discovery First described in 1886, the cause for CMT wasn’t discovered until more than one-hundred years later. In 1991, researchers announced and published the first cause of CMT, a duplication of a tiny segment of chromosome 17 (17p11.2 – 17p12), which they concluded is responsible for causing CMT1A (Raeymaekers, et al., 1991). A year later, this discovery was narrowed down to the exact gene—an extra copy of the PMP22 gene that’s present when the tiny chromosome 17p11.2-p12 segment is duplicated (Patel, et al., 1992). At the time, researchers believed there might only be a small handful of additional causes to find and this thing would be figured out. CMT, however, has proven itself to be, perhaps, the most complicated disease there is. Scientists have now discovered CMT-causing mutations in more than 120 genes. Mutations in these genes cause more than 150 individual CMT subtypes (Raymond, 2022). New discoveries are happening every year, and there’s no signs of slowing down. Scientists estimate that we are only about halfway to finding all genes that have CMT-causing mutations (Shy, 2020). However, some estimate that we might be closer after the recent discovery of SORD-deficiency (Züchner, 2021). Gracing the May 2020 cover of Nature Genetics, a truly prestigious achievement, researchers announced the discovery of a new CMT subtype caused by autosomal recessive mutations in the SORD gene (Cortese, et al., 2020). The investigators who make CMT subtype genetic discoveries get to name their discovery. The name they choose becomes known as the subtype name. Rather than choosing a conventional CMT name like CMT1K or CMT4M, for example, the investigators who discovered the CMT-causing mutations in the SORD gene chose to call it, simply, “SORD-deficiency.” Data show this new CMT subtype, SORD-deficiency, is the most common autosomal recessive CMT subtype, affecting approximately 3,000 CMTers in the US, approximately 4,000 CMTers in Europe, and approximately 60,000 worldwide—accounting for 10% of all axonal CMT cases. (Shendelman, 2022). For context, CMT in whole affects approximately 135,000 in the US, approximately 180,000 in Europe, and just over 3 million globally. Scientists have a firm grasp on the SORD gene and the biochemical function it’s responsible for. The biochemical process the SORD gene is a part of is implicated in diabetes and other diseases, and scientists have been studying this implication for decades. There was already pharmaceutical expertise in this area when scientists made the SORD-deficiency discovery. Because of this, researchers feel this might be the first truly treatable CMT subtype (CMTA, 2021). What is SORD-Deficiency? Also known as SORD-deficiency CMT, or SORD-CMT, or just SORD, whichever we call it, SORD-deficiency is a CMT subtype (Shendelman, 2022). Specifically, SORD-CMT is an axonal CMT subtype, and as an axonal subtype, it fits within the CMT2 nerve conduction and symptom profile. SORD-CMT is mostly a motor neuropathy (primarily affects the motor nerves), but there can be sensory nerve involvement. A likely description on a nerve conduction study (NCS) report would be along the lines of length-dependent axonal motor polyneuropathy (or sensorimotor polyneuropathy if there is also sensory nerve involvement). What is CMT2? CMT is clinically divided into two main groups according to nerve conduction study results (NCS): CMT1, classified as demyelinating, and CMT2, classified as axonal. These are differentiated by their respective nerve conduction profiles. Clinically, CMT1 has nerve conduction velocities (speeds) that are slower than 38 meters/second (and usually slower than 25 meters/sec) and amplitudes (signal strength) that are somewhat reduced; and CMT2 has velocities that are faster than 38 meters/second with significantly reduced amplitudes (Dyck, Lambert, & Mulder, 1963) (El-Abassi, 2014) (Stojkovic, 2016). Although these are basic and general rules-of-thumb, how CMT is clinically diagnosed without the benefit of a genetic confirmation is typically based on these criteria. Then, once the underlying genetic cause is identified, the diagnosis transitions to the subtype associated with the identified gene mutation. The genetic diagnosis, however, might not remain a CMT1 or a CMT2 classified subtype, such as CMT1B or CMT2D, for example. CMT1 is a group of ten demyelinating subtypes as determined by nerve conduction. However, there are twenty-eight demyelinating subtypes. CMT2 is a group of thirty-six CMT subtypes, but there are 114 axonal subtypes (Experts in CMT, 2022). Of these 114, there are twenty-three subtypes that have a dHMN name— eighteen dHMN subtypes plus five dSMA subtypes (dHMN and dSMA are synonymous (Inherited Neuropathies Consortium (INC), 2021)). dHMN is the acronym for Distal Hereditary Motor Neuropathy and dSMA is the acronym for Distal Spinal Muscular Atrophy. Despite the names, the CMT experts consider these to be CMT (Bird, 1998, Updated 2022) (Bansagi, et al., 2017). What is dHMN? The subtypes of dHMN are a length-dependent motor neuronopathy, meaning the issue originates within the motor neuron of the peripheral nerves and affects the longest peripheral motor nerves first and more severally than the shorter ones (the nerves that control the muscles of the feet and lower legs vs. the nerves that control the muscles of the hands, for example). The motor nerves are the nerves that control muscles and movement. Sometimes truncated to just HMN (Hereditary Motor Neuropathy), there is little to no sensory nerve involvement, and these subtypes exhibit an axonal CMT nerve conduction profile. As such, the dHMN subtypes are classified as axonal CMT and are therefore often clinically diagnosed as CMT2. Sometimes, however, dHMN (aka HMN, aka dSMA) is the clinical diagnosis when NCS results show a length-dependent axonal CMT and when there is only motor nerve involvement. This will be important in a moment. As a general rule-of-thumb, symptoms associated with CMT2 are typically length-dependent, again, meaning the longer nerves are often affected before the shorter ones, and often more severely. Typically, the lower legs and feet are more severely affected than the hands. Symptom onset can occur at any point in life. Nerve conduction can be quite variable from nerve to nerve and even side to side. How does SORD-CMT fit within this CMT2/axonal CMT classification? SORD-CMT symptom onset is usually in the second decade, typically by about 17 years old (CMTA, 2022). Symptoms are basically that of a motor-predominant CMT2 and/or dHMN, affecting only the motor nerves, in a length-dependent manner, with little to no sensory nerve involvement, and include difficulty with walking, frequent tripping, lower leg weakness, foot deformities, progressing to the need for mobility aids (leg bracing); and later on, hand weakness, for example. However, some can have upper limb sensory and motor involvement early on in their disease course. Although SORD-CMT is classified as an axonal CMT, some SORD-CMTers have nerve conduction that is more consistent with intermediate CMT (Record, et al., 2022). Intermediate CMT is a group of CMT subtypes as determined by NCS results. Intermediate CMT nerve conduction doesn’t necessarily comport with demyelinating CMT or with axonal CMT, it is somewhere in between, it is intermediate (El-Abassi, 2014). Intermediate CMT does not denote disease severity and refers only to nerve conduction. Regardless of the nerve conduction profile a CMTer who has SORD-CMT might have, SORD-CMT is classified as an axonal CMT subtype. CMTers who have SORD-CMT are often clinically diagnosed with either CMT2 or with dHMN (or HMN, and some possibly dSMA) based on symptoms and especially on NCS results. Past genetic testing for these CMTers failed to identify a conclusive genetic cause for their CMT. SORD-CMT and its cause were discovered and published only in 2020. Prior to this, the SORD gene was not part of any CMT genetic test. Nobody knew about this gene’s connection to CMT. Several commercial genetic testing companies moved quickly to offer SORD testing within a year of the initial discovery of its role in CMT. However, SORD genetic testing is not yet a part of the neuromuscular or neuropathy gene panels that are used in CMT genetic testing. So, physicians need to specifically order the SORD genetic test if they suspect a patient might have SORD-CMT (SORD genetic testing resources are discussed in Diagnosing SORD-CMT). Why this name, “SORD,” and why the caps lock? This Gene has a Name, and Its Name is “SORD” (for short) Genes have both a long-form name and a short-form called a symbol. The symbol is an abbreviation of the long-form gene name. The HUGO Gene Nomenclature Committee is the entity who manages these names and symbols. The "SORD" in SORD-deficiency is short for SORBITOL DEHYDROGENASE. Where SORBITOL DEHYDROGENASE is the gene name, SORD is the gene symbol (HGNC, 2022). It’s customary to write the gene name in all caps but is not required in literature. The gene symbol, however, is always written in all caps. The SORD gene codes for an enzyme aptly called sorbitol dehydrogenase (the gene provides the genetic code that makes the enzyme and provides the genetic instructions for how the enzyme functions). An enzyme is a biological catalyst (causes a biochemical change). SORD belongs to a group of enzymes called dehydrogenases. Dehydrogenases are a group of enzymes that each catalyze (change/convert) a compound to another by removing hydrogen atoms (de-hydrogen-ates, ergo de-hydro-gen-ace). Specific to the SORD gene, sorbitol dehydrogenase is the enzyme that converts sorbitol to fructose by removing a hydrogen atom from sorbitol. This action converts (changes) sorbitol to fructose. This is the important part in the context of SORD-CMT, and it all starts with glucose. The Less Traveled Path[way] of SORD-CMT Glucose is one of many different simple sugars. When we talk about blood sugar, we're talking about glucose. In biochemistry, anything ending in "ose" is a simple sugar. The body metabolizes (converts to energy) these simple sugars through various biochemical processes. Glucose is metabolized in many ways, and each is referred to as a pathway. Each of these pathways convert glucose to other sugars which are then, eventually, used by the cell for energy. The majority of glucose is converted to other substances that are used by the cell for energy via the hexokinase pathway. The hexokinase pathway is the biochemical chain reaction that converts hexoses to energy. As complicated as this might sound, you don’t have to be a biologist to know what all this is and how it works in the context of SORD-CMT "Medicine makes sense once we understand what the words are saying." --Medicosis Perfectionalis Hexokinase (hex-oh-kye-nace) is an enzyme that phosphorylates hexoses. Phosphorylates means "to add a phosphate group to a substance." A hexose is any sugar that contains six carbon atoms (hex- = six, -ose = sugar). These are referred to as six-carbon sugars. In biochemistry, "kinase" means "to phosphorylate." Put these together and hexokinase is an enzyme that converts into other substances sugars that contain six carbon atoms, and this is accomplished by adding a group of phosphates to the sugars. Glucose just happens to be a six-carbon sugar—a hexose. Adding a phosphate group to glucose converts it to a different sugar, and further down the complicated hexokinase pathway, after several additional biochemical conversions, the end result is fructose, which is then used by the cell for energy (Chaudhry & Varacallo, 2021). Another pathway in which glucose is converted to energy is the polyol pathway. The polyol pathway is a two-step biochemical conversion that converts monosaccharides to their corresponding polyol in the first step and then converts the polyol to fructose in the second step. Fructose is then used for energy by the cell. The polyol pathway is the important one for SORD-CMT. What does all this mean and why is this pathway important? A polyol is an alcohol sugar, of which there are many (poly- = many, -ol = alcohol sugar). The term, "alcohol sugar," is misleading though. Alcohol sugars are neither alcohol nor sugar. They are, however, a compound chemically similar to sugars (BiologyOnline, 2022). A monosaccharide (mono-sack-ah-ride) is any sugar that cannot be further reduced into a simpler sugar. A monosaccharide (mono- = one, -saccharide = sugar) is a sugar in its simplest form. The polyol pathway converts these simple sugars into their corresponding polyol sugar. Hence, polyol pathway. The first step in the two-step polyol pathway is aldose reductase. Aldose reductase is an enzyme that reduces aldoses to their corresponding polyol. Aldoses are a large family of monosaccharides. Biochemically, an aldose is a simple sugar that contains an aldehyde group (ald- = aldehyde, -ose = simple sugar) (BiologyOnline, 2022). Reductase (re-duck-tace) is any enzyme that reduces a substance to another substance. In biochemistry, metabolism (substance conversion) occurs in terms of electrons: if electrons are lost during the chemical conversion, the process is called oxidation—something is oxidized; and if electrons are gained, it’s a reduction—something is reduced. (The University of Hawaiʻi, 2022). Glucose, as you might have guessed, just so happens to be a member of the aldose family of simple sugars. The corresponding polyol for glucose is glucitol (gluc- = glucose derivative, -ol = alcohol sugar). Glucitol (gloose-eh-tall) is more commonly known as sorbitol. In the first step of the polyol pathway, aldose reductase converts glucose to sorbitol. Sorbitol cannot cross the cell wall and becomes trapped within the cell. To manage sorbitol levels within the cell, sorbitol must be converted to another substance. The second step of the polyol pathway, sorbitol dehydrogenase, converts sorbitol to fructose. Fructose is then used by the cell for energy. This solves the issue of sorbitol being trapped within the cell and reaching toxic levels as more glucose is converted by aldose reductase. It’s a simple, quick, and easy two-step (two-enzyme) process for managing glucose levels and acute (short-term) cell energy demands, especially when compared to the more complex hexokinase pathway. The hexokinase pathway handles the bulk of metabolizing glucose to energy. Under normal conditions, the polyol pathway is barely used, if at all. The polyol pathway, however, becomes activated when hyperglycemic conditions are present within the cell (elevated levels of glucose) or when the cell needs extra energy. Under normal conditions, sorbitol levels are very low. As sorbitol is produced by the polyol pathway, it’s converted to fructose and sorbitol levels are kept in check. If this pathway is inactive, glucose isn’t being converted to sorbitol within the cell. When the polyol pathway is active, the amount of glucose being converted is minimal compared to the hexokinase pathway, and the sorbitol that is produced is converted to fructose by sorbitol dehydrogenase (Shendelman, 2022). Normally low sorbitol levels are maintained by sorbitol dehydrogenase. So, what happens if sorbitol dehydrogenase can’t perform its job? Enter SORD-Deficiency CMT SORD-deficiency CMT is caused by autosomal recessive mutations in the SORD gene (autosomal = gene lives on a numbered chromosome (the SORD gene lives on chromosome 15), recessive = gene must have two mutations in order to cause the disease). Researchers have identified many different CMT-causing mutations within this gene since the initial discovery. Each of these can either cause the SORD enzyme to not be produced at all or they can cause the enzyme to completely shut off and stop working. Because the SORD enzyme no longer functions in this CMT subtype, SORD is deficient - the biochemical conversion performed by the SORD enzyme is deficient. Hence, SORD-deficiency as this CMT subtype name. The subtype name describes the biochemical impairment that causes CMT. When everything is running well, the polyol pathway, also called the aldose reductase pathway, runs smoothly. When activated in times of need, aldose reductase converts glucose to sorbitol and the SORD enzyme converts sorbitol to fructose. The cellular machinery is happy, and everything moves along nicely. However, the mutations that shut off the SORD enzyme throw a big boulder into this finely tuned machine, as you can imagine. All the sorbitol created by aldose reductase in the polyol pathway stays trapped within the cell from the very outset. This is normal with sorbitol. Sorbitol is unable to cross the cell wall. Essentially, all sorbitol created by the polyol pathway remains within the cell until SORD converts it to fructose. Since the mutations in the SORD gene that cause SORD-CMT cause the sorbitol dehydrogenase enzyme to completely stop working, sorbitol is not converted. The sorbitol, instead, remains within the cell, trapped. The more glucose that’s converted to sorbitol by aldose reductase, the higher the sorbitol levels climb, and they keep climbing, over time, until they reach levels that become toxic to peripheral nerves and their neurons, leading to neuronal and peripheral nerve impairment, or as we like to call it, CMT. And then, they keep climbing, unabated, as aldose reductase continues to do its job. The body does process sorbitol in other ways, albeit minimally. Certain enzymes called, “scavenger enzymes,” whose job it is to basically perform cellular housekeeping duties, is one way sorbitol is processed. The kidney’s also play a role in managing sorbitol. In the absence of a functioning SORD enzyme, while these methods do remove some sorbitol, they are quite inefficient and pale in comparison to the amount of sorbitol the SORD enzyme can handle (Shendelman, 2022). For the amount of sorbitol the body is able to process in the absence of a functioning SORD enzyme, aldose reductase keeps adding sorbitol back into the mix, and at a rate greater than what non-SORD sorbitol processing can handle. The result is chronically high sorbitol levels that become toxic to especially motor neurons thereby causing CMT symptom onset, and these things only worsen over time. The Toxicity of Our [Sorbitol] When SORD is deficient, the sorbitol created by the polyol pathway cannot be converted to fructose. This sorbitol ends up just sitting there, in the cells, trapped, accumulating over time because sorbitol cannot exit the cell. Eventually, sorbitol accumulates to levels high enough, toxic enough, to cause CMT symptoms to start. As sorbitol levels continue to accumulate, symptoms worsen. These elevated levels of sorbitol are quite toxic especially for motor neurons. Hence, SORD-CMT symptoms. Research has shown that overall symptom severity in SORD-CMT correlates with sorbitol levels in the blood (Shendelman, 2022). The higher the sorbitol levels, the worse the CMT. Because sorbitol continues to accumulate and causes damage over time, the older the CMTer who has SORD-CMT gets, the more severe their CMT becomes. It's well understood that high sorbitol levels via the polyol pathway in diabetes are a contributing factor to diabetes-induced peripheral neuropathy, or what is referred to as diabetic neuropathy. When glucose is high, such as what is commonly seen in diabetes, there’s more to convert. Elevated glucose activates the polyol pathway causing sorbitol levels to become higher as aldose reductase is converting more glucose. The higher sorbitol levels contribute to the acquired neuropathy often seen in diabetes. Because this is well described and understood in medical science, it makes sense that SORD-deficiency could cause CMT. The difference between diabetic sorbitol levels and SORD-CMT sorbitol levels is staggering though. Published literature suggests normal sorbitol levels are around 215ng/ml, with levels in diabetes around 400ng/ml (Preston & Calle, 2010). While there is some conflicting data in published literature regarding normal sorbitol levels and that which is seen in diabetes, regardless of the source reviewed for this publication, reported levels of normal vs. diabetes consistently show levels in diabetes are about twice that which is reported as normal by the respective source. By comparison, sorbitol levels in SORD-CMT are in excess of 10,000ng/ml and have been seen as high as 47,000ng/ml in some patients (one-hundred times normal, or higher) (Shendelman, 2022). SORD-CMT sorbitol levels far exceed anything diabetes can cause and far exceed anything obtainable through dietary intake. In the context of CMT, this is unique to only SORD-CMT. And these toxic levels, which continue to climb over time, cause CMT symptom onset and drive overall disease severity. Leveraging Inhibition SORD-CMT discovering scientist, Stephan Züchner MD, PhD, professor of human genetics and neurology, chair of the Dr. John T. Macdonald Foundation, Department of Human Genetics at the University of Miami Miller School of Medicine, co-founder and CEO of Genesis Project Foundation, believes SORD-CMT could quite possibly be the first truly treatable CMT subtype (CMTA, 2021). Dr. Züchner might not be too far off. The SORD-CMT discovery was published in May 2020. Today, November 2022, only two and a half years later, there is already a Phase III trial of a potentially disease-modifying treatment (DMT) for this subtype. The speed at which science has moved into a Phase III trial for SORD-CMT is unheard of. This has happened in part because of how well scientists understand the polyol pathway and its implication in diabetes as well as in other conditions, but even more so because the right pieces and the right expertise were already in place. In 2016, a small pharmaceutical company named Applied Therapeutics was founded by Shoshana Shendelman, PhD. The company quickly developed several experimental drugs in a class of drugs called Aldose Reductase Inhibitors (ARI). An ARI is a drug that blocks (inhibits) aldose reductase from doing its job. On one hand, this is a good thing because this shuts off the first step in the polyol pathway—converting glucose to sorbitol. This means controlling sorbitol levels. On the other hand, however, completely shutting off the actions of aldose reductase leads to unintended “off-target” consequences. Aldose reductase is most known for catalyzing the first step of the polyol pathway: converting glucose to sorbitol. Aldose reductase also converts other compounds. Aldose reductase converts compounds called aldehydes. Aldehydes are complex compounds that occur in the environment and are also naturally produced by the body’s metabolic activity. Glucose happens to be one of these many aldehydes. Yes, glucose is a simple sugar, but this simple sugar is also an aldehyde, and is an overall complex compound. If aldehydes are not adequately converted and metabolized to other compounds through biochemical processes, they can accumulate to toxic levels. Aldose reductase’s primary role, therefore, is to convert aldehydes to less harmful compounds which then get converted to even less harmful compounds, etc. Sometimes, the aldose reductase enzyme is but one step of a biochemical chain in a complex metabolic pathway. Where SORD-CMT is concerned, the aldose reductase enzyme is the first step in a simpler two-step enzymatic pathway. The well-known polyol pathway is just one of the ways aldose reductase carries out its function. Aldose reductase plays a role elsewhere and in other pathways, reducing harmful aldehydes to other less harmful compounds. When an ARI is introduced and aldose reductase is completely shut off, it can no longer convert any aldehyde. These aldehydes can then build to toxic levels, leading to unintended outcomes. This has been a major hurdle to developing successful ARI drugs for diabetic neuropathy and other conditions in which aldose reductase is implicated. Applied Therapeutics could very well have the solution, and this potential solution, in large part, is why and how there is already a Phase III clinical trial for SORD-CMT. Applied Therapeutics’ ARI development predates the SORD-CMT discovery. When the SORD-CMT discovery was published, the company already had specific expertise in managing the polyol pathway—they already had expertise in sorbitol dehydrogenase. One of Applied Therapeutics’ investigational novel (new) drugs, called AT-007, is an ARI that selectively inhibits (blocks) aldose reductase from converting glucose to sorbitol. The drug is designed to do this without causing “off-target” toxic effects associated with older ARI drugs that shut off aldose reductase completely. AT-007 targets the polyol pathway essentially shutting off aldose reductase at this location which then blocks glucose from converting to sorbitol. The result is a reduction in sorbitol levels without disrupting other critical biochemical conversion processes. When the SORD-CMT discovery was published, describing SORD-deficiency as the culprit, Applied Therapeutics recognized this unique CMT situation and was able to quickly leverage their aldose reductase expertise to translate their AT-007 ARI to the investigational needs of SORD-CMT. Applied Therapeutics partnered with Dr. Stephan Züchner and colleagues (the Nature Genetics publication team) to jump right into SORD-CMT and study the effect of one of their ARIs on cells from SORD-CMT patients and a fruit-fly model of SORD-CMT (yes, the fruit-flies lose their walking ability too, just like humans with SORD-CMT). Fortunately, this drug, AT-007, was already in a Phase III study for another rare disease that involves the aldose reductase pathway, so there was already a lot of information available on safety and the right dose to use, which allowed researchers to move very quickly (less than one year after the discovery of SORD-CMT) into a pilot study in SORD-CMT patients, and now into a Phase III study. A Pilot is Born Researchers in Miami developed a fruit-fly model of SORD-deficiency by “knocking out” the SORD enzyme (referred to as a drosophila SORD-deficiency model (drosophila = scientific name (genus) for fruit-flies), and in 2021, demonstrated that high sorbitol levels caused by a non-functional SORD enzyme led to motor neuron degeneration thereby mimicking the toxic effects of high sorbitol levels that lead to the same motor neuron degeneration in CMTers who have SORD-CMT. The investigative team then treated the fruit-flies with Applied Therapeutics’ investigational AT-007 drug. Working with the SORD-deficiency drosophila model, AT-007 demonstrated a significant reduction in sorbitol levels (Shendelman, 2022). This reduction resulted in a recovery of degenerated motor neurons, returning the neurons back to a healthy state. As part of this investigation, researchers cultured cells from CMTers who have SORD-CMT. After measuring sorbitol levels in these cells to be as high as one hundred times higher than cells cultured from healthy controls, the cells were treated with AT-007. AT-007 demonstrated that sorbitol levels in these cultured human cells could be reduced to levels that are comparable to the cultured cells from the healthy controls. This breakthrough set the stage for the first trial of AT-007 in SORD-CMT. On the heels of AT-007 demonstrating success reducing sorbitol levels in the lab, and still in 2021, Applied Therapeutics formed partnerships with CMT patient organizations. Collaborating with these partners, SORD-CMT study candidates were identified. Then, having also forged genetic testing partnerships, candidates underwent genetic testing for SORD-CMT. Of the volunteer CMTers who were confirmed to have SORD-CMT, eight were enrolled into an initial pilot study. Sorbitol levels of these eight CMTers ranged from 25,000ng/ml to as high as 47,000ng/ml (38,000ng/ml mean sorbitol level). The pilot study lasted thirty days and was an open-label study, meaning each participant knew of the drug that was being administered. Given once daily for thirty days, AT-007 demonstrated a significant reduction in sorbitol levels of between 54% and 75% (66% mean sorbitol reduction). While there was variability in the percentage of overall sorbitol reduction, every participant showed more than a 50% reduction. These reductions were achieved with no adverse increase in glucose levels, demonstrating that AT-007 can inhibit aldose reductase’s involvement in glucose conversion without causing an unwanted and potentially harmful increase in overall glucose levels. Another important finding was disease severity correlation. Although the pilot study consisted of just eight SORD-CMTers, important disease severity data were learned in addition to AT-007 sorbitol level reduction outcomes. Investigators learned that the higher the sorbitol levels were for an individual, the worse their overall disease severity. Participants with the highest sorbitol levels had a more severe symptom presentation—a more severe phenotype, such as needing leg braces from an early age, upper limb involvement (hand weakness, tremor, sensory nerve involvement (i.e., numbness, tingling) etc.), for example, and a greater overall disability compared to those who had a lower sorbitol level. Researchers learned that, while all SORD-CMTers have very high sorbitol levels, overall SORD-CMT disease severity correlates with sorbitol levels—the higher the sorbitol, the more severe the disease progression (Shendelman, 2022). After demonstrating AT-007 could safely and rapidly lower sorbitol levels and could sustain this trend with no reported severe adverse effects (SAEs), Applied Therapeutics designed the next step, a Phase III trial of AT-007 for SORD-CMT. If you’re thinking this is moving extremely fast, you’re not wrong. Applied Therapeutics just so happened to be in a unique position to facilitate this. AT-007 is a drug whose development predates SORD-CMT’s discovery. Applied Therapeutics has been developing AT-007 for use in other diseases in which the aldose reductase pathway is implicated, with the drug already in a Phase III trial for one of these diseases. Having a current Phase III trial with AT-007 positioned the company with unique expertise and an extensive knowledgebase that includes critical dosage data. Drawing on this expertise and knowledgebase, Applied Therapeutics, working with their forged SORD-CMT partnerships, moved with expedience to design a Phase III trial for AT-007 in SORD-CMT. Becoming INSPIREd Applied Therapeutics has named their SORD-CMT AT-007 trial “INSPIRE.” INSPIRE is the acronym for INhibiting Sorbitol Production through Inhibition of the aldose Reductase Enzyme (Applied Therapeutics, 2022). The purpose of the earlier pilot study was to assess AT-007’s ability to safely reduce toxic sorbitol levels. The study achieved this goal. The purpose of the Phase III INSPIRE trial is to continue assessing AT-007 safety and effectiveness, and to also assess therapeutic benefit of AT-007 for SORD-CMT. What does all this mean? "This trial is designed to investigate the ability of AT-007 versus placebo to reduce toxic sorbitol levels, and to evaluate the effect of AT-007 on improving symptoms of the disease over a longer period of time." --Applied Therapeutics The SORD-CMT AT-007 pilot study demonstrated the extremely high sorbitol levels seen in SORD-CMT could be safely reduced by the drug, that they could be quickly reduced, and that a continuing reduction in sorbitol levels was possible. This was the intention of the study. The pilot study was not intended to assess AT-007’s ability to slow or to stop disease progression, or the drug’s ability, via lowering toxic sorbitol levels, to improve SORD-CMT symptoms (the study was not designed to assess clinical improvement). To assess what happens when sorbitol levels are brought down, a new study was needed. Applied Therapeutics, building on the successes of and knowledge gained with the pilot study, designed the INSPIRE Phase III trial to assess not only AT-007’s ability to lower high sorbitol levels over the long-term, but to assess the influence on disease progression lowering sorbitol levels could potentially have— to assess clinical improvement. Designed as a twenty-four month, double-blind, placebo-controlled, international multi-center study to include up to fifty participants, the INSPIRE Phase III trial is intended to assess AT-007’s long-term sorbitol reduction potential along with the potential to slow or to stop disease progression and the potential to improve overall disease severity (clinical improvement). In a double-blind study, participants don’t know whether they’re getting the drug or a placebo, and the principal investigators don’t know which participants are getting the drug or the placebo. Placebo-controlled means some participants will receive a placebo and others will receive the drug; and, according to Applied Therapeutics, a randomized two-thirds of the study participants will receive the drug while the remaining randomized one-third will receive a placebo (a 2:1 active drug to placebo randomization). An international multi-center study is a trial that includes several different facilities located in more than one country that are enrolling study participants, evaluating study participants, and collecting study data. Applied Therapeutics is enrolling INSPIRE Phase III trial participants in the US who are ages 18-55 and in the EU who are 16-55 (the age differences are regulatory agency driven). There are six INSPIRE trial sites in the US and three in Europe. These sites evaluate participants according to an interval schedule set by the trial. The first part, at three months, measures sorbitol level reduction for comparison against the participant’s baseline that was established when they entered the study. At regular intervals thereafter, for a period of up to twenty-four months, in addition to routine sorbitol levels, glucose levels, and other related bloodwork, various metrics are evaluated using what’s called the CMT Functional Outcomes Measure (CMT-FOM) and the CMT Health Index (CMT-HI). The CMT-FOM and the CMT-HI are standardized functional assessments developed by CMT experts as a means by which to accurately measure overall disease progression and severity. The CMT-FOM is a performance-based measure assessing functional ability in adults with CMT (Eichinger, et al., 2018), while the CMT-HI is a disease-specific patient-reported outcome for Charcot-Marie-Tooth disease (Johnson, et al., 2018). In addition to these assessments, and also at regular intervals throughout the trial, leg MRIs are performed to assess what’s called “muscle-fat fraction.” In 2018, researchers demonstrated that an MRI technique that measures the amount of fat present within calf muscle tissue, developed at Queen Square Centre for Neuromuscular Diseases in London and referred to as the Queens Square calf muscle fat-fraction protocol, can be used as an outcome measure in CMT1A (Morrow, et al., 2018). This MRI technique measures the amount of fat that has replaced healthy calf muscle, and this measurement, researchers have shown, correlates with overall disease progression in CMT1A. Additional research has shown that this same MRI technique can be used to assess therapeutic outcomes by measuring progression, cessation of progression, or regression (improvement) of calf muscle fat-fraction. Although initially demonstrated only in CMT1A, many additional publications have replicated Morrow, et al. (2018), and the findings have been extrapolated to be reproducible in CMT across the board. Hence, its use in the INSPIRE study. While this has potential to be a particularly valuable tool for doctors to have in their CMT diagnostic and monitoring tool bag, it’s presently used only in experimental therapy outcome measures. As of this publication, Applied Therapeutics is nearing full enrollment in their INSPIRE Phase III trial. The study is on track to have the aforementioned three-month sorbitol levels reduction data readout by early 2023. The study is hopeful to hit statistical significance in the second half of 2023, at the twelve-month mark (statistical significance is the point at which data show the results are real and not occurring by chance), and to conclude the study in the second half of 2024, at the twenty-four-month mark, with clinical outcomes and final study data available shortly thereafter. SORD-CMT has gone from discovery and no available treatment, through a Phase I trial (drosophila SORD-CMT model outcomes), through a Phase II trial (the pilot study), and now into a Phase III trial with near full enrollment in only about two-and-a-half years. Even though INSPIRE is scheduled to complete in the second half of 2024, which is another two years from now, the speed at which we’ve gotten to this point is unheard of. And it’s happened because of the tireless work of everybody involved. Diagnosing SORD-CMT There’s a generalized set of guidelines that are used when diagnosing SORD-CMT. Diagnosing SORD-CMT isn’t any different than diagnosing any of the many other CMT subtypes. In order to diagnose CMT, doctors look for the right diagnostic picture—high arched feet (but feet can be flat, too), weakened ankles, lower leg atrophy, numbness or tingling in the feet & hands (although this would be found typically to a lesser extent with SORD-CMT, or to a lesser extent earlier in the disease course), reduced or absent reflexes, symptoms that can’t be explained by treatable conditions such as diabetes, G6PD-deficiency, or Vitamin B12-deficiency, for example. (Raymond, 2021). Then, if NCS results show very slow speeds, the clinical diagnosis is usually CMT1; and if speeds are only somewhat slowed, CMT2 (and sometimes dHMN (or HMN, or possibly dSMA) if there is only motor nerve involvement). After a doctor has made a clinical CMT diagnosis (the diagnosis that’s based on symptoms and NCS results), they’ll typically order CMT genetic testing. While genetic testing is not needed to definitively diagnose CMT, it is needed to pinpoint the exact subtype. There are many commercial labs that offer CMT genetic testing. Twenty years ago, access to CMT genetic testing was limited and costs were regularly prohibitive. Things have changed drastically and CMT genetic testing is now readily available. Despite the growth in testing accessibility, CMT genetic testing has some limitations. Scientists have discovered CMT-causing mutations in more than 120 different genes. A review of publicly available lists of genes included in genetic testing panels shows the larger panels include up to 89 of these genes (a genetic testing panel is a genetic test that analyzes more than one gene vs. a single-gene test). The SORD gene is not yet available in panels that are used in CMT genetic testing (GeneDx Charcot-Marie-Tooth Panel Test Code: J778, 2022) (GeneDx Hereditary Neuropathies Panel Test Code: 737, 2022) (Invitae Comprehensive Neuropathies Panel, 2022) (Invitae Charcot-Marie-Tooth Disease Comprehensive Panel, 2022). After exhausting these CMT genetic testing options without finding a cause, if the doctor feels SORD-CMT is a possibility, there are testing options available. There are at least two commercial labs offering SORD gene testing. Invitae Corp is a popular lab for CMT genetic testing. They offer SORD gene testing but only as part of a large and complex genetic test called Whole Exome Sequencing (WES) (Invitae - Exome, 2022). WES is a type of test that attempts to look at the coding regions of all genes. WES has limitations (Raymond, 2021), so to ensure the test covers the SORD gene, when ordering the test, the doctor would need to specifically request the SORD gene to be included in the analysis. According to Invitae Corp., the doctor can call them for ordering the test or can order the test through their provider portal, and when ordering, can specifically request SORD gene inclusion in the interpretive analysis. The second lab is GeneDx. GeneDx, like Invitae Corp., is a popular lab for CMT genetic testing. They offer SORD gene testing as a single-gene test. According to GeneDx, to order SORD gene testing, the doctor can call them and request their Exome Slice, Test Code: TG70, and manually add the SORD gene. The doctor can also order the test via GeneDx’s provider portal by searching for Test Code: TG70. The search result opens the Exome Slice Tool, and the doctor can easily add the SORD gene by simply typing “SORD” in the appropriate field (GeneDx - Slice Tool, 2022). Coincidentally, Applied Therapeutics is partnered with GeneDx for SORD genetic testing as part of their INSPIRE study candidate screening. Reviewing the websites of other labs who are popular with CMT genetic testing yielded no results for SORD gene testing. Testing might be available even though public facing websites don’t show availability. SORD testing costs, insurance coverage for the testing, etc., is highly individualized. Each lab can be contacted to discuss these costs if the doctor feels SORD gene testing should be explored. Get INSPIREd Has your doctor diagnosed you with CMT2 or dHMN based on symptoms and on NCS results that show an axonal CMT (or diagnosed you with HMN or dSMA (dSMA is synonymous with dHMN)? Has genetic testing not found your CMT genetic cause, so you are therefore a “CMT2, subtype unknown (or unknown cause)?” Are you between 18 and 55 in the US or 16 and 55 in Europe? Is there no established family history of CMT—you’re the first in the family diagnosed and nobody else in the family seems to have CMT? If yes to these questions, you might be a candidate for Applied Therapeutics’ INSPIRE study for SORD-CMT. Although almost at full enrollment, as of this publication, Applied Therapeutics is actively enrolling participants in their INSPIRE study. If you meet the above criteria (answered yes to each question), and you’re interested in participating in the INSPIRE study, after contacting Applied Therapeutics, the screening process begins. If they feel you meet study criteria, they will send somebody to you to perform a blood draw. This person is an employee and not a contractor/vendor. The blood draw is to check your sorbitol levels. When the blood test comes back, typically within a few days, and your sorbitol levels are at or above 10,000ng/ml, you essentially have SORD-CMT and meet the criteria for moving onto the next screening steps which will include genetic testing and an in-person visit to a study center. The sorbitol blood test, which is not available commercially, the SORD genetic testing (if sorbitol levels in the blood meet criteria for SORD-CMT), travel to and from the center (Applied Therapeutics handles all travel arrangements, including ground transportation so that study participants don’t have to stress about it), meals, and lodging are all covered costs. They even assign a concierge to each study participant in case there are any hiccups along the way, such as canceled or missed flights. The study also provides compensation for each participant (Shendelman, 2022). The INSPIRE study truly is unlike any other by every measure. If you meet study criteria and would like to be considered for inclusion, or you have already obtained SORD-CMT genetic confirmation through commercial genetic testing, you can send an email with all your contact info to sord@appliedtherapeutics.com. You can also visit their INSPIRE website to learn more about the study and to submit an interest form: https://www.appliedtherapeutics.com/inspire/. The CMT patient community consistently reports a very fast reply from Applied Therapeutics—within a couple of days, and sometimes within hours. After Applied Therapeutics has determined you meet the INSPIRE study criteria, the community consistently reports that the company continues moving very quickly with getting somebody to you for the initial screening, getting the sorbitol level results to you, getting somebody back to your door for going over blood test results, going over study paperwork, etc. The community also consistently reports that through everything, everybody with whom they’ve had contact within the study has treated them with the utmost respect, compassion, and grace; and they’ve wanted for nothing at every step of the way, and this includes concierge assistance with resolving cancelled flights. There isn’t enough praise for the company or for their INSPIRE study. The GENESIS The SORD-Deficiency discovery would not have been possible if not for the invaluable GENESIS platform. GENESIS is the genomics research and database platform developed by The Genesis Project Foundation. Cofounded and led by Dr. Züchner, The Genesis Project Foundation is a patient and scientist managed (501(c)(3)) (The Genesis Project, 2022). The Genesis Project Foundation focuses on finding genetic causes for rare diseases and on accelerating new treatments for rare diseases via these genetic discoveries. Since its founding in 2011, The Genesis Project’s genomics research database and platform, GENESIS, which boasts more than 18,000 stored genomes (and counting), has contributed to more than 100 rare disease gene discoveries (The Genesis Project - Gene Discoveries, 2022). These discoveries allow investigators the opportunity to develop first ever treatments for many rare diseases, and SORD-deficiency CMT is just one example. If not for the foundational work of Dr. Züchner and his team, and if not for the contributions from The Genesis Project’s GENESIS platform, SORD-deficiency CMT might not have been discovered for years to come. The Genesis Project offers researchers a unique opportunity to analyze and query thousands of genomes as they try to identify causes diseases. When a discovery is made, the speed at which researchers can then develop potential therapies is truly remarkable, as Applied Therapeutics’ INSPIRE trial has shown. The contributions of The Genesis Project help lead Cortese et, al. (2020) to the SORD-deficiency discovery. On the heels of this discovery, scientists were able to quickly leverage expertise into a potential treatment for this new CMT subtype. Please visit The Genesis Project Foundation to learn more about their work here. In Closing CMT does not cause SORD-deficiency. A CMTer who has CMT2A, for example, will not develop SORD-deficiency, and their CMT will not cause high sorbitol levels. The only CMT subtype that has high sorbitol as part of the disease is SORD-deficiency CMT. While the name “SORD-deficiency” has some inherent confusion, SORD-deficiency is the name of the subtype and is not a second diagnosis. Where some of the confusion might arise, for example, is with Vitamin B12-deficiency. Vitamin B12-deficiency, or what is pernicious anemia, can mimic CMT in many ways, as can anemia in general. Pernicious anemia is caused when the intestines cannot absorb Vitamin B12. Not absorbing Vitamin B12 in the digestive tract leads to Vitamin B12-deficiency. When Vitamin B12 is deficient, it’s typically easily treatable. For example, getting regular Vitamin B12 injections can keep Vitamin B12 levels in check. SORD-deficiency, however, is not like Vitamin B12-deficiency. Vitamin B12-deficiency is something a CMTer can have in addition to their CMT. SORD-deficiency is CMT, is the name of the CMT subtype. SORD-deficiency is not something a CMTer who has a different subtype will develop. A CMTer who has SORD-deficiency cannot get a shot to restore their SORD levels. If a CMTer has genetic confirmation—has a genetic diagnosis that is other than autosomal recessive mutations in the SORD gene, such as CMT4C, for example, they do not have SORD-deficiency and cannot develop SORD-deficiency. The sorbitol levels seen in SORD-CMT are astronomical. Normal sorbitol levels are around 215ng/ml. Due to increased glucose that’s seen in diabetes, sorbitol in diabetes is about double that which is normal, and this is due to aldose reductase having to convert more glucose to sorbitol in the polyol pathway. The difference between diabetes and SORD-CMT is that in diabetes, sorbitol dehydrogenase is functional, and although sorbitol levels are higher, they are only about double that which is normal. They are this way because of aldose reductase handling excess glucose. In contrast, in SORD-CMT, sorbitol dehydrogenase is non-functional or absent and sorbitol, therefore, is not converted and stays trapped within the cell. Levels will climb to well over 10,000ng/ml, regardless of glucose levels. In SORD-CMT, it doesn’t take elevated levels of glucose to cause these astronomically elevated levels of sorbitol. In SORD-CMT, glucose levels are normal. SORD-CMT is all the rage right now. The biochemistry that causes SORD-CMT is well studied, is well described, is well understood. The many symptoms and presentations of CMT can be treated and managed. There is an absence, however, of DMTs (disease-modifying treatments). Currently, there is a Phase III trial for CMT1A being conducted by a pharmaceutical company named Pharnext. They are trialing their investigational drug called, “PXT-3003” (Pharnext, 2022). This drug is being studied only in 1A. A study end-date was not found for this publication. There’s currently no other Phase III trial in CMT. Considering how well scientists already understand the enzymatic pathway that is implicated in SORD-CMT, coupled with gains demonstrated with Applied Therapeutics’ investigational selective ARI, AT-007, SORD-CMT could quite well be the first truly treatable CMT subtype. Yes, it is still early in the trial, and nobody knows what the data will reveal or if the drug will be successful. However, many, for the first time in their CMT lives, because of these things, have hope, and that is huge. Knowledge gained from the INSPIRE study might be translatable to other CMT subtypes, and this is the best part. CMT just might get cracked wide open in the very near future. To download a free copy of this article, follow this link. About the Author Kenneth Raymond was first diagnosed clinically with CMT1 in late 2002, at the age of 29. He was genetically confirmed to have CMT1A a year later. Kenneth has since devoted his life to studying, researching, and learning all things CMT, with an emphasis on the genetics of CMT as they relate to everyday CMTers, and with an equal emphasis on CMT-related respiratory impairment. As a member of the Charcot-Marie-Tooth Association’s Advisory Board, Kenneth serves as a CMT genetics expert, a CMT-related respiratory impairment expert, and as a CMT advocate who is committed to raising CMT awareness through fact-based information rooted in the latest understandings of CMT. References Applied Therapeutics. (2022). Applied Therapeutics: INSPIRE. Retrieved October 14, 2022, from Applied Therapeutics: https://www.appliedtherapeutics.com/inspire/ Bansagi, B., Griffin, H., Whittaker, R. G., Antoniadi, T., Evangelista, T., Miller, J., . . . Horvath, R. (2017, March 28). Genetic heterogeneity of motor neuropathies. Neurology, 88(13), 1226–1234. doi:https://doi.org/10.1212/WNL.0000000000003772 BiologyOnline. (2022). Biology Online Dictionary: Polyol. Retrieved October 17, 2022, from Biology Online: https://www.biologyonline.com/dictionary/polyol BiologyOnline. (2022). BiologyOnline Dictionary: Hexose. Retrieved October 17, 2022, from BiologyOnline: https://www.biologyonline.com/dictionary/hexose Bird, T. D. (1998, Updated 2022, September 28). Charcot-Marie-Tooth (CMT) Hereditary Neuropathy Overview. (A. H. Adam MP, Ed.) Seattle, Washington, USA: University of Washington. Retrieved October 2022, from https://www.ncbi.nlm.nih.gov/books/NBK1358/ Chaudhry, R., & Varacallo, M. (2021). Biochemistry, Glycolysis. Treasure Island, FL, USA: StatsPearls Publishing. Retrieved October 17, 2022, from https://www.ncbi.nlm.nih.gov/books/NBK482303/ CMTA. (2021). SORD Research. Retrieved October 17, 2022, from The Charcot Marie Tooth Association (The CMTA): https://www.cmtausa.org/our-research/for-patients-and-families/cmta-star-research-for-axonal-cmt/sord/ CMTA. (2022, March). Sorbitol Dehydrogenase (SORD) Deficiency. Retrieved October 17, 2022, from The Charcot-Marie-Tooth Association (The CMTA): https://www.cmtausa.org/understanding-cmt/types-of-cmt/sord/ Cortese, A., Zhu, Y., Rebelo, A. P., Negri, C., Courel, S., Abreu, L., . . . Züchner, S. (2020, May 4). Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes. Nature genetics, 52(5), 473–481. doi:https://doi.org/10.1038/s41588-020-0615-4 Dyck, P. J., Lambert, E. H., & Mulder, D. W. (1963, January 1). Charcot‐Marie‐Tooth disease nerve conduction and clinical studies of a large kinship. Neurology, 13(1). doi:https://doi.org/10.1212/WNL.13.1.1 Eichinger, K., Burns, J., Cornett, K., Bacon, C., Shepherd, M. L., Mountain, J., . . . Herrmann, D. N. (2018, October 9). The Charcot-Marie-Tooth Functional Outcome Measure (CMT-FOM). Neurology, 91(15), e1381–e1384. doi:https://doi.org/10.1212/WNL.0000000000006323 El-Abassi, R. E. (2014, January 13). Charcot-Marie-Tooth disease: an overview of genotypes, phenotypes, and clinical management strategies. PM & R : the journal of injury, function, and rehabilitation, 6(4), 342–355. doi:https://doi.org/10.1016/j.pmrj.2013.08.611 Experts in CMT. (2022, May). CMT-Associated Genes and Their Related Subtypes Database. Retrieved October 17, 2022, from Experts in CMT: https://www.expertsincmt.com/cmt-geneticsdatabase GeneDx - Charcot-Marie-Tooth Panel. (2022). Retrieved October 31, 2022, from GeneDx | Sema4: https://www.genedx.com/tests/detail/charcot-marie-tooth-panel-888 GeneDx - Hereditary Neuropathy Panel. (2022). Retrieved October 31, 2022, from GeneDx | Sema4: https://www.genedx.com/tests/detail/hereditary-neuropathy-panel-800 GeneDx - Slice Tool. (2022). Retrieved October 31, 2022, from GeneDx | Sema4: https://www.genedx.com/xomedx-slice-tool?code=TG70#!/slice-tool/main HGNC. (2022, October 16). HGNC Symbol Report for SORD. Retrieved October 17, 2022, from The HUGO Gene Nomenclature Committee (HGNC): https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:11184 Inherited Neuropathies Consortium (INC). (2021, July). CMT in Depth - Hereditary Motor Neuropathies (HMN). Retrieved 2021, from Rare Diseases Clinical Research Network: https://www.rarediseasesnetwork.org/cms/inc/Healthcare-Professionals/CMT Invitae - Exome. (2022). Retrieved October 31, 2022, from Invitae Corporation: https://www.invitae.com/en/providers/test-catalog/exome#5PjNxvc8IDF9MEVpzHcTOL Invitae Charcot-Marie-Tooth Disease Comprehensive Panel Test Code: 3201. (2022). Retrieved October 31, 2022, from Invitae: https://www.invitae.com/en/providers/test-catalog/test-03201 Invitae Comprehensive Neuropathies Panel Test Code: 3200. (2022). Retrieved October 31, 2022, from Invitae Corporation: https://www.invitae.com/en/physician/tests/03200/ Johnson, N. E., Heatwole, C., Creigh, P., McDermott, M. P., Dilek, N., Hung, M., . . . Herrmann, D. N. (2018, July 16). The Charcot-Marie-Tooth Health Index: Evaluation of a Patient-Reported Outcome. Annals of neurology, 84(2), 225–233. doi:https://doi.org/10.1002/ana.25282 Morrow, J. M., Evans, M., Grider, T., Sinclair, C., Thedens, D., Shah, S., . . . Reilly, M. M. (2018, September 18). Validation of MRC Centre MRI calf muscle fat fraction protocol as an outcome measure in CMT1A. Neurology, 19(12), e1125–e1129. doi:https://doi.org/10.1212/WNL.0000000000006214 Patel, P. I., Roa, B. B., Welcher, A. A., Schoener-Scott, R., Trask, B. J., Pentao, L., . . . Suter, U. (1992, June 1). The gene for the peripheral myelin protein PMP-22 is a candidate for Charcot-Marie-Tooth disease type 1A. Nature genetics, 1(3), 59–165. doi:https://doi.org/10.1038/ng0692-159 Pharnext - Pharnext Announces First Patient Enrolled in Open Label Extension of the Pivotal Phase III Study of PXT3003 for the Treatment of Charcot-Marie-Tooth Disease Type 1A, the PREMIER Trial. (2022, September 22). Retrieved October 31, 2022, from Pharnext, SA: https://pharnext.com/en/press-releases/pharnext-announces-first-patient-enrolled-in-open-label-extension-of-the-pivotal-phase-iii-study-of-pxt3003-for-the-treatment-of-charcot-marie-tooth-disease-type-1a-the-premier-trial Pisciotta, C., & Shy, M. E. (2018). Chapter 42 - Neuropathy, Handbook of clinical neurology, (Vol. 148). (H. L. Daniel H. Geschwind, Ed.) Elsevier. doi:https://doi.org/10.1016/B978-0-444-64076-5.00042-9 Preston, G. M., & Calle, R. A. (2010, May 4). Elevated Serum Sorbitol and not Fructose in Type 2 Diabetic Patients. Biomarker insights, 5, 33-38. doi:https://doi.org/10.4137/bmi.s4530 Raeymaekers, P., Timmerman, V., Nelis, E., De Jonghe, P., Hoogendijk, J. E., Baas, F., . . . Bolhuis, P. A. (1991). Duplication in chromosome 17p11.2 in Charcot-Marie-Tooth neuropathy type 1a (CMT 1a). The HMSN Collaborative Research Group. Neuromuscular disorders : NMD,, 1(2), 93–97. doi:https://doi.org/10.1016/0960-8966(91)90055-w Raymond, K. (2021, December 1). Pushing The Limits: Examining the Limitations of Genetic Testing in Charcot-Marie-Tooth Disease. (K. Raymond, Editor) Retrieved April 11, 2022, from Experts in CMT: https://www.expertsincmt.com/post/pushing-the-limits Raymond, K. (2022). Charcot-Marie-Tooth Disease Gene and Subtype Discovery: The Complete Bibliography - Fall 2022 Release. Detroit: Kenneth Raymond. Retrieved September 2022, from https://www.amazon.com/dp/B0B8BGW1LW Record, C. J., Pipis, M., Blake, J., Curro, R., Lunn, M. P., Rossor, A. M., . . . Reilly, M. M. (2022, April 13). Unusual upper limb features in SORD neuropathy. J Peripher Nerv Syst(127), 175-177. doi:https://doi.org/10.1111/jns.12492 Shendelman, S. (2022, October 3). Founder and CEO, Applied Therapeutics. CMT Patient & Research Summit: Clinical Trials Panel and Get to Know Us. (D. Herrmann, Interviewer) The Charcot-Marie-Tooth Association. Retrieved October 17, 2022, from https://www.youtube.com/watch?v=W9SEHz4Uk_A Shendelman, S. (2022, September 28). Founder and CEO, Applied Therapeutics. HNF Sord Webinar Part 2. (E. Lugo, Interviewer) Retrieved October 17, 2022, from https://www.youtube.com/watch?v=mWa7mAZb7kM&t=280s Shy, M. E. (2020, June 6). Director, Division of Neuromuscular Medicine-Neurology, University of Iowa give his presentation on Research and Clinical Trials in CMT. 2020 MDA Engage CMT Symposium: MDA Mission Spotlight. (N. Petrouski, Interviewer) Muscular Dystrophy Association. Retrieved July 2021, from https://www.youtube.com/watch?v=GWOOzQFWaYM&list=PLxofS4JHjGXXfMhWYiifLRSnHFflDJuv3 Stojkovic, T. (2016, November 17). Hereditary neuropathies: An update. PM & R : the journal of injury, function, and rehabilitation, 172(12), 775–778. doi:https://doi.org/10.1016/j.neurol.2016.06.007 The Genesis Project - Gene Discoveries. (2022). Retrieved October 27, 2022, from The Genesis Foundation: https://www.tgp-foundation.org/d-i-s-c-o-v-e-r-i-e-s The Genesis Project. (2022). Retrieved October 27, 2022, from The Genesis Project Foundation: https://www.tgp-foundation.org/ The University of Hawaiʻi. (2022). Energy Flow in Metabolism. Retrieved October 18, 2022, from The University of Hawaiʻi: http://www2.hawaii.edu/~johnb/micro/m130/m130lect8.html#:~:text=Energy%20in%20metabolism%20often%20flows,gained%2C%20this%20is%20called%20reduction. Züchner, S. (2021, October 27). Dr. Stephan Züchner: Exciting Genetic Discoveries Lead to Life-Changing CMT Therapies. CMT4Me Podcast. (C. Ouellette, & E. Ouellette, Interviewers) Charcot-Marie-Tooth Association. Retrieved November 2021, from https://cmt4me.buzzsprout.com/1849476/9429530-dr-stephan-zuchner-exciting-genetic-discoveries-lead-to-life-changing-cmt-therapies

Exploring the Burgeoning Question: “What is CMT?” “Why are you wearing shin guards? You play soccer?” “What’s wrong with your hands?” “What’s wrong with your legs?” Etc., Etc., Etc. We all know the drill. The answer to the seemingly never-ending questions involves those three lovely letters, C-M-T. And then, the proverbial follow-up, whether it’s a random person in public or even a healthcare provider, requires us to dig deep in hopes of giving them a straight-to-the-point answer that’ll leave them knowing just enough about our disease to remember the name should they hear it again, all the while hoping we give them enough information to know it’s not a tooth disease and that it has nothing to do with sharks. What is CMT? “What is CMT?” I’m always trying to improve on how I answer this question. I can easily rattle off some quick factoids, such as CMT is a heterogeneous group of inheritable peripheral polyneuropathies whose name comes from the three doctors who first described it in 1886: Drs. Charcot, Marie, and Tooth; and this name, CMT, has since become an umbrella term that refers to many different inheritable sensory and/or motor neuropathies. Quick and to the point, right? This doesn’t say much about what the disease is though. Medically, CMT is a genetically caused neuromuscular disease—neuro because peripheral nerve, muscular because the disease in the peripheral nerves causes symptoms in muscles. Genetically caused because each subtype is caused by a mutation in any one of many different genes. Medically, CMT is an inheritable multisystem neuromuscular peripheral polyneuropathy. Inheritable because each of the genetic mutations that cause CMT are inheritable. Peripheral because CMT is a disease of the peripheral nerves. Polyneuropathy because CMT affects more than one peripheral nerve at a time (poly), as opposed to only one peripheral nerve (mononeuropathy). Neuropathy because peripheral nerve disease. Then, multisystem because CMT can affect hearing, vision, breathing, genitourinary, and much more, in addition to feet/legs/hands. Statistically, CMT is the most commonly inherited neuromuscular disease nobody has ever heard of. This one is a weird dichotomy unto itself. CMT is a rare disease by every statistical and modeling measure. At the same time, when it comes to inheritable neuromuscular diseases, in totality, CMT is the most commonly inherited. In this context, common and rare can peacefully coexist even if it seems like they shouldn’t. These above are just a select few examples of how CMT can be described. All of these descriptions are fine and dandy, but not only are these difficult to remember, firing off any of them to Jane Q. Public tends to render confusion about a disease they’ve never heard of. Is there a viable solution—a grand unifying answer, so to speak? The Elevator Speech I’m often asked to give my “45-second elevator speech” on what CMT is. My response typically hits several talking points and is usually along the lines of “CMT stands for Charcot-Marie-Tooth disease and is a rare inheritable neuromuscular peripheral neuropathy named after the three doctors who first described it more than 130 years ago. Although rare by definition, affecting only 1 in every 2,500 people, and totaling about 3 million people worldwide, CMT is the most commonly inherited peripheral nervous system disease. CMT causes the peripheral nerves to stop working correctly; and this leads to muscle weakness and atrophy, joint changes, difficulty with walking, and hand issues. Some who have CMT have breathing issues, hearing impairment, vision problems, bladder issues, and GI issues. The disease progressively worsens over one’s lifetime, there is currently no treatment, the disease can’t be cured, and it affects everybody very differently from one another.” Sometimes, people will ask follow-up questions. Other times, we part ways with only a, “whoa,” and maybe they’ll recognize the name the next time they hear it. My “elevator speech” has been a go-to for many years, having evolved only slightly since my initial CMT diagnosis. It’s very easy for me to throw it out there anytime I’m asked. Does it say enough about what CMT is as a whole that it could be adopted by anybody who needs a quick go-to description? Until a week ago, I thought it did and I thought it could. What changed? Bicyclists as a Catalyst For the first time, I attended the Charcot-Marie-Tooth Association’s Cycle 4 CMT fundraising event held annually the last weekend of August in Charlotte, Vermont. This event is huge and people from all over the place, not just locals, attend and/or participate. I met and spoke with many CMTers. Some CMTers were cycling participants riding a treacherous 40-mile course through the western Vermont mountains even though there were shorter less-challenging routes. Some CMTers were there to participate in non-cycling activities. Some were event volunteers. Some were parents who do not have CMT, but their child does (or children do). Some were members of the CMTA leadership and social media teams. Some of the CMTers at Cycle 4 CMT used wheelchairs, canes, walkers, etc. Some CMTers wore leg braces. Some CMTers had breathing issues. Some CMTers had severely twisted and deformed feet. Some CMTers had hearing loss. Some CMTers had speech impairment. Some CMTers had . I’m confident there were many hidden symptoms that went unmentioned and unnoticed. Without a doubt, it was the most diverse single-source representation of what CMT is that I have experienced in-person. As I spoke with CMTers and as I looked around, it became apparent that my go-to elevator speech is grossly inadequate and under-represents what CMT is. It's well established that CMT can and does affect everybody differently, and even within the same family. CMT can cause many things. Not everybody who has CMT will experience all symptoms of CMT. The mix of symptoms, the severity of individual symptoms, the rate of disease progression, and the overall disease severity can be quite different for every CMTer. What one CMTer experiences cannot be used to gauge or to predict what the disease will be for the next CMTer, regardless of subtype. It’s one thing for me to read it, and another for me to witness these concepts firsthand. Is There a Solution for the Question? What is CMT? The answer to that question, as it turns out, is quite different for every CMTer. My CMT is different than somebody else’s CMT. CMT, for me, looks quite different than does CMT for another. CMT, for me, is twisted, contorted, crooked feet that have led to tendons tearing requiring corrective reconstruction surgery of my right foot (and upcoming surgery for my left foot). CMT, for me, is weakened hands that easily cramp, a knee that used to dislocate before corrective surgery, bilateral hearing loss, unrelenting fatigue, chronic whole-body pain, progressively weakening upper leg muscles, spine changes (kyphoscoliosis), premature degenerative joint changes, speech/vocal difficulties, and for me, CMT is breathing issues. For another CMTer, CMT is wheelchair dependency, is an inability to hold and use a pen or pencil, is 24/7 mechanical ventilation via tracheostomy, and is total deafness. Yet, for another, CMT is none of these things, or a is a combination of these. What is CMT? True to CMT, there isn’t a one-size-fits-all answer. The answer to the proverbial question is unique to the CMTer who is asked. The answer is even unique to the healthcare provider and to the scientific investigator. There are wrong answers to the question, such as a suggestion that CMT is an autoimmune disease. While CMT might share symptoms with some autoimmune diseases, such as Multiple Sclerosis (MS) and Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) for example, CMT is decidedly not an autoimmune disease. Nonetheless, the answer to the burgeoning question is dependent on what CMT looks like for the one who’s giving the answer. If you were to line up ten random CMTers—somebody who has CMT or somebody whose loved one has CMT, and ask each, “what is CMT?” each of the ten answers are likely going to be very different from one another. The differences are not born of inaccuracy or of a misunderstanding of their disease. The differences instead come from how differently CMT looks for each individual and from how each person individually experiences CMT. What is CMT? For me, CMT is a cruel and often debilitating neuromuscular disease that looks very different from person-to-person. For me, what was once an easy answer to a complex question, or what was a complex answer to an easy question, has become exponentially more difficult to answer. As a CMTer, it’s easy to answer the question by simply describing what CMT looks like for me. As an advocate, however, I’ve learned my “45-second elevator speech,” while it gives a lot of information, is a disservice to the CMT community as a whole. The solution? I resolve to do better. I have to do better. I will do better. About the Author Kenneth Raymond was first diagnosed clinically with CMT1 in late 2002, at the age of 29. He was genetically confirmed to have CMT1A a year later. Kenneth has since devoted his life to studying, researching, and learning all things CMT, with an emphasis on the genetics of CMT as they relate to everyday CMTers. As a member of the Charcot-Marie-Tooth Association’s Advisory Board, Kenneth serves as a CMT genetics expert, a CMT-related respiratory impairment expert, and as a CMT advocate who is committed to raising CMT awareness through fact-based information rooted in the latest understandings of CMT.

Unraveling the Confusion and the Chaos of the Many CMT2A Names Science is dynamic, ever evolving, and never sits still. When it comes to CMT, and especially CMT genetics, the science is approaching warp speed. In December 1990, there wasn’t a single known cause of CMT. By Christmas Eve 1993, there were three known causes. By May 1, 1998, there were six genes discovered to have CMT-causing mutations. By the end of 2011, marking the end of the first 20 years of CMT gene discovery, researchers and scientists had discovered 55 genes having CMT-causing mutations. Today, 11 years later, scientists have discovered another 65 genes, bringing the total 120 genes discovered to have mutations that cause CMT. Sometimes, a discovery is a correction to a previous discovery. A review of published literature reveals two such corrections. When scientists and researchers discover a new cause for CMT, they publish their findings in a research paper. The research paper is referred to as “published literature.” The phrase, “in the literature,” or “in the published literature,” refers to published research papers. The researcher or group of researchers who discover a new cause for CMT get to pick the name for their discovery. There’s a CMT naming nomenclature scientists and researchers use as a guideline for naming their discovery—the CMT-causing genetic mutation, and this name becomes known as the subtype name, as in CMT2A, for example (Raymond 2021). And this is where our story begins. Discovering the Elusive CMT2A Cause Before scientists found the first genetic CMT cause, there were three basic CMT types. These were CMT1, CMT2, and CMT3. Whether a CMTer had CMT1 or CMT2 depended on their nerve conduction study (NCS) results (Stojkovic, et al., 2016) (Gondim and Thomas 2019). If nerve conduction speeds were slower than thirty-eight meters/sec, amplitudes were somewhat reduced, and each nerve evaluated showed the relative same, it was CMT1. If nerve conduction speeds were faster than thirty-eight meters/second, amplitudes were significantly reduced, and there was variability between the various nerves evaluated, it was CMT2. Doctors used CMT3 as the diagnosis when CMT symptom onset was in infancy. CMT3, today, is no longer used (Bird, 1998, Updated 2022). CMT1 and CMT2, however, are in use, and the nerve conduction criteria that separate the two from one another are the same today as they were back then. The very first discovered cause for CMT happened in 1991. Scientists discovered the genetic cause for CMT1, and aptly named this discovery CMT1A (Raeymaekers, et al., 1991). Scientists had been able to figure out by this time that there would likely be more than one cause for CMT1. This first discovery, a duplication of a tiny segment of chromosome 17, 17p11.2-p12, to be exact, Raeymaekers(1991) understandably named their discovery 1A, with the “A” indicating it was the first discovered cause for CMT1. A year later, in 1992, researchers pinned down the exact gene implicated in CMT1A—a duplication of the PMP22 gene (Patel, et al., 1992). While the exact gene involved discovered by Patel(1992) might seem like a correction to the chromosome segment duplication discovery by Raeymaekers(1991), the chromosome segment duplication is the reason for the PMP22 gene duplication. Raeymaekers(1991) discovered the duplication, and Patel(1992) clarified the exact gene. Where scientists had predicted more than one cause for CMT1, they had also predicted more than one cause for CMT2. With the first CMT1 discovery coming in 1991, the cause for what CMT researchers and scientists had already dubbed CMT2A remained elusive for ten years. Finally, in 2001, the breakthrough discovery everybody was struggling to find was published. Scientists working in Japan at the University of Tokyo discovered a mutation in the KIF1B gene causing CMT2 and linked their discovery to CMT2A (Zhao, et al., 2001). Finally, we had the cause for CMT2A. Or did we? Genetic Roommates The CMT2A-causing mutation in the KIF1B gene was discovered in just one family by Zhao(2001). While this was truly a breakthrough discovery, researchers and scientists had a challenging time finding this KIF1B mutation in other CMTers, in other families. Try as they may, it just wasn’t happening. Stephan Züchner, MD, PhD, Professor and Chairperson of the Department for Human Genetics at the University of Miami Miller School of Medicine, co-founder and CEO of The Genesis Project, tells the story in a CMT4Me podcast of how, despite all of his efforts, could not find the Zhao(2001) KIF1B mutation in any CMTer who was thought to have CMT2A. Instead, what he did discover, was a mutation in a gene at the same genetic address, and this gene is the MITOFUSIN2 gene, or MFN2 for short (Stephan Züchner 2021). In 2004, after having identified his MFN2 discovery as the actual culprit in many CMTers who had CMT2A, Dr. Züchner published his findings as the cause for CMT2A (Züchner, et al., 2004). Although published literature doesn’t give the reason for this discrepancy between KIF1B and MFN2 in the linkage to CMT2A, the confusion likely stems from the two gene’s cytogenic address. A gene’s cytogenic location (address) is the distinct location within a chromosome where a gene lives. Both the KIF1B gene and the MFN2 gene live on chromosome 1. Specifically, both genes live at 1p36.22. Chromosomes are divided into two basic parts (segments): a short arm (p) and a long arm (q). The “p” and “q” are always lower case. Each arm is subdivided into bands (a number) and sub-band (another number), with the “band” and “sub-band” being separated by a decimal point. In cytogenic location expression, 1p36.22, for example, the first number (1 – 22, or an X or Y) is the chromosome, and everything starting with either a “p” or a “q” and after is the specific location within the chromosome. Putting it all together, 1p36.22 is the house number, street, city, and postal code for both the KIF1B and the MFN2 genes. They are literal genetic roommates. The Confusion Sets In After the KIF1B association to CMT was discovered, we had a genetic confirmation for CMT2A. Things were great for a few years. Then came the MFN2 discovery that was proven as the actual gene with the responsible mutation. One would think that this was it, that KIF1B would see itself out, that MFN2 was the way. This would be the easiest outcome, but nothing is ever easy with CMT. At some point after Dr. Züchner’s MFN2 discovery, CMT2A as a subtype name split into two. Published literature doesn’t give a date, but the KIF1B-associated CMT2A discovery became known as CMT2A1, the MFN2-associated CMT2A discovery became known as CMT2A2. CMT2A1 was the name used for KIF1B-associated CMT2A because this discovery came first. CMT2A2 was used for MFN2-associated CMT2A because this discovery came second. Keep in mind, both actually referred to the same thing after the Züchner(2004) MFN2 discovery proved that the earlier KIF1B discovery by Zhao(2001) was incorrect. Everybody became used to this bit of confusion and all was well for a few years, until a new MFN2 discovery in 2011 changed it all up, again. CMT2A, regardless of which gene we’re associating with this subtype, is caused by an autosomal dominant mutation in its associated gene. To add to the CMT2A confusion, scientists discovered an autosomal recessive CMT-causing mutation in the MFN2 gene. The scientists who made this discovery named it CMT2A2B (Polke, et al., 2011). If the autosomal dominant Züchner(2004) MFN2 discovery is called CMT2A2, it makes sense that the autosomal recessive Polke(2011) discovery should be called CMT2A2B, right? The “B” simply indicates the discovery follows Züchner(2004), because not confusing. Let’s review real quick. 2A1 equals autosomal dominant KIF1B. 2A2 equals autosomal dominant MFN2. 2A2B equals autosomal recessive MFN2. Now that we have a handle on the origins of the many names, there’s another monkey wrench to throw into the mix, because why not? Clarifying the Confusion Everybody was used to the confusion of CMT2A1, CMT2A2, and CMT2A2B. The CMTer community wasn’t a huge fan, but we had a handle on it. Published literature doesn’t give a date, but by c.2013, CMT2A2 morphed into CMT2A2A. CMT2A1 remained as the association to KIF1B. With the autosomal recessive MFN2 Polke(2011) discovery being known as CMT2A2B, in what was likely an effort to clear up all the confusion, the autosomal dominant MFN2 Züchner(2004) discovery morphed into CMT2A2A. Because, again, not confusing. For a period of time, we had CMT2A1, CMT2A2, and CMT2A2A all referring to the exact same thing. CMT2A2 and CMT2A2A are literally the same thing linked to the same mutations in the same gene. Another way to look at CMT2A2 and CMT2A2A, in a hopefully not confusing way, is autosomal dominant MFN2-associated CMT, which we can shorten to AD-MFN2-CMT. Who am I kidding? That’s even more confusing! Am I right? A solution is on its way though. By the late 20-teens, scientists, researchers, CMT experts, and practicing clinicians alike were trying to come up with a solution to this CMT2A multiple name conundrum. One paper suggested scrapping the long used naming conventions in favor of an inheritance pattern-gene format, as in AD-MFN2-CMT (Magy, et al.,2018). While this works for scientists, researchers, doctors, etc, asking a CMTer to explain to somebody what AD-MFN2-CMT is is a huge ask, especially with complex gene names such the SH3TC2 gene, which would translate to AR-SH3TC2-CMT (AR = autosomal recessive). It’s so much easier to say and explain CMT4C (Senderek, et al., 2003). Have no fear, a solution is on the horizon. At some point, and again, published literature doesn’t provide a date, CMT2A1, CMT2A2, and CMT2A2A were merged into simply CMT2A, which is where we are today. The KIF1B association to CMT was officially retracted in 2020 (Clinical Genome Resource 2020). Today, any internet search returns for CMT2A, CMT2A1, CMT2A2, and CMT2A2A all refer to the same thing—they are synonymous with one another. Any internet search return or mentions of CMT2A that is caused by KIF1B mutations is synonymous with CMT2A that’s caused by MFN2 gene mutations, but the KIF1B association should be disregarded. CMT2A2B is still CMT2A2B. Although the KIF1B association to CMT has been retracted, the KIF1B gene still is present on some CMT genetic test panels. Should a CMT genetic test result include a KIF1B mutation, the MFN2 gene needs to be re-examined and in a much closer analysis, especially if the MFN2 gene was not included in the gene panel. While there are KIF1B mutations that are associated with causing different diseases, scientists no longer consider the KIF1B gene to have any connection to any neuromuscular disease (Charcot-Marie-Tooth Association (CMTA) 2020). Beyond the CMT2A confusion, there are two additional subtypes caused by mutations in the MFN2 gene. In total, various mutations in the MFN2 gene are associated with causing four CMT subtypes. In addition to CMT2A and CMT2A2B, certain mutations in this gene are associated with a particularly severe subtype called CMT2B4 (Nicholson, et al., 2008), and certain mutations in this gene are associated with the subtype called HMSN-6A (Züchner, et al., 2006). HMSN is the acronym for Hereditary Motor and Sensory Neuropathy. Despite its name, this is a CMT subtype (Reilly, 2000). Although there are four different subtypes associated with the MFN2 gene, each subtype is caused by different mutations within the gene. Remember the Second Correction? In 2009, scientists discovered mutations in the MED25 gene were causing CMT, and they named their discovery CMT2B2 (Leal, et al., 2009). The same lead author later discovered the data was flawed. In 2018, Leal published a correction to the MED25 discovery. It turns out the actual culprit is mutations in the PNKP gene (Leal, et al., 2018). Rather than everybody going haywire and producing a new subtype name, the subtype simply remained CMT2B2. The likely reason for the confusion? You guessed it. The two genes are roommates, with both living at chromosome 19q13.33. Any internet search returns for MED25-associated CMT2B2 are synonymous with PNPK-associated CMT2B2. Genetic tests haven’t yet caught up with this correction and still include the MED25 gene without having added the PNKP gene. Like KIF1B vs. MFN2, a test result that identifies a CMT-causing MED25 mutation should examine the PNKP gene in close detail. In Closing If CMT is nothing else, it is confusing, and the CMT2A naming saga lives up to CMT’s confusing ways. Out of the many CMT2A names, CMT2A, CMT2A1, CMT2A2, and CMT2A2A, one unifying name has emerged: CMT2A. Today, each of the now formers are known simply as CMT2A. When researching symptom profiles, any finding of CMT2A1, CMT2A2, or CMT2A2A refers to and is synonymous with CMT2A. If you’ve been diagnosed with CMT2A1, CMT2A2, or CM2A2A, the diagnosis is the same as CMT2A and each are interchangeable with one another. Today, we have only two simple CMT2A subtypes: CMT2A, or course, and CMT2A2B. What’s the difference? CMT2A is caused by autosomal dominant mutations in the MFN2 gene and CMT2A2B is caused by autosomal recessive mutations in the MFN2 gene. Beyond these two, different autosomal dominant mutations in the MFN2 gene cause the CMT subtype called HMSN-6A, and different autosomal recessive mutations in this gene cause the early onset and often severe CMT2B4. CMT isn’t about genes, per se. Rather, CMT is about certain mutations in certain genes. Having a mutation in a gene that has CMT-causing mutations doesn’t necessarily mean the mutation is causing CMT. It takes the right mutation, and when multiple subtypes are caused by mutations in a single gene, such as with the MFN2 gene, the mutation itself dictates which subtype the CMTer has. It’s important to note, not every mutation in a CMT-associated gene causes CMT. Some mutations are benign and harmless. About the Author Kenneth Raymond is a CMTer who was first diagnosed with CMT1 in late 2002, at the age of 29. He was genetically confirmed to have CMT1A a year later. Kenneth has devoted his life since diagnosis to studying, researching, and learning all things CMT, with an emphasis on the genetics of CMT as they relate to everyday CMTers. As a member of the Charcot-Marie-Tooth Association’s Advisory Board, Kenneth is a CMT genetics expert, a CMT-related respiratory impairment expert, and is a CMT advocate who is committed to raising CMT awareness through fact-based information rooted in the latest understandings of CMT. Kenneth is also the founder of Experts in CMT, whose goal, through education and awareness, is to improve the lives of those who are living with Charcot-Marie-Tooth disease. References Bird, T. D. 1998 September 28 (Updated 2021 May 20). Charcot-Marie-Tooth (CMT) Hereditary Neuropathy Overview. Edited by Ardinger HH, Pagon RA, et al. Adam MP. Seattle, Washington: GeneReviews® [Internet]. Accessed 2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1358/. Charcot-Marie-Tooth Association (CMTA). 2020. 2020 Patient and Family Conferences - STAR Research Update (Axonal Type 2 and Unknown Variants). Accessed July 2021. https://www.cmtausa.org/living-with-cmt/find-resources/patient-family-conferences/. Clinical Genome Resource. 2020. Clinical Genome Resource. October. Accessed August 2021. https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ae6ffeae-9609-47bf-89a9-4863cf6ef05c-2020-10-05T161930.420Z. Gondim, Francisco de Assis Aquino MD, PhD, MSc, FAAN, and Florian P MD, PhD, MA, MS Thomas. 2019. What is the role of EMG and NCS in the workup of Charcot-Marie-Tooth (CMT) disease? Edited by PharmD, PhD Francisco Talavera. February. Accessed November 2021. https://www.medscape.com/answers/1173484-176746/what-is-the-role-of-emg-and-ncs-in-the-workup-of-charcot-marie-tooth-cmt-disease. Ionasescu, V. V., Trofatter, J., Haines, J. L., Summers, A. M., Ionasescu, R., & Searby, C. 1992. "X-linked recessive Charcot-Marie-Tooth neuropathy: clinical and genetic study." Muscle & nerve 15 (3): 368–373. doi:https://doi.org/10.1002/mus.880150317. Leal, A., Bogantes-Ledezma, S., Ekici, A. B., Uebe, S., Thiel, C. T., Sticht, H., Berghoff, M., Berghoff, C., Morera, B., Meisterernst, M., & Reis, A. 2018. "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25." Neurogenetics 19 (4): 215–225. doi:https://doi.org/10.1007/s10048-018-0555-7. Leal, A., Huehne, K., Bauer, F., Sticht, H., Berger, P., Suter, U., Morera, B., Del Valle, G., Lupski, J. R., Ekici, A., Pasutto, F., Endele, S., Barrantes, R., Berghoff, C., Berghoff, M., Neundörfer, B., Heuss, D., Dorn, T., Young, P., et al. 2009. "Identification of the variant Ala335Val of MED25 as responsible for CMT2B2: molecular data, functional studies of the SH3 recognition motif and correlation between wild-type MED25 and PMP22 RNA levels in CMT1A animal models." Neurogenetics 10 (4): 375–376. doi:https://doi.org/10.1007/s10048-009-0213-1. Magy, L., Mathis, S., Le Masson, G., Goizet, C., Tazir, M., & Vallat, J. M. 2018. "Updating the classification of inherited neuropathies: Results of an international survey." Neurology 90 (10). doi:https://doi.org/10.1212/WNL.0000000000005074. Montecchiani, C., Pedace, L., Lo Giudice, T., Casella, A., Mearini, M., Gaudiello, F., Pedroso, J. L., Terracciano, C., Caltagirone, C., Massa, R., St George-Hyslop, P. H., Barsottini, O. G., Kawarai, T., & Orlacchio, A. 2015. "ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease." Brain : a journal of neurology 139 (Pt 1): 73–85. doi:https://doi.org/10.1093/brain/awv320. Nicholson, G. A., Magdelaine, C., Zhu, D., Grew, S., Ryan, M. M., Sturtz, F., Vallat, J. M., & Ouvrier, R. A. 2008. "Severe early-onset axonal neuropathy with homozygous and compound heterozygous MFN2 mutations." Neurology 70 (19): 1678–1681. doi:https://doi.org/10.1212/01.wnl.0000311275.89032.22. Patel, P. I., Roa, B. B., Welcher, A. A., Schoener-Scott, R., Trask, B. J., Pentao, L., Snipes, G. J., Garcia, C. A., Francke, U., Shooter, E. M., Lupski, J. R., & Suter, U. 1992. "The gene for the peripheral myelin protein PMP-22 is a candidate for Charcot-Marie-Tooth disease type 1A." Nature genetics 1 (3): 59–165. doi:https://doi.org/10.1038/ng0692-159. Polke, J. M., Laurá, M., Pareyson, D., Taroni, F., Milani, M., Bergamin, G., Gibbons, V. S., Houlden, H., Chamley, S. C., Blake, J., Devile, C., Sandford, R., Sweeney, M. G., Davis, M. B., & Reilly, M. M. 2011. "Recessive axonal Charcot-Marie-Tooth disease due to compound heterozygous mitofusin 2 mutations." Neurology 77 (2): 168–173. doi:https://doi.org/10.1212/WNL.0b013e3182242d4d. Raeymaekers, P., Timmerman, V., Nelis, E., De Jonghe, P., Hoogendijk, J. E., Baas, F., Barker, D. F., Martin, J. J., De Visser, M., & Bolhuis, P. A. 1991. "Duplication in chromosome 17p11.2 in Charcot-Marie-Tooth neuropathy type 1a (CMT 1a). The HMSN Collaborative Research Group." Neuromuscular disorders : NMD, 1 (2): 93–97. doi:https://doi.org/10.1016/0960-8966(91)90055-w. Raymond, Kenneth. 2021. CMT-Associated Genes and Their Related Subtypes: The Definitive Guide. 1st. Detroit: Kenneth Raymond. Accessed November 2021. https://www.cmtausa.org/understanding-cmt/cmt-associated-genes-the-definitive-guide/. Reilly, M. M. 2000. "Classification of the hereditary motor and sensory neuropathies." Current opinion in neurology 13 (5): 561–564. https://renaissance.stonybrookmedicine.edu/sites/default/files/Classification%20of%20the%20hereditary%20motor%20and%20sensory%20neuropathies.pdf. Senderek, J., Bergmann, C., Stendel, C., Kirfel, J., Verpoorten, N., De Jonghe, P., Timmerman, V., Chrast, R., Verheijen, M. H., Lemke, G., Battaloglu, E., Parman, Y., Erdem, S., Tan, E., Topaloglu, H., Hahn, A., Müller-Felber, W., et al. 2003. "Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy." American journal of human genetics 73 (5): 1106–1119. doi:https://doi.org/10.1086/379525. Stephan Züchner, MD, PhD, interview by Chris Oulette and Elizabeth Oulette. 2021. "Dr. Stephan Züchner: Exciting Genetic Discoveries Lead to Life-Changing CMT Therapies." CMT4Me Podcast. Charcot-Marie-Tooth Association, (October 27). Accessed November 2021. https://cmt4me.buzzsprout.com/1849476/9429530-dr-stephan-zuchner-exciting-genetic-discoveries-lead-to-life-changing-cmt-therapies. Stojkovic, T. 2016. "Hereditary neuropathies: An update." PM & R : the journal of injury, function, and rehabilitation 172 (12): 775–778. doi:https://doi.org/10.1016/j.neurol.2016.06.007. Zhao, C., Takita, J., Tanaka, Y., Setou, M., Nakagawa, T., Takeda, S., Yang, H. W., Terada, S., Nakata, T., Takei, Y., Saito, M., Tsuji, S., Hayashi, Y., & Hirokawa, N. 2001. "Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bbeta." Cell 105 (5): 587–597. doi:https://doi.org/10.1016/s0092-8674(01)00363-4. Züchner, S., De Jonghe, P., Jordanova, A., Claeys, K. G., Guergueltcheva, V., Cherninkova, S., Hamilton, S. R., Van Stavern, G., Krajewski, K. M., Stajich, J., Tournev, I., Verhoeven, K., Langerhorst, C. T., Baas, F., Bird, T., Shy, M., et al. 2006. "Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2." Annals of neurology 59 (2): 276–281. doi:https://doi.org/10.1002/ana.20797. Züchner, S., Mersiyanova, I. V., Muglia, M., Bissar-Tadmouri, N., Rochelle, J., Dadali, E. L., Zappia, M., Nelis, E., Patitucci, A., Senderek, J., Parman, Y., Evgrafov, O., Jonghe, P. D., Takahashi, Y., Tsuji, S., Pericak-Vance, M. A., Quattrone, et al. 2004. "Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A." Nature genetics 36 (5): 449–451. doi:https://doi.org/10.1038/ng1341.

Examining the Limitations of Genetic Testing in Charcot Marie Tooth Disease Charcot-Marie-Tooth disease, or CMT for short, is a heterogeneous group of inherited peripheral neuropathies. CMT is rare, affecting approximately only 3 million people worldwide, but it’s the most commonly inherited peripheral neuropathy. Although CMT symptoms can be treated and well-managed, the disease itself has no known effective treatment or cure. The elusive treatment and cure are a consequence of the ever-expanding catalog of genes discovered to have CMT-causing mutations. Due to this expanding catalog, CMT is perhaps one of the fastest growing areas in human genetics. Discoveries in CMT genetics are occurring at breakneck speed. Scientists discovered the first CMT genetic link in 1991. Scientists have continued to make new CMT genetic discoveries every year since. The number of genes discovered to have CMT-causing mutations in the last 10 years eclipses the number of genes discovered in the first 20 years. Despite these gains, a CMT genetic test result that fails to identify a known CMT genetic cause is still a common outcome, leaving many CMTers with more questions than there are answers. It All Started When The first CMT-associated gene discovery was published in June 1992. This discovery, a duplication of the PMP22 gene, is the cause for CMT1A (Patel, et al., 1992). We normally have two copies of this gene. CMTers who have CMT1A, however, have a third copy (in rare cases, there are four copies of this gene – a triplication). About a year prior to this discovery, scientists had narrowed down the cause of CMT1A to a duplication of the segment of chromosome 17 where the PMP22 gene lives (Raeymaekers, et al., 1991). Raeymaekers et al. (1991) found that 128 CMTers from 12 different families who had CMT1 each had a duplication of a small segment of chromosome 17 (17p11.2-p12). This duplication segregated with the disease, meaning that members of these 12 families who did not have CMT did not have this chromosome 17 segment duplication. Raeymaekers et al. (1991) concluded this discovery to be the cause for CMT1A. Patel et al. (1992), however, identified the specific gene involved. And, things were only just getting started. In January 1993, scientists announced they had discovered the cause of a Type 1 CMT called Hereditary Neuropathy with liability to Pressure Palsies (HNPP) after finding CMTers with this phenotype each had a deletion of one-copy of the PMP22 gene (Chance, et al., 1993). The second gene discovered by scientists to have a CMT-causing mutation was the MPZ gene, with having a mutation causing CMT1. They published this finding in September 1993, calling their discovery CMT1B (Hayasaka, et al., 1993). The year closed out with scientists publishing on Christmas Eve the first X-Linked CMT discovery, after finding a CMT-causing mutation in the GJB1 gene (formerly called CONNEXIN32) (Bergoffen, et al., 1993). CMT-associated genes were elusive for the next few years. Scientists didn’t make a new CMT-associated gene discovery until 1996 when they found CMT-causing mutations in the NTRK1 gene (Indo, et al., 1996) (this discovery would not be categorized as CMT until the 2010s). A year later, scientists discovered CMT-causing mutations in the PHYH gene (Mihalik, et al., 1997) (this discovery, too, would not be categorized as CMT until the 2010s). The last CMT-associated gene discovery made by scientists in the 1990s came in 1998 when they found CMT-causing mutations in the EGR2 gene (Warner, et al., 1998). The 90’s started with scientists wanting to discover the cause of CMT. The decade ended with scientists having discovered CMT-causing mutations in six different genes, accounting for eight unique subtypes. As if this wasn’t overwhelming enough, the turn of the century ushered in an explosion of genes discovered to have CMT-causing mutations. The 1990’s brought six CMT-associated gene discoveries, from 1991 through 1998. New gene discovery was elusive in 1999. Scientists then announced in 2000 they had discovered CMT-causing mutations in four genes: MTMR2 (Bolino, et al., 2000), NDRG1 (Kalaydjieva, et al., 2000), NEFL (Mersiyanova 2000), and GAN (Bomont, et al., 2000) (this would not be categorized as CMT until the 2010s). Scientists discovered another five genes with CMT-causing mutations in 2001: PRX (Guilbot, et al., 2001), ELP1 (formerly called IKAP) (Anderson, et al., 2001), SPTLC1 (Dawkins, et al., 2001), KIF1B (Zhao, et al., 2001), and IGHMBP2 (Grohmann, et al., 2001). Zhao et al. (2001) found CMT-causing mutations in the KIF1B gene were responsible for causing CMT2A. However, scientists later found, in 2004, that the actual culprit was a mutation in the MFN2 gene (Züchner, et al., 2004), but the KIF1B association to CMT was not retracted until 2020 (Clinical Genome Resource 2020). The new millennium was off to one heck of a jammed packed start. In only the first two years of the new century, of the new millennium, scientists discovered nine genes having CMT-causing mutations. Although scientists found one of those discoveries to be inaccurate, the remaining eight genes still exceed the number of CMT-associated genes discovered in the previous nine years. By the time the end of 2010 rolled around, marking the end of the first 20 years of CMT-associated gene discovery, scientists had found CMT-causing mutations in a staggering 55 different genes. Fast forward another eleven years to present day, late 2021, and scientists have discovered another 65 genes having CMT-causing mutations, for a total of 120 CMT-associated genes over the span of thirty years (Raymond, 2021). With all of this expansiveness and ginormity, how is it that CMT genetic testing is limited? Commercially Speaking There are many commercial laboratories offering genetic testing services for CMT. A review of publicly available CMT genetic test gene lists from various commercial laboratories reveals there isn’t any one commercial laboratory that includes every discovered CMT-associated gene in their CMT panels (a panel is a genetic test that analyzes several genes, as opposed to a test that analyzes a single gene). Commercial laboratories each have their own criteria for deciding what to include or exclude in their panels. For this reason, there is variability from panel to panel, laboratory to laboratory. Knowing what’s included is essential, and what’s included vs. what’s excluded is the most significant variable across all CMT genetic tests. Invitae Laboratories is arguably the most frequently used laboratory for CMT genetic testing in the US and Canada. Their Comprehensive Neuropathies Panel test 03200 analyzes 102 genes, with an option to add an additional nine for a total of 111 genes (Invitae Comprehensive Neuropathies Panel 2021). Despite this panel’s expansiveness, only 89 genes are associated with CMT. These 89 genes are associated with causing 118 individual CMT subtypes (Raymond, 2021). Considering there are 120 genes discovered to have CMT-causing mutations, plus an additional five chromosomal locations scientists suspect as having a CMT-causing mutation but have not yet identified the specific gene, all collectively accounting for 155 individual CMT subtypes, the reasons why a CMT genetic test might not identify a cause become clear. A much larger and different kind of genetic test often used for CMT, and one that isn’t limited to only laboratory selected genes on a panel, called Whole Exome Sequencing, has its limitations also. Whole Exome Sequencing (WES) is a type of genetic test that attempts to look at all coding exons in all of our more than 20,000 genes. A gene has two basic parts: an intron and an exon. An intron is the part of the gene that holds noncoding-genetic-material. The exon is the part of the gene that holds all the coding-genetic-material. Coding-genetic-material is the part of a gene that codes (instructs) a certain molecular process, and each individual gene has its own molecular process that it codes. WES attempts to look at the coding part of every gene for errors in how the gene is assembled. These errors, which are akin to spelling errors, are gene mutations, and these mutations are sometimes responsible for causing diseases such as CMT. WES analyzes our DNA and pipes all of the sequenced genetic data into a computer program. A clinician then inputs into the program symptom and condition keywords provided by the doctor who ordered the WES. The program uses an algorithm to sort the tens of thousands of pages of genetic sequence data to identify genes that scientists have associated with causing conditions that match the symptom and condition keywords the clinician entered into the algorithm. After the algorithm sorts the data, the program generates a list of genes that are responsive to the keyword inputs. Clinicians then sort and verify this list as they compile what is called the primary gene list. The primary gene list is then analyzed for any present mutations, and clinicians generate the WES interpretation report based on their findings within the primary gene list. Sometimes, this process is fully automated and sometimes there is an abundance of manual data analysis. The level of automation is at each laboratory’s discretion. WES is not a genetic test that analyzes specific genes like what a gene panel does. WES attempts to analyze all genes. However, clinicians can manually sort WES data for specific genes, then manually add the specific genes to the dataset that is used to generate the primary gene list. WES, however, has technology limitations that might omit some genes. Another WES limitation pertaining to CMT is that scientists believe they have identified only about half of all genes that likely have CMT-causing mutations (Michael Shy 2020). If genes potentially have CMT-causing mutations but are not yet identified by scientists, WES is not going to capture these as responsive genes and clinicians tasked with compiling WES primary gene lists aren’t going to know to manually sort for these genes. Another limitation to WES is the keywords. WES results are only as good as the keywords used to generate the final report. If keywords don’t match CMT symptom profiles, for example, or symptom keywords are too generalized and vague, WES might not return a result that accurately represents a CMTer’s true genetic profile. In short, CMT genetic testing results, whether WES or otherwise, might not be definitive. If they’re not, how can doctors definitively diagnose CMT? When Genetic Testing isn’t Enough CMT was first described in 1886. Doctors knew what it was, and they could tell it was inheritable from how it appeared to run in families. But, the cause was elusive for the next 100 years. Nobody could have predicted prior to the first CMT genetic discovery that underlying causes would balloon to the enormity they have in the thirty years since the first discovery. Despite the profound number of CMT-associated genes, scientists believe we are only halfway to discovering all genes with CMT-causing mutations. Today, approximately 95% of CMTers who have a demyelinating CMT are able to obtain a genetic confirmation. In sharp contrast, only about 50% of CMTers who have an axonal CMT are able to obtain a genetic confirmation, and some scientists suggest this number might be as low as 30% (Shy, 2020). CMT genetics expert, Stephan Züchner, M.D., Ph.D., professor and Chair of the Dr. John T. Macdonald Foundation, Department of Human Genetics, University of Miami, Miller School of Medicine, suggests that discoveries like the CMT-causing mutations in the SORD1 gene (Cortese, et al., 2020) have the potential to cut down on the overall number of CMT-associated genes yet to be discovered given the number of CMTers who are likely to have SORD-deficiency CMT (Züchner, 2021). According to Dr. Züchner, there are at least 3,300 CMTers in the US alone who likely have this newly discovered SORD-deficiency CMT. Dr. Züchner suggests that discoveries like this might quite possibly mean that scientists are much closer to discovering all CMT-associated genes than previously thought. However, because all have not been discovered, CMT genetic testing remains unfortunately diagnostically limited, and therefore cannot necessarily serve as a standalone diagnostic tool. CMT genetic testing is but only one piece of the diagnostic picture doctors consider when diagnosing CMT. Symptoms, family history, and nerve conduction study results all play an equal role when diagnosing CMT, and together, often inform the doctor's genetic testing decisions. Richard A. Lewis, MD, Professor of Neurology, Cedars-Sinai Medical Center; Director, CMTA Center of Excellence, explains that to definitively diagnose CMT, one needs the appropriate clinical picture—numbness and weakness in the feet and usually in the hands occurring with reduced reflexes, plus a family history of the same problems that cannot be due to other causes such as diabetes. Also, the nerve conduction studies should show evidence of neuropathy—nerve conduction velocities that are very slow fit a diagnosis of CMT1, and if not very slow, CMT2. Having pes cavus (high arches) since early in life is supportive evidence of a CMT diagnosis. But other neuropathies can give a similar clinical picture and similar nerve conduction study findings. To be certain it’s CMT, Dr. Lewis explains, an abnormal genetic test would be proof. However, genetic testing doesn’t always detect a problem and that doesn’t mean that a genetic disorder such as CMT is not the cause. In addition, genetic testing results can be difficult to interpret and can be confusing to the patient. A definitive diagnosis depends on a doctor putting all this information together; and, it is important not to miss a treatable cause of neuropathy. With all of this complexity in mind, Dr. Lewis advises that it is best to get a good neurologic evaluation if you have neuropathy. The Pursuit of… Although CMT genetic testing is part of the diagnostic work up for CMT, the genetic testing often is a personal choice. The personal reasons for testing or not testing are as many as there are CMTers. A CMT genetic test might not be definitive insofar as the test might not identify a known CMT cause. Often, the test identifies only variants of unknown or uncertain significance (VUS) in CMT-associated genes. A VUS is a mutation in which scientists have not yet determined whether it causes something or is benign (harmless), and a VUS finding in a gene that is known to have CMT-causing mutations is a common finding. A VUS finding in a CMT-associated gene can create confusion for CMTers, the finding can be difficult for doctors to interpret, and the finding requires a more sophisticated diagnostic analysis by the ordering doctor. The frequency at which VUS findings occur in CMT genetic testing lends itself to the often lacking clear-cut and overt genetic confirmation of a CMT clinical diagnosis. This often adds to a CMTer’s frustration, and understandably so. With these pitfalls, why undergo genetic testing? CMT genetic testing is as much of an integral part of diagnosing CMT as are symptoms, family history, and nerve conduction studies. A nerve conduction study often precedes genetic testing, and the results can inform a clinical diagnosis. Before genetic testing is performed, when nerve conduction study findings are consistent with demyelinating CMT, doctors use CMT1 as a blanket diagnosis, and when consistent with axonal CMT, CMT2 (Gondim and Thomas, 2019). However, the only way doctors can identify the exact CMT subtype is through genetic testing that identifies a known CMT-causing genetic mutation (El-Abassi, et al., 2014), or, as Dr. Lewis explains, through a more sophisticated analysis of all diagnostic findings in the case of a genetic test VUS finding. The blanket diagnosis of CMT1 or CMT2 is descript as a clinical diagnosis but infers no genetic cause. Raymond (2021) identifies 27 demyelinating CMT subtypes and 112 axonal CMT subtypes. Upon genetic confirmation, a CMT1 or CMT2 clinical diagnosis can change, and is dependent upon the identified CMT-causing gene mutation. There are four categories in which demyelinating CMT is found—CMT1, CMT4, CMTX, and [Gene Name]-CMT; and there are ten categories in which axonal CMT is found—CMT2, CMTX, dHMN, dSMA, GAN, HMSN, HSAN, HSN, SMA-LEP, [Gene Name]-CMT (Raymond, 2021). It’s easy to see how a CMT1 or CMT2 clinical diagnosis might change after the underlying CMT-causing mutation is identified, but why does knowing the exact subtype matter? CMT clinical trials are often subtype specific. CMT, due to its heterogeneity (many unique causes, many diverse presentations), is a collection of 155 genetically distinct diseases. Each of these 155 genetically distinct diseases is a CMT subtype. Researchers often target a specific subtype in their clinical trials. As such, clinical trials typically require that every participant have genetic confirmation of their CMT (genetic confirmation = identified subtype). Gene therapy as a potential treatment and even as a potential cure for CMT involves targeting a specific gene or gene mutation. Therefore, a potential gene therapy for CMT4C, for example, which is caused by autosomal recessive mutations in the SH3TC2 gene (Senderek, et al., 2003), would likely be of no benefit to a CMTer who has CMT1H, which is caused by autosomal dominant mutations in the FBLN5 gene (Brozkova, et al., 2020). For these reasons, identifying the underlying responsible CMT-causing genetic mutation is essential. Although CMT genetic testing might come up empty, testing is critical in these circumstances. Another reason for CMT genetic testing is family planning. CMT is inheritable. CMT is inheritable because each of the genetic mutations that cause the disease are inheritable. How CMT is inherited, that is, how it’s passed on, is dependent solely on the underlying CMT-causing genetic mutation. CMT is passed on in one of five ways. Each of these are known as an inheritance pattern, and each inheritance pattern carries its own chances of inheritance (Raymond, 2021). In order to know the chances a CMTer has for passing on their CMT to their children, especially when there is no established family history of CMT, the underlying responsible genetic mutation must be identified. Without knowing the genetic cause, understanding the chances of inheritance is guess work (albeit a highly educated and informed guess), and this can impact family planning. A carefully reviewed detailed family history, however, can reveal a likely inheritance pattern when the investigator has the specialized training needed to understand and recognize the patterns. While CMT is inheritable, one does not have to have inherited it in order to have it. A CMTer whose CMT was not inherited from a parent has CMT that is caused by a spontaneous and random gene mutation that occurred at or shortly after conception. CMT that was not inherited from a parent is called a de novo, or new case. A CMTer who has a de novo CMT case has the same chances of passing on their CMT as though they had inherited it, and those chances are solely dependent on the underlying CMT-causing genetic mutation. Finding the Undiscovered A significant limitation to CMT genetic testing is the magnitude of undiscovered genes with CMT-causing mutations. Less than half of all CMTers today are able to obtain genetic confirmation of their CMT. The disparage in large part stems from so many unknown CMT-associated genes. The Genesis Project Foundation is leading efforts to shore up this void. Cofounded and led by Dr. Züchner, The Genesis Project Foundation is a patient and scientist managed (501(c)(3)). The Genesis Project Foundation focuses on finding genetic causes for rare diseases and on accelerating new treatments for rare diseases via these genetic discoveries. Since its founding in 2011, The Genesis Project’s genomics research database and platform, GENESIS, which boasts more than 18,000 stored genomes (and counting), has contributed to more than 100 rare disease gene discoveries. Many of these discoveries are CMT-associated genes. These discoveries lead to CMTers being able to obtain genetic confirmation when previous testing has failed. These discoveries also lead to potential treatments. To say the work of Dr. Züchner and Genesis Project team changes lives is an understatement. In Closing CMT can be extremely difficult for doctors to diagnose, especially when there’s no established family history. The doctor has to consider the totality of all diagnostic findings. Despite gains in CMT genetic discovery and gains in commercially available genetic testing, a genetic test might not confirm a CMT clinical diagnosis. When genetic testing does not reveal a genetic cause, having an appropriate clinical picture of CMT symptoms, together with appropriate nerve study findings, and having family members who also fit the same clinical picture, can lead to a definitive CMT clinical diagnosis after exhausting all causes of acquired neuropathy (such as diabetes) and after exhausting all causes of otherwise treatable neuropathy. A CMT clinical diagnosis is definitive insofar as serving as a reliable diagnosis for demyelinating CMT—CMT1, or axonal CMT—CMT2, but a clinical diagnosis does not infer a genetic cause, i.e., the specific subtype. Identifying the specific subtype requires genetic testing. CMT genetic testing is required for identifying the specific CMT subtype, but the testing has inherent limits. By this, the test might not identify a CMT genetic cause. A test that does not overtly identify a CMT-causing mutation when a CMTer has the appropriate clinical picture and nerve study findings supportive of a CMT clinical diagnosis means only that the underlying cause was not yet tested for, and the result means nothing more. Genetic test results in this situation specifically do not rule out CMT. In this situation, a CMT clinical diagnosis that prompted a genetic test still stands, is still a reliable diagnosis, and is still a definitive diagnosis when all other causes of neuropathy have been exhausted, even though the exact subtype remains elusive. About the Author Kenneth Raymond is a CMTer who was first diagnosed with CMT1 in late 2002, at the age of 29. He was genetically confirmed to have CMT1A a year later. Kenneth has devoted his life since diagnosis to studying, researching, and learning all things CMT, with an emphasis on the genetics of CMT as they relate to everyday CMTers. As a member of the Charcot-Marie-Tooth Association’s Advisory Board, Kenneth is a CMT genetics expert and is a CMT advocate who is committed to raising CMT awareness through fact-based information rooted in the latest understandings of CMT. References Anderson, S. L., Coli, R., Daly, I. W., Kichula, E. A., Rork, M. J., Volpi, S. A., Ekstein, J., & Rubin, B. Y. 2001. "Familial dysautonomia is caused by mutations of the IKAP gene." American journal of human genetics 68 (3): 753–758. doi:https://doi.org/10.1086/318808 Bergoffen, J., Scherer, S. S., Wang, S., Scott, M. O., Bone, L. J., Paul, D. L., Chen, K., Lensch, M. W., Chance, P. F., & Fischbeck, K. H. 1993. "Connexin mutations in X-linked Charcot-Marie-Tooth disease." Science 262 (5142): 2039–2042. doi:https://doi.org/10.1126/science.826610 Bolino, A., Muglia, M., Conforti, F. L., LeGuern, E., Salih, M. A., Georgiou, D. M., Christodoulou, K., Hausmanowa-Petrusewicz, I., Mandich, P., Schenone, A., Gambardella, A., Bono, F., Quattrone, A., Devoto, M., & Monaco, A. P. 2000. "Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2." Nature genetics 25 (1): 7–19. doi:https://doi.org/10.1038/75542 Bomont, P., Cavalier, L., Blondeau, F., Ben Hamida, C., Belal, S., Tazir, M., Demir, E., Topaloglu, H., Korinthenberg, R., Tüysüz, B., Landrieu, P., Hentati, F., & Koenig, M. 2000. "The gene encoding gigaxonin, a new member of the cytoskeletal BTB/kelch repeat family, is mutated in giant axonal neuropathy." Nature genetics 26 (3): 370–374. doi:https://doi.org/10.1038/81701 Chance, P. F., Alderson, M. K., Leppig, K. A., Lensch, M. W., Matsunami, N., Smith, B., Swanson, P. D., Odelberg, S. J., Disteche, C. M., & Bird, T. D. 1993. "DNA deletion associated with hereditary neuropathy with liability to pressure palsies." Cell 72 (1): 143–151. doi:https://doi.org/10.1016/0092-8674(93)90058-x Clinical Genome Resource. 2020. Clinical Genome Resource. October. Accessed August 2021. https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ae6ffeae-9609-47bf-89a9-4863cf6ef05c-2020-10-05T161930.420Z Cortese, A., Zhu, Y., Rebelo, A. P., Negri, S., Courel, S., Abreu, L., Bacon, C. J., Bai, Y., Bis-Brewer, D. M., Bugiardini, E., Buglo, E., Danzi, M. C., Feely, S., Athanasiou-Fragkouli, A., Haridy, N. A., Inherited Neuropathy Consortium, Zuchner, S. 2020. "Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes." Nature genetics 52 (5): 473–481. doi:https://doi.org/10.1038/s41588-020-0615-4 Dawkins, J. L., Hulme, D. J., Brahmbhatt, S. B., Auer-Grumbach, M., & Nicholson, G. A. 2001. "Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I." Nature genetics 27 (3): 309–312. doi:https://doi.org/10.1038/85879 El-Abassi, R., England, J. D., & Carter, G. T. 2014. "Charcot-Marie-Tooth disease: an overview of genotypes, phenotypes, and clinical management strategies." PM & R : the journal of injury, function, and rehabilitation 6 (4): 342–355. Accessed November 2021. doi:https://doi.org/10.1016/j.pmrj.2013.08.611 Gondim, Francisco de Assis Aquino MD, PhD, MSc, FAAN, and Florian P MD, PhD, MA, MS Thomas. 2019. What is the role of EMG and NCS in the workup of Charcot-Marie-Tooth (CMT) disease? Edited by PharmD, PhD Francisco Talavera. February. Accessed November 2021. https://www.medscape.com/answers/1173484-176746/what-is-the-role-of-emg-and-ncs-in-the-workup-of-charcot-marie-tooth-cmt-disease Grohmann, K., Schuelke, M., Diers, A., Hoffmann, K., Lucke, B., Adams, C., Bertini, E., Leonhardt-Horti, H., Muntoni, F., Ouvrier, R., Pfeufer, A., Rossi, R., Van Maldergem, L., Wilmshurst, J. M., Wienker, T. F., Sendtner, M., Rudnik-Schöneborn, et al. 2001. "Mutations in the gene encoding immunoglobulin mu-binding protein 2 cause spinal muscular atrophy with respiratory distress type 1." Nature genetics 29 (1): 75–77. doi:https://doi.org/10.1038/ng703 Guilbot, A., Williams, A., Ravisé, N., Verny, C., Brice, A., Sherman, D. L., Brophy, P. J., LeGuern, E., Delague, V., Bareil, C., Mégarbané, A., & Claustres, M. 2001. "A mutation in periaxin is responsible for CMT4F, an autosomal recessive form of Charcot-Marie-Tooth disease." Human molecular genetics 10 (4): 415–421. doi:https://doi.org/10.1093/hmg/10.4.415 Hayasaka, K., Himoro, M., Sato, W., Takada, G., Uyemura, K., Shimizu, N., Bird, T.D., Conneally, P.M., and Chance, P.F. 1993. "Charcot-Marie-Tooth neuropathy type 1B is associated with mutations of the myelin P0 gene." Nature Genetics 5 (1): 31-34. doi:https://doi.org/10.1038/ng0993-31 Indo, Y., Tsuruta, M., Hayashida, Y., Karim, M. A., Ohta, K., Kawano, T., Mitsubuchi, H., Tonoki, H., Awaya, Y., & Matsuda, I. 1996. "Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis." Nature genetics 13 (4): 485–488. doi:https://doi.org/10.1038/ng0896-485 2021. Invitae Comprehensive Neuropathies Panel. May 03. https://www.invitae.com/en/physician/tests/03200/ Kalaydjieva, L., Gresham, D., Gooding, R., Heather, L., Baas, F., de Jonge, R., Blechschmidt, K., Angelicheva, D., Chandler, D., Worsley, P., Rosenthal, A., King, R. H., & Thomas, P. K. 2000. "N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom." American journal of human genetics 67 (1): 47–58. doi:https://doi.org/10.1086/302978 Mastaglia, F. L., Nowak, K. J., Stell, R., Phillips, B. A., Edmondston, J. E., Dorosz, S. M., Wilton, S. D., Hallmayer, J., Kakulas, B. A., & Laing, N. G. 1999. "Novel mutation in the myelin protein zero gene in a family with intermediate hereditary motor and sensory neuropathy." Journal of neurology, neurosurgery, and psychiatry 67 (2): 174–179. doi:https://doi.org/10.1136/jnnp.67.2.174 Mersiyanova, I. V., Perepelov, A. V., Polyakov, A. V., Sitnikov, V. F., Dadali, E. L., Oparin, R. B., Petrin, A. N., & Evgrafov, O. V. 2000. "A new variant of Charcot-Marie-Tooth disease type 2 is probably the result of a mutation in the neurofilament-light gene." American journal of human genetics 67 (1): 37–46. doi:https://doi.org/10.1086/302962 Michael Shy, MD, interview by Nicole Petrouski. 2020. "Director, Division of Neuromuscular Medicine-Neurology, University of Iowa give his presentation on Research and Clinical Trials in CMT." 2020 MDA Engage CMT Symposium: MDA Mission Spotlight. Muscular Dystrophy Association. June 6. Accessed July 2021. https://www.youtube.com/watch?v=GWOOzQFWaYM&list=PLxofS4JHjGXXfMhWYiifLRSnHFflDJuv3 Mihalik, S. J., Morrell, J. C., Kim, D., Sacksteder, K. A., Watkins, P. A., & Gould, S. J. 1997. "Identification of PAHX, a Refsum disease gene." Nature genetics 17 (2): 185–189. doi:https://doi.org/10.1038/ng1097-185 Patel, P. I., Roa, B. B., Welcher, A. A., Schoener-Scott, R., Trask, B. J., Pentao, L., Snipes, G. J., Garcia, C. A., Francke, U., Shooter, E. M., Lupski, J. R., & Suter, U. 1992. "The gene for the peripheral myelin protein PMP-22 is a candidate for Charcot-Marie-Tooth disease type 1A." Nature genetics 1 (3): 59–165. doi:https://doi.org/10.1038/ng0692-159 Raeymaekers, P., Timmerman, V., Nelis, E., De Jonghe, P., Hoogendijk, J. E., Baas, F., Barker, D. F., Martin, J. J., De Visser, M., & Bolhuis, P. A. 1991. "Duplication in chromosome 17p11.2 in Charcot-Marie-Tooth neuropathy type 1a (CMT 1a). The HMSN Collaborative Research Group." Neuromuscular disorders : NMD, 1 (2): 93–97. doi:https://doi.org/10.1016/0960-8966(91)90055-w Raymond, Kenneth. 2021. CMT-Associated Genes and Their Related Subtypes: The Definitive Guide. 1st. Detroit: Kenneth Raymond. Accessed November 2021. https://www.cmtausa.org/understanding-cmt/cmt-associated-genes-the-definitive-guide/ Raymond, Kenneth. 2021. "Where'd it Come From? Where's it Going? Exploring The Inheritance Patterns of Charcot Marie Tooth Disease." The Cryptid Sloth. October 29. Accessed November 2021. https://www.thecryptidsloth.com/post/the-inheritance-patterns-of-cmt Safka Brozkova, D., Stojkovic, T., Haberlová, J., Mazanec, R., Windhager, R., Fernandes Rosenegger, P., Hacker, S., Züchner, S., Kochański, A., Leonard-Louis, S., Francou, B., Latour, P., Senderek, J., Seeman, P., & Auer-Grumbach, M. 2020. "Demyelinating Charcot-Marie-Tooth neuropathy associated with FBLN5 mutations." European journal of neurology 27 (12): 2568–2574. doi:https://doi.org/10.1111/ene.14463 Senderek, J., Bergmann, C., Stendel, C., Kirfel, J., Verpoorten, N., De Jonghe, P., Timmerman, V., Chrast, R., Verheijen, M. H., Lemke, G., Battaloglu, E., Parman, Y., Erdem, S., Tan, E., Topaloglu, H., Hahn, A., Müller-Felber, W., et al. 2003. "Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy." American journal of human genetics 73 (5): 1106–1119. doi:https://doi.org/10.1086/379525 Stephan Züchner, MD, PhD, interview by Chris Oulette and Elizabeth Oulette. 2021. "Dr. Stephan Züchner: Exciting Genetic Discoveries Lead to Life-Changing CMT Therapies." CMT4Me Podcast. Charcot-Marie-Tooth Association, (October 27). Accessed November 2021. https://cmt4me.buzzsprout.com/1849476/9429530-dr-stephan-zuchner-exciting-genetic-discoveries-lead-to-life-changing-cmt-therapies Warner, L. E., Mancias, P., Butler, I. J., McDonald, C. M., Keppen, L., Koob, K. G., & Lupski, J. R. 1998. "Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies." Nature genetics 18 (4): 382–384. doi:https://doi.org/10.1038/ng0498-382 Zhao, C., Takita, J., Tanaka, Y., Setou, M., Nakagawa, T., Takeda, S., Yang, H. W., Terada, S., Nakata, T., Takei, Y., Saito, M., Tsuji, S., Hayashi, Y., & Hirokawa, N. 2001. "Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bbeta." Cell 105 (5): 587–597. doi:https://doi.org/10.1016/s0092-8674(01)00363-4 Züchner, S., Mersiyanova, I. V., Muglia, M., Bissar-Tadmouri, N., Rochelle, J., Dadali, E. L., Zappia, M., Nelis, E., Patitucci, A., Senderek, J., Parman, Y., Evgrafov, O., Jonghe, P. D., Takahashi, Y., Tsuji, S., Pericak-Vance, M. A., Quattrone, et al. 2004. "Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A." Nature genetics 36 (5): 449–451. doi:https://doi.org/10.1038/ng134

Exploring The Inheritance Patterns of Charcot-Marie-Tooth Disease Charcot Marie Tooth disease, or CMT for short, is a rare, complex, heterogeneous inheritable peripheral polyneuropathy. Although rare, CMT is the most commonly inherited peripheral nervous system disease. First named for the three physicians who first described the disease in 1886, Jean-Martin Charcot [shahr’kō] (1825-1893), Pierre Marie (1853-1940), both from France, and Howard Henry Tooth (1856-1925) from England, CMT as a modern-day disease name has morphed into an umbrella term that represents a wide variety of inherited sensory and/or motor neuropathies. CMT is inheritable because each of the more than 100 CMT subtypes are caused by mutations in genes that are inheritable. We normally have two copies of every gene, with only a few exceptions. We inherit one copy from each parent. Any mutations present in the gene copy inherited from each parent are also inherited. How CMT is inherited and the chances of inheriting CMT from a parent are solely dependent on the underlying CMT-causing mutation itself. How CMT is inherited is called an inheritance pattern, and there are five inheritance patterns in all. The five inheritance patterns are autosomal dominant, autosomal recessive, X-Linked dominant, X-Linked recessive, and mitochondrial inheritance. What’s it All Mean? In genetics and inheritance, dominant refers to a gene with one mutation and recessive refers to a gene that has two mutations. Autosomal refers to a gene that lives on any of the numbered chromosomes (1-22)—the autosomes. X-Linked refers to a gene that lives on the X-chromosome. Mitochondrial inheritance refers to a gene that lives in the mitochondrial genome. Gender is of no consequence to autosomal inheritance, whether dominant or recessive. Chromosomal gender is a factor for X-Linked inheritance and for mitochondrial inheritance. Chromosomal females have two X-chromosomes, having inherited one from each parent. Because there are two halves, just as there are with each of the autosomes, the rules governing X-Linked inheritance for XX-females are the same as they are for autosomal inheritance, whether dominant or recessive. X-Linked inheritance rules are different for chromosomal males. The rules are different because chromosomal males have only one X-chromosome, having inherited it from their mother, only from their mother, and never from their father. In place of a second X-chromosome, chromosomal males have a Y-chromosome, having inherited this from their father, only from their father, and never from their mother. This distinction will become evident later on. Mitochondrial inheritance is strictly maternal, that is, from mother to child, regardless of the children’s gender. There is some recent research suggesting mitochondrial inheritance is also paternal, but concrete evidence seems elusive. Autosomal Dominant Autosomal dominant inheritance is the most straightforward inheritance pattern. CMTers whose CMT is autosomal dominant in inheritance have a 50/50 chance of passing on their CMT to each of their children, regardless of gender and regardless of their children’s gender. Autosomal dominant inheritance means that the gene with the CMT-causing mutation lives on an autosome and the gene has a CMT-causing mutation in only one of its two copies. At conception, either the copy of the gene with the CMT-causing mutation will be passed on from the parent who has it, or the copy without the mutation will be passed on. It’s a 50/50 randomization. The second copy of the gene, which would not have a CMT-causing mutation, would be passed on/inherited from the other parent. A CMTer whose CMT is autosomal dominant in inheritance has a CMT-causing mutation in one of the two associated gene copies and the other copy has no CMT-causing mutation. Autosomal recessive inheritance isn’t as straightforward. Autosomal Recessive – Sarah’s Story A CMTer whose CMT is autosomal recessive in inheritance has a CMT-causing mutation in both copies of the associated gene, and the gene lives on one of the autosomes. When inherited, one copy of the mutation was inherited from the mother, and the other was inherited from the father. A CMTer whose CMT is autosomal recessive in inheritance usually will be the first one in the family to have CMT. This is because the associated gene must have two mutations, and when there is only one, it does not cause CMT. It’s not uncommon for people to have only one copy of an autosomal recessive CMT-causing mutation and not know it. Having just one copy does not cause CMT, as having both copies is required for causing the related autosomal recessive CMT. From each parent, we inherit one copy of each gene that lives on any of the autosomes. Both parents each have two copies of these autosomal genes, and the copy of each that is passed on/inherited is completely randomized. Hypothetically, two parents each have one copy of a CMT-causing mutation in their PRX gene. The PRX gene lives on chromosome 19. Because each have only one copy of this mutation, neither have CMT. They don’t even know they each have this mutation. These two parents then have two children, Sarah, and Billy. Sarah has CMT4F. Billy does not. Why? CMT4F is caused by autosomal recessive mutations in the PRX gene. CMTers who have CMT4F, have a mutation in both copies of their PRX gene. Sarah has CMT. Her genetic testing revealed that she has a CMT-causing mutation in each copy of her PRX gene, and therefore has CMT4F. Sarah was the first in the family diagnosed. Nobody in the family had ever heard of CMT, and nobody else has any hint of CMT. Following Sarah’s genetic confirmation, her brother, Billy, and both parents underwent genetic testing. Genetic testing revealed both parents each have a CMT-causing mutation in one copy of their PRX gene, but the other copy each parent has does not. Billy’s testing revealed he doesn’t have any CMT-causing mutations in his PRX gene. Sarah’s parents each have one copy of an autosomal recessive CMT-causing mutation in their PRX gene. Neither parent has CMT. Neither parent has CMT because having only one copy of an autosomal recessive CMT-causing mutation is insufficient to cause the associated autosomal recessive CMT. The autosomal recessive CMT in this case is CMT4F. Each parent having only this one copy of this mutation means they are each a genetic carrier of this mutation but not of CMT, and not of CMT4F. Both parents, each having this mutation in only one copy of their PRX gene, had a 50/50 chance of passing on their one copy to Sarah, and they each had a 50/50 chance of passing on their one copy to Billy. Overall, both Sarah and Billy had a 25% chance of inheriting both CMT-causing mutations (one from each parent). Sarah randomly inherited her mother’s PRX gene copy that has the mutation instead of the PRX gene copy that does not, and she randomly inherited her father’s PRX gene copy that has the mutation instead of the PRX gene copy that does not. Billy, on the other hand, inherited the opposite PRX gene copies from each parent. A CMTer who has an autosomal recessive CMT has a CMT-causing mutation in each copy of the associated gene. Because of this, each of their children will inherit one copy of this CMT-causing mutation, regardless of gender. Sarah’s children will each randomly inherit one of her PRX gene copies. Because both copies have a CMT-causing mutation, each of Sarah’s children will inherit from Sarah one copy of her CMT-causing mutation. However, Sarah’s children will not have Sarah’s autosomal recessive CMT. Instead, they will be a genetic carrier of one copy of this CMT-causing mutation, but not of CMT, just like Sarah’s parents. Billy, on the other hand, has no CMT-causing mutations in either of his two PRX gene copies. He can’t pass on to his children genetic mutations he does not have. Therefore, his children will not be a genetic carrier of his family’s autosomal recessive CMT-causing PRX gene mutation. X-Linked Inheritance X-Linked CMT is so called because the gene with the CMT-causing mutation lives on the X-chromosome. Unlike autosomal CMT, chromosomal gender is a factor with X-Linked inheritance patterns. Chromosomal gender is a factor because chromosomal females have two X-chromosomes, inheriting one from each parent while chromosomal males have only one X-chromosome, inheriting it only from their mother and never from their father. In place of a second X-chromosome, chromosomal males have a Y-chromosome, inheriting it only from their father and never from their mother. Chromosomal female = XX, and chromosomal male = XY. This is the easiest part of X-Linked inheritance, whether X-Linked dominant or X-Linked recessive. Chromosomal females who have X-Linked dominant CMT have a CMT-causing mutation in one copy of a gene that lives on the X-chromosome. Their other copy of the associated gene, which lives on their second X-chromosome, does not have a CMT-causing mutation. Chromosomal females who have X-Linked recessive CMT have a CMT-causing mutation in both copies of the associated gene—one gene copy on each of their two X-chromosomes. For chromosomal females who have X-Linked CMT, whether dominant or recessive, the rules that govern the inheritance pattern are the exact same as they are for autosomal inheritance, whether dominant or recessive, respectfully. There is no difference between autosomal dominant and X-Linked dominant, or autosomal recessive and X-Linked recessive, except for where the gene lives—on an autosome or on the X-chromosome. The rules, however, are different for chromosomal males who have X-Linked CMT, whether dominant or recessive. Chromosomal males who have X-Linked CMT have a CMT-causing mutation in a gene that lives on the X-chromosome. Chromosomal males have only one X-chromosome. They don’t have a second X-chromosome for a second copy of the associated gene. For X-Linked dominant CMT, this is easy. However, despite having only one copy of each X-Linked gene, and despite recessive inferring a mutation in each of two copies of a gene (not one), chromosomal males can have X-Linked recessive CMT. Because chromosomal males have only one X-chromosome and therefore only one copy of each X-Linked gene, having an X-Linked recessive CMT-causing mutation in their only copy of the associated gene is sufficient for causing the associated X-Linked recessive CMT. In a sense, for chromosomal males, X-Linked CMT isn’t dominant or recessive in inheritance. It’s just simply X-Linked inheritance. The genetic properties of dominant and recessive don’t apply, per se, because chromosomal males have only one X-chromosome and therefore only one copy of each X-Linked gene. Chromosomal males who have X-Linked CMT will pass their X-Linked CMT-causing mutation to each of their chromosomal female children without exception. Conversely, they will not and cannot pass it onto any of their chromosomal male children. Chromosomal males pass on their only X-chromosome to their chromosomal female children, and they pass on their Y-chromosome to their chromosomal male children. If the X-Linked CMT is an otherwise X-Linked recessive CMT, their chromosomal female children would be a genetic carrier of this one X-Linked recessive mutation, but not CMT, just as though it was an autosomal recessive CMT. If the X-Linked CMT is an otherwise X-Linked dominant CMT, their chromosomal female children would then also have the associated X-Linked dominant CMT. A chromosomal female who is a genetic carrier of one copy of an X-Linked recessive CMT-causing mutation has a 50/50 chance of passing on this mutation to each child. A chromosomal female child who inherits this one copy of an X-Linked recessive CMT-causing mutation will also be a genetic carrier of this mutation, but not of CMT. A chromosomal male who inherits this one copy of an X-Linked recessive CMT-causing mutation will have the associated CMT because they have only one X-chromosome and therefore only one copy of each X-Linked gene and having only one is sufficient to cause the associated X-Linked recessive CMT. De Novo – Cori’s Story CMT is inheritable, yes. One does not have to have inherited it in order to have it though. A CMTer whose CMT was not inherited from a parent has CMT that is caused by a spontaneous and random gene mutation that occurred at or shortly after conception. CMT that was not inherited from a parent is called a de novo, or new case. A de novo CMT case is not uncommon. Many CMTers who are the first in their family diagnosed are usually a de novo case. There are situations in which not everything is as it appears though. It’s not uncommon for recessive CMT-causing genetic mutations to go undetected. When a CMTer has a de novo recessive CMT, whether autosomal or X-Linked, it might not be a truly de novo case. Often, as with Sarah’s story up above, a first-in-the-family CMTer who has a recessive CMT inherited one-half of their recessive CMT-causing mutation from each parent. The parents usually have no idea they have these mutations. Usually, genetic testing in these situations reveals that each parent has one copy of the recessive CMT-causing mutation, and this genetically explains how the CMTer came to have their recessive CMT, like how Sarah up above did. Sarah’s wasn’t a random spontaneous mutation. However, there are times when this is not the genetic case. Cori is genetically confirmed to have CMT4C. CMT4C is caused by autosomal recessive mutations in the SH3TC2 gene. Cori, like many CMTers who have recessive CMT, is the first diagnosed in her family. No other family members have any signs, symptoms, or even the slightest inkling of CMT. Family genetic testing revealed that Cori’s mother has one of Cori’s two SH3TC2 mutations, and Cori’s father doesn’t have any mutations in this gene. One of Cori’s siblings has the same mutation as their mother, and the others have no mutations in this gene. How is it then that Cori has CMT4C since only her mother has only one CMT-causing mutation, and why does her mother and one sibling not have CMT? Autosomal recessive CMT is caused by a gene that lives on an autosome having two CMT-causing mutations, with one mutation on each of the gene’s two copies. The SH3TC2 gene lives on chromosome 5. CMT4C is caused by this gene having two CMT-causing mutations, with one mutation on each of the gene’s two copies. These things add up the make CMT4C autosomal recessive in inheritance. Cori’s mother has just one of these two CMT-causing mutations. Having just one is insufficient to cause CMT. One copy of her SH3TC2 gene has a CMT-causing mutation, and the other copy does not. This means that each of her children had a 50/50 chance of inheriting this one mutation. Each of her children would either get her SH3TC2 copy with the mutation, or the copy without. Cori and one of her siblings inherited this one mutation, and Cori’s other sibling did not. Why is Cori the only one in her family with CMT? Cori’s mother, like Sarah’s, is a genetic carrier of one copy of an autosomal recessive CMT-causing mutation. Cori’s one sibling is also. Neither have CMT because their one mutation in the SH3TC2 gene is insufficient to cause CMT. It takes having two mutations in this gene to cause CMT. Cori also inherited her mother’s one SH3TC2 mutation. Cori has CMT. Specifically, Cori has CMT4C. Cori inherited only one copy of her CMT-causing mutation from her mother. Cori’s father has no CMT-causing mutations in his SH3TC2 gene. This means that Cori’s second CMT-causing mutation in her SH3TC2 gene occurred randomly spontaneously on its own at or shortly after conception. Cori’s second, non-inherited SH3TC2 mutation is a de novo mutation. Because Cori has this de novo mutation as the second CMT-causing mutation in her SH3TC2 gene, but other family members have only one CMT-causing mutation in this gene, Cori is the first and the only member of her family to have CMT. Because Cori has two mutations, one in each of her two copies of the SH3TC2 gene, each of Cori’s children will randomly inherit one of Cori’s two mutations. Her children, however, will not have CMT, but will be a genetic carrier of one copy of an autosomal recessive CMT-causing mutation. Mitochondrial DNA – The Lonely One We have two genomes. One is nuclear DNA, or what is referred to as DNA, or regular DNA. The other is mitochondrial DNA. Nuclear DNA is found in the nucleus of all our cells. Hence, nuclear DNA. Nuclear DNA holds over 20,000 genes that are found on 23 pairs of chromosomes. This is the DNA everybody is familiar with. Mitochondrial DNA, on the other hand, is found in the mitochondria of our cells. Mitochondrial DNA contains only 37 genes. Thirteen of these genes are responsible for making enzymes involved in oxidative phosphorylation. Oxidative phosphorylation is a process that uses oxygen and simple sugars to create a chemical called adenosine triphosphate (ATP). ATP is mitochondria’s main energy source. There is one subtype of CMT, ATP6-associated CMT (ATP6-CMT), caused by mutations in the ATP6 gene. The ATP6 gene lives in mitochondrial DNA. Can you guess why the gene is named ATP6? Because this gene lives in mitochondrial DNA, the inheritance pattern of ATP6-CMT is mitochondrial inheritance. Mitochondrial DNA is inherited from only the mother, never from the father (refer to the earlier mention), and a mother passes on her mitochondrial DNA equally to each of her children. In Closing There are no CMT genes and CMT isn’t about genes, per se. Rather, CMT is about mutations in genes. The term given to describe a gene that has a CMT-causing mutation is CMT-associated gene. An argument can be made that a gene with a CMT-causing mutation constitutes a CMT gene, but it comes down to personal preference. CMT is an extremely complex and diverse disease, and the genetic causes are just as diverse. While CMT is the most commonly inherited rare disease, a CMTer does not have to have inherited it in order to have it. How CMT is inherited is determined solely by the underlying responsible genetic mutation. The underlying responsible genetic mutation not only determines the inheritance pattern, but also determines the specific subtype. As of publication, there are 120 discovered CMT-associated genes plus five additional chromosomal locations suspected of having a gene with a CMT-causing mutation, but the exact gene has not yet been identified. These discoveries account for 155 individual CMT subtypes that are organized into 14 Type categories. Autosomal dominant CMT encompasses 81 subtypes. Autosomal recessive CMT makes up 67 subtypes. X-Linked dominant CMT has 3 subtypes. X-Linked recessive has 6 subtypes. One CMT subtype is inherited via mitochondrial DNA. To date, there are no discovered CMT-associated genes found on chromosome 13 nor on the Y-chromosome. Should scientists discover a CMT-associated gene on the Y-chromosome, it would constitute a chromosomal male-to-chromosomal male inheritance only, as only chromosomal males have a Y-chromosome. The genetics of CMT are forever growing as are the understandings of CMT genetics. While all causes are not yet known resulting in the causes of CMT not yet being fully described or understood, the inheritance patterns of CMT are well understood and described. Scientists, physicians, clinicians, and CMT genetic experts don’t necessarily need to know the exact genetic cause of a CMTer’s CMT to identify its inheritance pattern. A carefully reviewed detailed family history can reveal a likely inheritance pattern when the investigator has the specialized training needed to understand and see the patterns. Once the underlying genetic mutation is identified, however, its inheritance pattern and what the inheritance pattern potentially means for the CMTer comes to full light, as the underlying responsible mutation determines the CMT’s inheritance pattern. About the Author Kenneth Raymond is a CMTer who was first diagnosed with Type 1 CMT in late 2002, at the age of 29. He was genetically confirmed to have CMT1A a year later. Kenneth has devoted his life since diagnosis to studying, researching, and learning all things CMT, with an emphasis on the genetics of CMT as they relate to everyday CMTers. As a member of the Charcot-Marie-Tooth Association’s Advisory Board, Kenneth is a CMT genetics expert and is a CMT advocate who is committed to raising CMT awareness through fact-based information rooted in the latest understandings of CMT.

Clarifying the Misconceptions of CMT-Related Respiratory Impairment Kenneth Raymond and Ashraf Elsayegh, MD, FCCP, FAASM When the respiratory muscles are affected by CMT, the result is a very specific kind of respiratory impairment. This respiratory impairment, however, is shrouded in misconceptions and misunderstandings that often lead to poor treatment choices and therapeutic outcomes. Charcot-Marie-Tooth Association (CMTA) Advisory Board member and CMT pulmonology expert Ashraf Elsayegh, MD, FCCP, FAASM, Division of Pulmonary/Critical Care, Cedars Sinai Medical Center, Associate Clinical Professor of Medicine UCLA School of Medicine, explains that respiratory impairment is grouped into two basic categories: diseases of lung tissue (lung disease), and diseases affecting the chest cavity (thoracic cavity respiratory disease). CMT-related respiratory impairment is a respiratory disease of the thoracic cavity, whereas diseases such as COPD are diseases of lung tissue, the two are not related nor connected, and one does not cause the other. Understanding the fundamental differences between lung disease and thoracic cavity disease is key to achieving successful therapeutic outcomes. Charcot Marie Tooth disease, or CMT for short, is an expansive and complex inheritable neuromuscular disease that can affect motor nerves, sensory nerves, and/or autonomic nerves, or any combination of these. The motor nerves are the peripheral nerves that control skeletal muscle function. The sensory nerves are the peripheral nerves that carry sensory signals (touch, temperature, etc.) from all parts of the body to the spinal cord. The autonomic nerves are the peripheral nerves that control automatic processes, such as heart rate, organ function, etc. Because CMT affects the nerves that control skeletal muscle function, CMT has the potential to affect every skeletal muscle group, including the respiratory muscles. And when CMT does, it causes muscle weakness. The Basics When CMT causes respiratory impairment, it is called CMT-Induced Neuromuscular Respiratory Muscle Weakness. This is a very specific type of respiratory impairment caused by weakened respiratory muscles. Respiratory muscles are used to expand and contract the chest cavity (thoracic cavity), which, in turn, facilitates breathing. When a CMTer’s respiratory muscles become weakened due to the neuromuscular disease affects of CMT, the ability to fully expand the chest cavity so that the lungs can completely inflate and fully fill with air becomes impaired. The result is an impairment of the ability to draw a full breath, and this leads to shortness-of-breath, or SOB for short. The medical term for this scenario is hypoinflation. Hypoinflation is a condition in which the lungs don’t fully inflate when drawing a breath. CMTer’s who have CMT-induced neuromuscular respiratory muscle weakness have an impaired ability to fully inflate their lungs as the result of a weakening of the muscles whose job it is to fully expand the chest cavity when taking a breath. Dr. Elsayegh explains that this type of hypoinflation is the result of weakened respiratory muscles and is not the result of lung disease. This is an important distinction. When CMT causes respiratory symptoms, the root cause is weakened respiratory muscles. The cause is not with the lungs or with the airways. CMT is not a disease of the lungs and nor is CMT a disease of the airways. Restrictive vs. Obstructive vs. Neuromuscular A widely held misconception is that CMT can cause both restrictive lung disease and obstructive lung disease, and CMT-related respiratory impairment is itself a restrictive lung disease. CMTers have even been diagnosed by their doctor with “CMT-Related Restrictive Lung Disease.” Full disclosure: I have until authoring this article understood and described CMT-related respiratory impairment to be a restrictive lung disease. Full stop. CMT does not cause restrictive lung disease, per se (restrictive lung disease can occur as a consequence of the effects of neuromuscular respiratory muscle weakness), and CMT-induced neuromuscular respiratory muscle weakness is not a restrictive lung disease. As Dr. Elsayegh explains, CMT-induced neuromuscular respiratory muscle weakness is not a restrictive lung disease or an obstructive lung disease, and it is not any kind of lung disease. To fully understand this, we have to dive into the fundamental differences between each of these. Restrictive lung disease is a disease of lung tissue in which the lungs cannot fully expand due to a stiffening or hardening of lung tissue. Examples of restrictive lung disease include sarcoidosis, pulmonary fibrosis, and lung disease that can occur as a consequence of scoliosis. Each of these restrict the lungs from fully inflating—a hardening of the lungs. Obstructive lung disease, commonly referred to as Chronic Obstructive Pulmonary Disease, or COPD for short, is a disease of lung tissue and airways in which the lungs can’t fully empty on exhale. COPD is a blanket term for several lung diseases that are each an obstructive lung disease. Examples of obstructive lung disease are emphysema, chronic bronchitis, and asthma. Each of these either obstruct the airways inside the lungs and slow down the movement of air within the lungs or destroy the alveoli resulting in an inability to fully empty. This results in air becoming trapped in the lungs before taking the next breath—a condition called air trapping. COPD also results in hyperinflation, a condition in which the lungs become much larger in size. Neuromuscular respiratory muscle weakness causes a type of respiratory impairment that is the result of weakened respiratory muscles due to the effects of a neuromuscular disease. The muscle weakness can progress enough to cause an impairment of the ability to fully expand the thoracic cavity causing the lungs to not fully inflate with each breath. This type of respiratory impairment is not caused by diseased or damaged lung tissue but is caused by weakened muscles. Examples of neuromuscular diseases that can cause neuromuscular respiratory muscle weakness are CMT, ALS (Lou Gehrig’s disease), and Myasthenia Gravis. Is It CMT, or…? Restrictive lung disease, obstructive lung disease, and CMT-induced neuromuscular respiratory muscle weakness each cause SOB. How each cause SOB is different from one another. Restrictive lung disease causes SOB by impairing the ability to fully inflate the lungs due to lung tissue losing its elasticity and expandability. Obstructive lung disease causes SOB by impairing the ability to fully empty the lungs on exhale due to the airways inside the lungs becoming obstructed (usually by mucus), due to inflammation and constriction of the airways, or due to loss of lung alveoli. CMT-induced neuromuscular respiratory muscle weakness causes SOB by impairing the ability of the chest cavity to fully expand, which then limits how much the lungs inflate with each breath. When a CMTer has respiratory symptoms, such as SOB, how can a pulmonologist know if it’s due to CMT or something else? A Pulmonary Function Test, or PFT for short, is a test that pulmonologists use for measuring pulmonary function, just as the name suggests. Specifically, a PFT is used to measure how well the respiratory system is working. A PFT measures several different parameters. The data garnered from these parameters tell the pulmonologist the overall condition of the respiratory system. The data can show if there is respiratory impairment, the data can show the severity of any present respiratory impairment, and the data can show if any present respiratory impairment is restrictive or obstructive, The data can also indicate the presence of respiratory muscle weakness. In an oversimplification, on PFT’s, restrictive lung disease will show hypoinflation (the lungs not fully inflating) and obstructive lung disease will show air trapping (the lungs not fully emptying). Because of its associated hypoinflation, explains Dr. Elsayegh, CMT-induced neuromuscular respiratory muscle weakness will exhibit a restrictive lung disease pattern on PFT's. This likely is from where the confusion and misconceptions arise regarding the type of respiratory impairment CMT can cause. CMT-induced neuromuscular respiratory muscle weakness being considered a restrictive lung disease likely has its roots in the restrictive lung disease pattern exhibited on PFT’s. This type of respiratory impairment exhibits a restrictive lung disease pattern, Dr. Elsayegh explains, because CMT-induced neuromuscular respiratory muscle weakness impairs the ability to fully expand the chest cavity which in turn limits how much the lungs are able to inflate with each breath. This mimics restrictive lung disease on a PFT. However, because CMT does not affect the lungs themselves, and instead affects the muscles used for breathing, the type of respiratory impairment CMT can cause is not restrictive lung disease. Instead, it is neuromuscular respiratory muscle weakness. Knowing the difference between the two is paramount to successful treatment outcomes. Restrictive and obstructive lung disease both cause SOB. Both can cause a lower oxygen saturation (SpO2) in the blood (hypoxemia) leading to a condition called hypoxia. Both can cause carbon dioxide retention leading to a condition called hypercapnia. Restrictive lung disease causes hypoinflation—not getting enough air in. Obstructive lung disease causes hyperinflation—air gets in, but not all of it gets back out. These things are caused by damage to the airways inside the lungs. Neuromuscular respiratory muscle weakness causes a hypoinflation condition similar to restrictive lung disease, but because the lungs themselves are not diseased, Dr. Elsayegh explains, the condition is not truly a restrictive lung disease. However, it is imperative to understand that neuromuscular respiratory muscle weakness can also cause hypercapnia. Common treatment approaches for restrictive and obstructive lung disease are basically oxygen as needed, an inhaler or two, and nebulizer treatments. Oxygen is used to treat hypoxemia/hypoxia, and inhalers/nebulizer treatments are used to open the airways and to prevent them from closing up. These things make sense, right? If you can’t breathe right, do the therapeutic things that are designed to make you breathe right. It makes perfect sense. However, when CMT has caused the respiratory impairment, conventional therapy approaches are contraindicated. The reasons are rooted in the underlying cause of the impairment. CMT-induced neuromuscular respiratory muscle weakness, Dr. Elsayegh explains, typically will not cause lower oxygen levels, but can lead to higher carbon dioxide levels. This might seem counterintuitive, but the reasons for this are straightforward. Respiratory impairment caused by neuromuscular muscle weakness has no adverse effect on lung tissue or the airways inside the lungs. The lungs retain their ability to efficiently pull adequate amounts of oxygen into the bloodstream from what is able to be inhaled with each breath, even if the lungs do not fully inflate. While oxygen stays normal, carbon dioxide can rise because of an impairment of the ability to efficiently filter out and exhale adequate amounts of carbon dioxide. In order for the lungs to empty out carbon dioxide efficiently, the lungs have to fully exhale an adequate amount of air. The lungs can only exhale the amount of air that is inhaled. If the lungs can’t fill with an amount of air that is needed to adequately pull enough carbon dioxide from the bloodstream, too much carbon dioxide can remain, causing carbon dioxide levels in the body to rise. This is hypoinflation at work. An inherent adverse effect of hypoinflation that is caused by neuromuscular respiratory muscle weakness is not lower oxygen, but higher carbon dioxide. Remembering that hypoinflation causes shortness-of-breath, conventional wisdom states oxygen is needed. Can’t breathe, need oxygen, right? Not in this case. Because hypoinflation caused by neuromuscular respiratory muscle weakness does not cause lower oxygen levels, Dr. Elsayegh explains, giving oxygen when not needed can lead to higher carbon dioxide production in the body thereby by causing carbon dioxide levels to rise even higher, and possibly to unsafe levels. Respiratory muscle weakness does not adversely affect the inside of the lungs. Respiratory muscle weakness does not impair the lungs’ ability to adequately oxygenate the blood and oxygen levels will remain normal when respiratory impairment is caused by neuromuscular respirator muscle weakness. Although CMT-induced neuromuscular respiratory muscle weakness mimics restrictive lung disease on PFT, monitoring oxygen levels during the test can reveal that the underlying root cause of any present impairment is neuromuscular respiratory muscle weakness rather than with damaged lung tissue. Another indicator that a CMTer’s respiratory impairment is caused by neuromuscular respiratory muscle weakness is if there is a significant change in any indicated hypoinflation when supine (lying flat). Typically, when lying flat in the presence of neuromuscular respiratory muscle weakness, a CMTer will have a much tougher time breathing, and especially breathing in, leading to an increase in SOB. An increased SOB when lying flat is called orthopnea. A PFT performed to include an assessment also when lying flat can highlight this difference, providing further evidence that the exhibited restrictive lung disease pattern might actually be respiratory impairment caused by neuromuscular respiratory muscle weakness. While CMT does not cause restrictive lung disease, and CMT-induced neuromuscular respiratory muscle weakness is not restrictive lung disease, there is one caveat we need to discuss. We’ve established that CMT does not cause restrictive lung disease and that CMT-induced neuromuscular respiratory muscle weakness is not a restrictive lung disease. There is one situation, however, in which CMT can contribute to or even lead to restrictive lung disease. It’s well understood that CMT can cause scoliosis. Sometimes, the scoliosis can become severe enough to affect the lungs. Scoliosis can sometimes become severe enough to reduce the size of the physical space of the chest cavity. This can cause a change in the shape of the chest cavity and can significantly reduce the volume of the chest cavity. When scoliosis has become severe enough to cause this, the amount of space the lungs have to inflate becomes limited. Dr. Elsayegh explains that this can lead to restrictive lung disease. While CMT in this case might have caused the scoliosis and contributed to its progression, CMT did not directly attack the lung tissue. Rather, the restrictive lung disease is the result of a non-lung disease process acting on the lungs. This scoliosis-induced restrictive lung disease can occur with or without CMT-induced neuromuscular respiratory muscle weakness. When scoliosis becomes severe enough to cause respiratory impairment, surgery to correct the scoliosis might be a viable treatment option. When both scoliosis-induced restrictive lung disease and CMT-induced neuromuscular respiratory muscle weakness are present, the neuromuscular respiratory muscle weakness must be treated in addition to the scoliosis-induced restrictive lung disease. One cannot be successfully treated without treating the other. Breathe Easy, Young Padawan CMT has no known effective treatment that directly treats the disease itself. However, many of the things that CMT causes can successfully be treated, and this includes CMT-induced neuromuscular respiratory muscle weakness. The treatment approaches are different, however, than they are for diseases of lung tissue such as COPD. Restrictive and obstructive lung disease treatments target lung tissue—the airways inside the lungs that are diseased or damaged. For CMT-induced neuromuscular respiratory muscle weakness, the treatment approaches target the weakened muscles—the muscles are the culprit, not the lungs. Inhalers, nebulizer treatments, and supplemental oxygen typically have no effect on CMT-induced neuromuscular respiratory muscle weakness because these things do not treat respiratory muscles that have been weakened by a neuromuscular disease. CMT specialists, including Dr. Elsayegh, prefer to treat CMT-induced neuromuscular respiratory muscle weakness with what is called non-invasive ventilatory support. A non-invasive ventilator, or NiV for short, is a BiPap, only better. Most have heard of CPAP and BiPap. Both are commonly used to treat obstructive sleep apnea (OSA). CPAP, which stands for Continuous Positive Airway Pressure, is a small tabletop machine that outputs air at a specified pressure, through a hose connected to a mask that is worn by the person. BiPap, which stands for Bi-Level Positive Airway Pressure is the same, except this machine will drop the pressure down for exhaling. Both are designed to treat OSA by working to keep the upper airway open when sleeping. NiV takes things a step farther by providing what’s called volume support. A non-invasive ventilator is a small tabletop machine just like a CPAP and BiPap, complete with a hose connecting the machine to a mask that is worn by the person. It even looks like a CPAP or BiPap set up. An NiV can be used to treat OSA, and is the preferred treatment for CMTers who have OSA, but an NiV adds additional capabilities CPAP and BiPap do not have. In an oversimplification, NiV provides volume support by delivering a volume of air that is equal to the tidal volume of the lungs. Lung tidal volume is the amount of air the lungs need to move in or out of the lungs with each respiratory cycle in order to maintain adequate oxygenation. A respiratory cycle is one breath in, one breath out. The machine delivers a consistent volume of air with each respiratory cycle. The volume of air, being equal to the lungs’ tidal volume, helps the lungs to inflate more fully, and with less muscle effort, thereby easing the overall workload of the respiratory muscles. With some of the respiratory muscle workload being alleviated, the muscles are given a break. Because the muscles don’t have to work as hard, breathing is easier. NiV isn’t just for sleeping though. NiV can also be used during the day, and many CMTer’s who use NiV, including this CMTer, use it during the day when needed. Sometimes, the respiratory muscles just need a rest, and NiV can provide that assistive rest. The respiratory muscles facilitate breathing. They also are involved in coughing. When the respiratory muscles weaken, a weak cough can develop. A weak cough can impede the natural ability to clear secretions. Not being able to clear secretions can lead to increased SOB, respiratory infections, pneumonia, and other adverse health effects. A device called a cough assist can help with clearing secretions which in turn helps to prevent further illness. Along with NiV, a cough assist device is a common therapy for CMTers who have CMT-induced neuromuscular respiratory weakness. The Specialized Specialist While CMT can cause respiratory impairment, not every CMTer will develop it. CMTers, whether they have CMT-induced neuromuscular respiratory muscle weakness or not, can also develop diseases that effect lung tissue, such as COPD or sarcoidosis for example. CMT does not cause these other respiratory diseases, of course, but CMT-induced neuromuscular respiratory muscle weakness can complicate the management of lung disease, and vice-versa. Being able to know the full extent and root cause of any present respiratory impairment is paramount, and a CMTer who has respiratory impairment of any kind is usually best served by a neuromuscular pulmonologist for getting to the root cause of the impairment. What is a neuromuscular pulmonologist? A neuromuscular pulmonologist is a pulmonologist who specializes in respiratory impairment that is caused by neuromuscular disorders that affect the respiratory system. Pulmonologists are highly trained and specialized doctors who treat people who have a wide range of respiratory conditions. A neuromuscular pulmonologist encompasses all of that training and specialized skill, then adds a neuromuscular component that other pulmonologists might not have. I don’t mean to discount the skill and expertise of pulmonologists. A pulmonologist who specializes in neuromuscular respiratory diseases though, has the specialized training, experience, and specialized skillset for recognizing and treating neuromuscular respiratory muscle weakness that CMT can cause, and that other pulmonologists might not recognize because of its similarities to restrictive lung disease. Treating CMT-induced neuromuscular respiratory muscle weakness as though it is restrictive lung disease ignores the neuromuscular respiratory muscle weakness and treats lung tissue that might not be diseased or damaged, and this can lead to a worsening of symptoms. A neuromuscular pulmonologist will know forthrightly how to recognize and treat these different components, and this can lead to better treatment outcomes for CMTers. Neuromuscular pulmonologists can be difficult to find. They are a rare specialist among specialists. Dr. Elsayegh’s advice for finding a neuromuscular pulmonologist is to simply start calling pulmonology offices. Ask them if the doctor sees neuromuscular patients. If they do, ask them how many neuromuscular patients they see in a week. If they see less than 25 neuromuscular patients, or so, per week, they likely will not have the neuromuscular experience that CMTers who have respiratory impairment need, and the CMTer should probably keep searching. Neuromuscular clinics who offer pulmonology care have neuromuscular pulmonology expertise and are ideal. There are even some CMT clinics, such as the CMTA’s Centers of Excellence CMT clinic at Cedars Sinai that offer respiratory care for CMTers. Dr. Elsayegh happens to be the neuromuscular pulmonologist who treats CMTers with respiratory impairment at this clinic. These clinics would be the preferred treatment centers, for obvious reasons. In Closing CMT is an extremely complex disease that can affect many things. While CMT can cause respiratory impairment, it doesn’t cause it for every CMTer. The severity of CMT-induced neuromuscular respiratory muscle weakness can be widely variable. The reasons for this are unknown. Published literature depicts CMT-induced respiratory muscle weakness as exceedingly rare. Anecdotal evidence, coupled with a growing case count of CMTers presenting with CMT-induced neuromuscular respiratory muscle weakness suggests that respiratory involvement in CMT is higher than published literature suggests. How high is unknown at publication as there doesn’t seem to be publicly available prevalence data. By anecdotal evidence in the CMT community, CMT-induced neuromuscular respiratory muscle weakness is likely under-diagnosed or often misdiagnosed as something it’s not (such as restrictive lung disease). Successful treatment outcomes for CMT-induced neuromuscular respiratory muscle weakness depend on proper diagnosis. Proper diagnosis requires a thorough understanding of the fundamentals of the type of respiratory impairment neuromuscular respiratory muscle weakness causes. A specialist who understands these fundamentals and who understands the nuances of neuromuscular respiratory muscle weakness, such as a neuromuscular pulmonologist, will have the experience and specialized training that a CMTer needs when respiratory impairment has developed. Treatments that target lung disease while ignoring a CMTer’s neuromuscular respiratory muscle weakness will likely be of no benefit, especially when there isn’t any present lung disease. A neuromuscular pulmonologist will know these differences and will know how to expertly treat the underlying neuromuscular respiratory muscle weakness. A CMTer who has CMT-induced neuromuscular respiratory muscle weakness can also additionally have lung disease. CMT does not cause lung disease, but when a CMTer has lung disease in addition to CMT-induced neuromuscular respiratory muscle weakness, both conditions must be treated together as separate conditions if treatment is to be successful. CMTers don’t have to suffer with breathing issues. There are many non-invasive treatment options available, and these treatments can give back a CMTer’s life. Would you like a copy of this article for yourself, or to share with friends and family, or to share with your doctor(s) and care team? You can download a free copy exclusively from the Charcot-Marie-Tooth Association by clicking here. About the Authors Ashraf Elsayegh, MD, FCCP, FAASM is a distinguished physician and researcher based in Los Angeles, California. With over 18 years of experience, Dr. Elsayegh is a foremost expert in the field of pulmonary medicine as it relates to neuromuscular disease. He currently practices at Cedars-Sinai Medical Center and is an associate clinical professor at UCLA School of Medicine. His clinical and research interests revolve around respiratory function in the neuromuscular patient with special interest in diaphragm dysfunction. Dr. Elsayegh has authored and published numerous articles and textbooks in the field of pulmonary medicine and pulmonary complications in neuromuscular patients. In addition, he has lectured worldwide on these topics. Dr. Elsayegh has been treating neuromuscular patients, including those with Amyotrophic Lateral Sclerosis (ALS) and Charcot-Marie-Tooth (CMT) for over 18 years. He is an adviser on numerous boards in the fields of pulmonary medicine, critical care medicine, sleep medicine, and neuromuscular disease. Kenneth Raymond is a CMTer who was first diagnosed with Type 1 CMT in late 2002, at the age of 29. He was genetically confirmed to have CMT1A a year later. He was subsequently diagnosed with CMT-induced neuromuscular respiratory muscle weakness in 2019. Kenneth has devoted his life since diagnosis to studying, researching, and learning all things CMT, with an emphasis on the genetics of CMT as they relate to everyday CMTers. As a member of the Charcot-Marie-Tooth Association’s Advisory Board, Kenneth is a CMT advocate who is committed to raising CMT awareness through fact-based information rooted in the latest understandings of CMT.

Decoding the Myth and Laying it to Rest The differences between what the two words represent help us to know which side of the argument is the accurate side. The looming question inherent in the argument is exceedingly easy to answer. Is CMT a type or form of Muscular Dystrophy, does CMT fall under the umbrella of MD, and is CMT classified as MD? The clear-cut easy answer is no, CMT is not any of these things, categorically. Well, then, what is CMT? CMT is many things. CMT is an inheritable peripheral neuropathy. CMT is a genetic neuromuscular disease. CMT is a peripheral polyneuropathy. CMT is a disease of the peripheral nervous system that exerts its effects on the muscles those nerves control. There are many different descriptors and many different acronyms that explain what CMT is. For everything that CMT is, CMT is not a muscle disease. How do we know this though? CMT is a disease of the peripheral nerves. Every cause of CMT is a mutation in a gene that codes a molecular process in the peripheral nerves. These mutations cause a disruption in the molecular process that the host gene controls in the peripheral nerves. This is the oversimplified way that CMT directly affects the nerves that control the muscles but does not directly affect the muscles themselves. For all the plethora of causes of CMT, none are a genetic mutation that disrupts a molecular process in muscle tissue. The muscles suffer because the nerves that control them are diseased, but not because the muscles are directly diseased. It’s quite an easy premise, yet so inherently complex. It doesn’t have to be quite so complex though. The word use that explains a component of the disease process of CMT helps to sort out how CMT is not a muscular dystrophy disease. Likewise, word use that describes a component of muscular dystrophy diseases helps to sort out how and why CMT is not any type of muscular dystrophy disease. The Root of The Matter CMT causes muscle atrophy. It’s a hallmark of CMT in especially the feet, lower legs, and hands. What is atrophy? Atrophy is muscle wasting, right? That’s easy. Atrophy has a specific medical definition though, just as does dystrophy. Atrophy and dystrophy both describe wasting, but each have very distinct medical definitions, and they are not interchangeable with one another. Atrophy describes tissue wasting that is the result of a process that is separate from that tissue. The muscle wasting in CMT, by definition, is atrophy because the wasting occurs as a result of a disease process in something that is not muscle tissue. Specifically, in CMT, that disease process is in the peripheral nerves, but the atrophy is in a different tissue than the peripheral nerves—skeletal muscle. Hence, the wasting is atrophy. There are three types of muscle atrophy, each with a different root cause. Physiologic atrophy is atrophy caused by not using the muscles enough. This can usually be reversed by proper diet and exercise. Pathologic atrophy is usually seen with aging and malnutrition/starvation. Neurogenic atrophy is muscle atrophy that occurs with injury to, or disease of, the nerve that controls the atrophied muscle. CMT causes neurogenic atrophy. The neurogenic atrophy is the result of the disease process within the peripheral nerves, but not because of a disease process within the muscle tissue. Neurogenic atrophy is the most severe of the three types of atrophy because muscle tissue lost to neurogenic atrophy is not recoverable. Often, CMTers can become sedentary as a result of disease progression. This brings about physiologic atrophy on top of the neurogenic atrophy that CMT already causes, thereby making matters worse for the CMTer. Physiologic atrophy can be overcome though, and even prevented via healthy diet and adequate proper exercise, even when neurogenic atrophy cannot be undone. Dystrophy, however, is different than atrophy. Like atrophy, dystrophy has a specific medical definition. Dystrophy describes tissue wasting that is the direct result of a disease process within the tissue that is wasting. With muscle dystrophy, or muscular dystrophy as it is often called, as opposed to muscle atrophy, the muscles themselves are directly diseased, and the muscle wasting is the direct result of the muscle tissue being diseased. In muscular dystrophy diseases, by definition, the muscle wasting is dystrophy because the muscle tissue itself is diseased, and that results in the muscle tissue wasting. Hence, the origin of the name itself, muscular dystrophy: skeletal muscle tissue wasting as a result of a disease process within the muscle tissue, and not from a disease process in a tissue that is outside of or separate from the muscle tissue. The Etymology Made Easy The root word of atrophy and dystrophy is trophy. The word “trophy” originates from the Greek word for food, “trophe.” Adding the negative prefix, “a,” gives us “atrophe,” meaning “lack of food,” thus giving rise to “atrophy:” wasting away due to lack of food. In CMT, skeletal muscle wastes away because the disease process in the peripheral nerves prevents the skeletal muscles from receiving proper signals that are required for the muscles to maintain adequate nutritional balance. In this context, the nerve signals are the food, and the nutritional balance is the amount of adequate healthy nerve signals the muscles need in order to properly function. The disease process in the nerves cause the muscles to waste. The wasting, by medical definition, is therefore atrophy. Building off of trophe, the prefix “dys” is the medical prefix for bad or difficult, as in “dysfunction,” meaning bad function, or as in “dyspnea,” meaning difficult breathing. Added to trophe, “dystrophe” means bad food or difficult nutrition, thereby giving rise to “dystrophy:” wasting away due to a dysfunction in the nutritional process. In muscular dystrophy, the disease process within the muscle causes the muscle tissue to waste from a dysfunction in the ability to process what the muscle tissue needs to maintain nutritional balance. In this context, the nerve signals are the food that need to be processed, and the mechanisms by which the muscle tissue processes this food in order to maintain its nutritional balance of adequate and healthy nerve signals is dysfunctional. Due to this contextual nutritional dysfunction within the muscle tissue, the muscle tissue wastes away. This type of wasting, by medical definition, is therefore dystrophy. From Where Does the CMT is MD Arise? The root of the misconception that CMT is a type of MD stems from the MDA, an organization, including CMT as a disease that it provides research funding and patient services for. The notion that this then qualifies or classifies CMT as muscular dystrophy is incorrect. The MDA clarifies this within the structure of how they categorize and classify the many diseases they “cover.” It may come as a surprise, too, that muscular dystrophy diseases represent only about 1/6th of the diseases that the MDA provides research funding and patient services for. Muscular Dystrophy as a disease is a group of eight diseases according to the Muscular Dystrophy Association. The MDA’s description of the Muscular Dystrophy disease classification reads, “The muscular dystrophies are a group of diseases that cause weakness and degeneration of the skeletal muscles.” The MDA classification in its entirety lists eight diseases as muscular dystrophies. These are Becker MD, the Congenital Muscular Dystrophies (CMD) as a single entry (Bethlem CMD, Fukuyama CMD, Muscle-Eye-Brain disease (MEBs), Rigid Spine Syndromes, Ullrich CMD, and Walker-Warburg syndromes (WWS)), Duchenne MD, Emery Dreifuss MD [not to be confused with Emery Dreifuss Syndrome – a connective tissue disorder], Fascioscapulohumeral MD, Limb-Girdle MD, Myotonic dystrophy (DM), and Oculopharyngeal MD. This is the exhaustive list of every muscular dystrophy the MDA includes. In an email, the MDA clarified for this discussion that there are only these eight muscular dystrophy diseases, and CMT is not one of the eight (emails provided in the Appendix). Beyond these eight muscular dystrophies in the MDA’s muscular dystrophy disease classification, are forty-three non-muscular dystrophy diseases that are organized into six separate disease type categories. I’m not going to list all forty-three diseases that are not muscular dystrophy diseases “covered” by the MDA. The six non-muscular dystrophy disease categories, however, are Motor Neuron Diseases, Ion Channel Diseases, Mitochondrial Diseases, Myopathies, Neuromuscular Junction Diseases, and finally Peripheral Nerve Diseases where we find CMT and GAN [GAN is a type of axonal CMT]. The MDA description of their classification of peripheral nerve diseases reads, “In peripheral nerve diseases, the motor and sensory nerves that connect the brain and spinal cord to the rest of the body are affected, causing impaired sensations, movement or other functions.” This is the MDA’s description of the category they place CMT into – a disease that affects the peripheral nerves. The MDA’s CMT webpage explains that CMT is a spectrum of nerve disorders, and the page makes no mention of CMT being a muscle disease nor a type of muscular dystrophy disease. The MDA themselves explain that CMT is not a muscular dystrophy disease. It is said that CMT “falls under the umbrella of MD.” I prefer not to use the term, “umbrella.” The use not only fosters confusion, but the statement itself has a fundamental inaccuracy. MD is an acronym that represents a group of diseases, and nothing more. This group of diseases is not a group that CMT belongs to. Therefore, the statement and all that it implies is inaccurate. It would be a more accurate statement to say that CMT “falls under the umbrella of the MDA.” It would be more accurate because the MDA, as a non-profit organization, includes CMT as one of the forty-three non-muscular dystrophy diseases that it provides research funding and patient services for, or “covers under its umbrella.” There is, however, a distinct and fundamental difference between MD—a group of muscle tissue diseases, and MDA—a non-profit organization. CMT causes muscle atrophy, but CMT does not cause muscle dystrophy. At its very core, the muscular dystrophy diseases are so called because the disease causes muscle dystrophy. Becker Muscular Dystrophy, for example, is a disease of muscle tissue, and the disease causes muscle dystrophy. The same holds true for each of the other seven muscular dystrophy diseases. The muscle wasting is medically defined as dystrophy because the tissue that is wasting is diseased. In contrast, CMT is a disease of the peripheral nerves that control the muscles. Because the muscle wasting in CMT is not caused by the muscle tissue itself being diseased, the wasting is medically defined as atrophy. By this very premise and definition, CMT does not meet the medical criteria to be a muscular dystrophy disease, and is therefore not a type of MD. If CMT is not MD, why does the MDA include it? The MDA was founded in 1950 by Paul Cohen, who had muscular dystrophy disease. The MDA explains that the organization was originally founded to focus on the eight types of muscular dystrophy diseases. Over the years, however, their mission has expanded to cover an additional forty-three non-muscular dystrophy neuromuscular diseases. CMT is one of these forty-three. CMT was included because CMT is a neuromuscular disease – neuro meaning nerve, and muscular meaning muscle, with the two combined defining a disease of the nerves that affects muscles—but not because CMT is a muscular dystrophy disease. I contacted the MDA for comment on whether CMT was a form of MD, and their public relations office responded with, “No Sir, CMT is not a form of muscular dystrophy,” and they explained that, “CMT is a peripheral neuropathy, which is a different disease than muscular dystrophy, both muscular dystrophy and CMT are types of neuromuscular disease, but they are not the same thing.” In Closing In the end, not only because of everything discussed here, but also because of many more criteria, CMT is not a type or form of any muscular dystrophy disease. Yes, the MDA is an organization who provides research funding and patient services for CMT. No, CMT does not fall “under the umbrella of MD.” MD and MDA are two completely different acronyms that are not interchangeable with one another. The MDA including diseases within their funding program does not make those diseases a muscular dystrophy disease, and this is especially true for CMT.

What is a Normal Result and What is a CMT Result? One of the best diagnostic tools that doctors have available to them for assisting with diagnosing Charcot Marie Tooth disease is a Nerve Conduction Study. A Nerve Conduction Study, or NCS for short, and sometimes coupled with Electromyogram, or EMG for short, provides a detailed snapshot of the nerve conduction characteristics of each peripheral nerve that the doctor assesses. These tests are part of the electrodiagnostic toolbox. The evaluating doctor chooses which peripheral nerves to assess based on many factors. Typically, when the doctor suspects CMT, and there is no established family history, they will opt to assess, or “look at” peripheral nerves in both the upper and the lower extremities—the arms and the legs. The approach, though, is usually symptom driven, and by doctor discretion. What information does the doctor gain by testing the nerves, and what makes these tests so diagnostically valuable? The diagnostic value of performing an NCS, and sometimes including an EMG in conjunction with the NCS, is such that the resulting data provides the necessary information the doctor requires for determining if the suspected CMT is even CMT at all, and if it is CMT, the type of CMT that it most likely is. When it is CMT, the electrodiagnostic data will reflect peripheral nerve conduction characteristics that are consistent with that which CMT is known to exhibit. Further, the data garnered can show if the CMT is a demyelinating type—CMT1, or if the CMT is an axonal type—CMT2, or if the CMT is somewhere in between—Intermediate CMT, and when it’s Intermediate CMT, interpreting the peripheral nerve conduction characteristics can be difficult. When the doctor determines that symptoms point to CMT, the data from an NCS can confirm what the doctor suspects. The data returned by the test does not represent a pass/fail, positive/negative, yes/no result though. Instead, the doctor interprets the data to mean something that is tangible. The doctor then has to answer the proverbial question. Is it CMT, or is it not CMT? When the doctor feels that clinical symptoms are consistent with CMT, and the doctor determines that the electrodiagnostic data is consistent with CMT, the consensus is that the doctor can diagnose CMT based upon this information. How, though, does the doctor know if the electrodiagnostic data suggest that the CMT is a Type 1, or if the CMT is a Type 2, or if the CMT is a type somewhere in between? The answer is in the data set. A Shocking Good Time Electrodiagnostics can be an invaluable diagnostic tool for doctors. However, just as with evaluating the clinical symptoms of CMT, electrodiagnostics cannot be relied upon as a stand-alone diagnostic tool. The nerve conduction characteristics of CMT are not absolute. While demyelinating CMT and axonal CMT can be discernible by their respective nerve conduction characteristics, there are many variables. With these variables in mind, there is a consensus on nerve conduction characteristics that are consistent with demyelinating CMT (CMT1), that are consistent with axonal CMT (CMT2), and then characteristics that are consistent with Intermediate CMT. Although there are many evaluated metrics in nerve conduction studies, there are four metrics that appear frequently in CMT electrodiagnostic reports and in published research/case study papers regarding CMT. The four metrics that frequently appear are Nerve Conduction Velocity, or NCV, Compound Muscle Action Potential, or CMAP, Sensory Nerve Action Potential, or SNAP, and F-Wave Latency, often referred to as F-Wave. All these fancy words might be intimidating, but they do not have to be. Before we can discuss what indicates CMT on nerve conduction study, we first must discuss what the fancy words are that make up the metrics we will be discussing. The metric that receives the most attention where CMT is concerned is Nerve Conduction Velocity, or NCV for short. NCV is the metric that represents the constant speed at which the nerve transmits a signal. The NCV value is expressed as meters per second, or m/sec. Compound Muscle Action Potential (sometimes called Compound Motor Action Potential, depending on author), or CMAP, is a measurement of how well a motor nerve, a nerve that controls a muscle, transmits a signal. The CMAP value measures in millivolts, or mV. Sensory Nerve Action Potential, or SNAP, is a measurement of how well a sensory nerve, a nerve that transmits sensory stimuli (touch, hot, cold, etc.), transmits a signal. The SNAP value measures in microvolts, or µV. F-Wave Latency, or F-Wave, is a measurement of the time it takes for a signal to travel the full length of a motor nerve. The F-Wave value measures in milliseconds, after 2 standard deviations, or 2-SD msec, and sometimes 2σ msec. The CMAP, SNAP, and F-Wave Latency metrics are each distance dependent, meaning that the value given comes from a specified length. See? Nothing to it. Now that we know what the metrics represent, we need to discuss the normal values of each before we can discuss the abnormal values that are consistent with CMT. Each of the parameters discussed have an associated normal value range. Normal NCV is ~60 m/sec in the upper extremities, and ~48 m/sec in the lower extremities. These values are the excepted normal for both motor and sensory nerves. The normal values of conduction velocity are easy to explain. The normal values for the other metrics are different for each nerve, and therefore, take a little longer to discuss. We will start with the normal values for the motor nerves. Starting in the lower extremities, the Peroneal Nerve has a normal CMAP amplitude of 2mV or higher, over a 9cm distance. The Peroneal Nerve controls the muscles that pick up the foot, invert the foot, and extend the toes. The Tibial Nerve has a normal amplitude of 3mV or higher, over an 8cm distance. The Tibial Nerve controls the muscles that rotate the legs, bend the knees, rotate the ankle, and flex the toes. In the upper extremities, the Median Nerve has a normal CMAP amplitude of 4mV or higher, over a 7cm distance. The Median Nerve controls the muscles of the forearm, the thumb, the index finger, and the middle finger. The Ulnar Nerve has a normal CMAP amplitude of 6mV, also over a 7cm distance. The Ulnar Nerve controls the muscles that bend and move the hand, the muscles that control the ring finger, and the muscles that control the pinky finger. The Radial Nerve has no established normal CMAP values. And now, the sensory nerves. For the sensory nerves, the Sural Nerve, in the lower extremities, has a normal SNAP amplitude of 6µV, over a 14cm distance. The Sural Nerve provides sensation in the lower legs and feet. Moving to the upper extremities, the Median Nerve has a normal SNAP amplitude of 20µV, over a 14cm distance. The Median Nerve provides sensation for the forearm, thumb, index finger, and one-half of the ring finger, including the nail bed. The Ulnar Nerve has a normal SNAP amplitude of 10µV, also over a 14cm distance. The Ulnar Nerve provides sensation for the other one-half of the ring finger, and sensation for the pinky finger. The Radial Nerve has a normal SNAP of 20µV, over a 10cm distance. The Radial Nerve provides sensation for most of the arm and most of the back of the hand. Still with me? Good. On to the F-Wave Latency normal values. What the F? F-Wave Latency is a measure of the length of time it takes a signal to travel the full length of a nerve. It is easy to see that the length of a given nerve will dictate how long it takes a signal to travel its entire length. If you think of it like walking a hallway at your normal pace, the longer the hallway, the longer it takes to get to the end. The time it takes to get to the end of the hallway is a representation of F-Wave Latency, or F-Wave. Because the normal F-Wave value for each nerve is dependent on its overall length, there is an accepted normal value that correlates with overall patient height. The taller a person, the longer a given nerve will be, and the longer it takes a signal to travel the full length of that nerve. For sake of even more confusing details though, we will discuss the normal values for a person who is 5 feet 11 inches. In the lower extremities, the normal F-Wave value for the Peroneal Nerve in somebody who is 5 feet 11 inches is 51-2D msec (51milliseconds, after 2 standard deviations). The normal Tibial Nerve F-Wave value is 57-2D msec. In the upper extremities, the normal F-Wave value for the Median Nerve is 30-2D msec, and the normal F-Wave value for the Ulnar Nerve in somebody who is 5 feet 11 inches is 31-2D msec. Piece of cake. I know what you are thinking. All of this is a lot of very technical information about a lot of very technical things. You are right. Nerve Conduction Study is very technical, and that is why it takes a highly trained doctor to interpret the results of these studies. Now, however, you are familiar with the terms and the normal values associated with those terms when you see them on a test report. Electrodiagnostic reports for CMT might not be as intimidating for you now. You do not have to worry though. You do not have to commit any of this to memory, and there is not going to be a test. But having now discussed what all the normal values are, we can move onto what any abnormal values might represent as they relate t0 CMT. That’s Not Normal Knowing the normal values of the common metrics used in the electrodiagnostics of CMT is only half the battle. Sure, discussing the normal values of each is very technically involved, but we must first know what the normal values are so that we can know when the values are abnormal. It is critical to be familiar with those normal values as we discuss what is abnormal, and then as we discuss how those abnormal values can help a doctor to discern between that which is a demyelinating type of CMT (CMT1), that which is an axonal type of CMT (CMT2), and that which is an Intermediate CMT. As with all things CMT, there is always an exception to the rule. Obtaining nerve conduction characteristics is only one piece of the CMT diagnostic puzzle, and the results cannot serve as a stand-alone diagnostic tool. However, there is a consensus on some general values that depict the three main types of CMT—demyelinating, axonal, and Intermediate. Type 1 CMT is demyelinating. Typically, the nerve conduction characteristics of demyelinating CMT are such that conduction velocity becomes uniformly slowed, diffuse, and stable. The stability makes conduction blocking rare. Nerve conduction blocking is a condition that occurs when there is a difference of CMAP amplitude at either end of the nerve. There usually is not a difference in demyelinating CMT. Usually, NCV values are less than 38 m/sec, are often ~20 m/sec, and can be as low as 4 m/sec in severe cases. CMAP amplitudes are often normal to only slightly reduced, and F-Wave responses are usually prolonged. These values are typically uniform in all nerves without much change over time, but some sensory nerve SNAP values can progress to become absent. EMG can show evidence of denervation. The nerve conduction characteristics of axonal CMT can be drastically different, and more complex. Type 2 CMT is axonal. Typically, the nerve conduction characteristics of axonal CMT are such that conduction velocities can range from ~38 m/sec to just slower than normal. CMAP values are typically below 4mV, and SNAP values are typically less than 10µV. Sural Nerve SNAP responses can often be absent, and Phrenic Nerve (the nerve that controls the diaphragm) can exhibit reduced CMAP amplitude values also. EMG can reveal signs of chronic denervation. Contrasting with the stable values typically present in demyelinating CMT, the values in axonal CMT can vary from nerve to nerve, and they can change drastically over time. Often, in axonal CMT, the longer nerves will exhibit abnormal characteristics before the shorter nerves. The nerves of the lower legs (Peroneal, Tibial, Sural) can often exhibit worse characteristics than the nerves of the hands (Median, Ulnar, Radial), and sometimes the nerves of the lower legs will exhibit these abnormal values while the nerves of the hands can show almost no discernible abnormality. For these reasons, axonal CMT sometimes carries the description, “length-dependent motor and/or sensory neuropathy,” and sometimes, “length-dependent distal motor and/or sensory neuropathy.” Both refer to axonal CMT. This variability in nerve conduction characteristics in the same person can make diagnostic interpretations difficult for the doctor, and that translates into frustration for the CMTer. Then, there is Intermediate CMT. Intermediate CMT is an interesting diagnosis from a nerve conduction characteristic standpoint. Intermediate CMT gets its name not from the associated disease severity, but from the nerve conduction characteristics that are associated with Intermediate CMT. The nerve conduction characteristics that are consistent with demyelinating CMT (CMT1) are straightforward. The nerve conduction characteristics that are consistent with axonal CMT (CMT2) are not as cut-and-dry as those typically associated with demCMT1, but the characteristics are specific enough, despite their inherent variability, that a doctor can interpret them to be axonal CMT. Intermediate CMT, however, exhibits nerve conduction characteristics that overlap that which is characteristic of demyelinating CMT and that which is characteristic of axonal CMT. This presents a difficult diagnostic challenge for the doctor. A skilled doctor, however, can interpret the nerve conduction characteristics to be consistent with Intermediate CMT. Do you remember when I mentioned that there are some variables to these rules? Well, in keeping in the spirit of CMT, the nerve conduction characteristics commonly associated with the three main types of CMT are not absolute. But What About… All the discussed nerve conduction characteristic values are only a general rule-of-thumb meant to help guide the diagnosing doctor. These parameters, however, are not written in stone. The doctor still needs to interpret the data to mean something, and then translate that data into diagnostic relevance, if any. Even with the distinct differences exhibited by demyelinating CMT and axonal CMT, a doctor cannot rely only on nerve conduction characteristics to make their diagnosis. The doctor has to consider the nerve conduction characteristics with the overall diagnostic findings as they build the complete picture. As with all things CMT, there is always an exception to the rule, and especially with nerve conduction characteristics. The distinction between demyelinating and axonal CMT is not always clear. Published literature depicts many exceptions to the rule of distinction. In a large study of CMTers with 1A, researchers report that nerve conduction velocities range from 17-20 m/sec. Yet, in other studies, researchers report that nerve conduction velocities in 1A range from 10-42 m/sec, breaching the 38 m/sec threshold for CMT2. CMT1A is not alone in this defiance of the rules. CMT1B can be quite the anarchist. Typically, in CMT, nerve conduction velocities that are near normal present in CMT2, but not in CMT1. However, in CMT1B, although typical nerve conduction velocities are 5-15 m/sec, studies have shown that nerve conduction velocities can exhibit a range of 4-59 m/sec, far exceeding the 38 m/sec ceiling threshold for CMT1. In one paper, researchers report normal nerve conduction velocities in younger members of a family with 1B, whereas older relatives in the same family had severely slowed nerve conduction velocities. In another study of a single family with 1B, nerve conduction velocities were significantly slower than what is associated with 1A, yet in another study, researchers compared 119 CMTers who had 1A to 10 CMTers who had 1B, and found no nerve conduction velocity differences. Adding to the diagnostic confusion with demyelinating CMT, let me introduce you to the nerve conduction velocities exhibited in CMTX1. X-Linked CMT subtype 1, that is, CMTX1, has a disease process that is primarily demyelinating. We know this because the underlying responsible gene mutation is in a gene that codes a molecular process in peripheral nerve myelin. However, nerve conduction characteristics tend to be more variable than what is typically associated with demyelinating CMT, and axonal features are more common. Nerve conduction characteristics can be asymmetrical like what is typically associated with axonal CMT. Nerve conduction block can also occur with CMTX1, unlike what is typically seen in other demyelinating types of CMT. The nerve conduction velocity range in CMTX1 is typically 25-43 m/sec in men, and 31-50 m/sec in women, falling well within that of Intermediate CMT. The consensus is that the difference between men and women is because of the number of X chromosomes each have. Although the nerve conduction characteristics depict an Intermediate CMT, we know that CMTX1 is demyelinating because of its underlying responsible gene mutation. The responsible mutation for CMTX1 is a mutation in the GAP JUNCTION PROTEIN, BETA 1 gene (GJB1). To generalize, in peripheral nerve myelinating Schwann cells, the GJB1 gene facilitates the transfer of nutrients, ions, and other molecules to the inner most myelin layers. The responsible mutation causes a dysfunction of those transfers. Therefore, and despite its electrodiagnostic characteristics, CMTX1 is a demyelinating CMT. This example perfectly illustrates that making the distinction between demyelinating CMT and axonal CMT cannot rest solely on nerve conduction characteristics. The examples we discussed are just a small snippet of the exceptions to the rules for CMT nerve conduction characteristics that can serve as a guide to the doctor when differentiating between demyelinating, axonal, and Intermediate CMT. These few examples also demonstrate that the doctor cannot rely solely on electrodiagnostic findings to diagnose CMT. Electrodiagnostic findings are only one part of the diagnostic picture for CMT, just as are clinical symptoms. As discussed and demonstrated, the nerve conduction characteristics, when considered together with clinical symptoms and patient complaints, can be sufficient for the doctor to diagnose CMT. The limit to this is being able to pinpoint the exact subtype. Outside of an established family history of genetically confirmed CMT, the only way to know the exact subtype is through genetic testing. True to form with CMT though, when a genetic test does not identify the underlying responsible genetic cause, but nerve conduction characteristics and clinical symptoms are consistent with CMT, the non-confirmatory genetic test result is not a reliable diagnostic tool. The genetic test for CMT is not required for diagnosing CMT, but only for pinpointing the exact subtype.

Is the Generations Deep Notion That CMT Can and Does Skip a Generation Fact or Fiction? The Answer is Easy, But The Road Trip to Get There is Not. Wherever there is an appearance of CMT skipping a generation, there is an explanation, even when getting to that explanation requires that we follow a fleeting trail of breadcrumbs. That trail, true to form for CMT, is often complex and confusing. Everything about CMT is complex and inherently confusing. The genetics and inheritance of CMT are no different. Arising from these complexities are many misconceptions. Among these is the notion that CMT can skip a generation. CMT does not and cannot skip a generation. To know the how and why requires that we unwrap some of the mysteries of CMT inheritance, and I’m here to do just that. All the CMT experts agree that CMT does not and cannot skip a generation. Because of how the gene mutations that cause CMT are inherited, CMT cannot skip a generation. There are several variables that contribute to this misconception, and I’ll explain several. First and foremost, we have to toss out what we know about the words “dominant” and “recessive.” Their use in genetics is different than what we’re used to in conventional use. In genetics and inheritance patterns, in the most basic sense, dominant refers to needing one copy of a mutation to cause the disease, and recessive refers to needing two. And, in our case, of course, we’ll focus only on CMT. The term "carrier," as it relates to CMT, derives from the recessive types of CMT, whether autosomal or X-Linked (some of the Type 2’s, some of the X-Linked, all the Type 4’s, and all the Intermediate Recessives). We normally have two copies of every gene. We inherit one copy from our mom and one copy from our dad. The exception is with the X-chromosome. Males have only one X-chromosome, and this one X-chromosome is inherited from only their mom. Because males have only one X-chromosome, they have only one copy of each of the genes that live on the X-chromosome. This detail only adds to the misconception that CMT can skip a generation. The Autosomal Recessive Conundrum Autosomal recessive types of CMT are caused by a mutation in both copies of a gene that lives on any of the numbered chromosomes (numbered 1-22, and are referred to as the autosomes, hence, autosomal). When only one copy of the gene has a mutation, it is not sufficient to cause the associated type of CMT. When somebody has that one copy of the gene mutation, they are a "carrier" of that one copy of the mutation, but not of CMT. Somebody who is a carrier of this one copy of an autosomal recessive mutation has a 50/50 chance of passing it on to each of their children. Their children who do inherit this one copy of the mutation will not have CMT unless they inherit the second needed copy from their other parent or unless the second needed copy occurs randomly (de novo) at conception. I'll have more on de novo CMT in a moment. This one copy of the autosomal recessive mutation can go generations deep, but there will not be CMT unless through inheritance from the other parent or through a de novo occurrence the second needed mutation is introduced. Only then can the person have the associated autosomal recessive CMT. If any of the children do not inherit this one copy of the mutation from their "carrier" parent, they will not have the mutation to pass onto their children, and their children cannot inherit that which the parent does not have. This sounds confusing now, but this will make sense in a moment, I promise. The Autosomal Dominant Conundrum The misconception of CMT skipping a generation can also come from dominant types of CMT (all the Type 1’s, most of the Type 2’s, 2 of the X-Linked types, all the Intermediate Dominants). Autosomal dominant types of CMT are caused by a mutation in only one copy of the associated gene, and this gene lives on any one of the numbered chromosomes. Because there needs to be only one copy of the mutation for there to be these types of CMT, autosomal dominant types of CMT are far more common than autosomal recessive types. When somebody has an autosomal dominant type of CMT, they have a 50/50 chance of passing on their CMT causing mutation to each of their children, regardless of gender. When any of the children inherit this mutation, they have the associated CMT, and it is only a matter of time before symptoms start to show. The children who do not inherit this CMT causing mutation will not have the associated CMT. They cannot pass on this CMT causing mutation to their children because they do not have the mutation to pass on. Where the misconception of skipping comes into play here is when somebody has a dismissively mild case. CMT can affect everybody vastly differently, and even within the same family. It is not uncommon for somebody to be the first in the family diagnosed, to then find out that a parent has it but that the parent’s was dismissively mild. It can also be common to find out that a grandparent has/had it badly, but the parent seemingly did not. From this, some infer that the CMT skipped a generation. What really took place was that the parent was so dismissively mild that there was no reasonable reason to suspect they, too, have/had CMT. I’ll use myself as an example. Skipper, No Skipping I have CMT1A. CMT1A is autosomal dominant in inheritance—need only one copy of the responsible mutation to cause it. I was the first diagnosed in my family. I was diagnosed in late 2002, at 29 years old, with a Type 1 CMT, based on Nerve Conduction Study, or NCS for short. Almost one-year later to the day, I received genetic confirmation of 1A. Shortly thereafter, my dad was diagnosed, at 60 years old. My dad was evaluated for CMT not because he was symptomatic, but because he was willing to find out if there was a family history, or if my CMT was de novo—a new spontaneous occurrence. I was very CMT-symptomatic from an early age. Like most who are the first in the family diagnosed, my diagnostic journey was eventful. In sharp contrast, my dad’s CMT was dismissively mild. Nobody ever suspected he had anything neuromuscular going on. My dad’s CMT was dismissively mild despite him having essentially the same nerve conduction characteristics as me—the typical 1A NCS results of ~19 meters/sec velocities, prolonged latencies, somewhat reduced action potential amplitudes, etc. This is a testament to nerve conduction characteristics not correlating with 1A severity. After my dad was diagnosed, something about his biological father suddenly clicked. My dad was adopted by his stepdad when he was 6 years old. This was post-WWII Detroit, in 1948. My dad’s biological father, like most 20-something men at the time, was a WWII veteran. I never met the guy. The story is that he was a P52 pilot. My sister has his US Army Air Corp. portrait, but not much is known. The story also includes that he moved back to his hometown of London, Ontario after the war. My dad met him in the 80s and got to know him a little bit, and this is where the CMT story picks up. My dad never talked about his biological father. He only brought him up the one time after the CMT diagnosis. My sister and I knew he existed, but this is the extent of it. My dad said that my grandfather had serious issues with his legs, and he could barely walk. He seemingly lived out his last twenty years confined to a wheelchair and drawing Veteran’s Disability because his issues were deemed to be caused by his military service. As the story goes, he started having issues in his late twenties, shortly after WWII, and shortly after moving to Canada. It’s a safe bet that my dad’s biological father had CMT1A. My dad had it, and it’s a safe bet that he inherited it from his biological father. I inherited the 1A causing mutation from my dad. The story suggests that my grandfather, whom I never met, had a fairly severe case of 1A. My dad’s CMT was so mild that nobody ever suspected anything. I am right in the middle of the two, more severe than my dad, and less severe than my grandfather. From the outside looking in, it’s easy to presume that CMT skipped a generation in my family. My grandfather had it bad. Some would argue that I, too, have it bad (albeit with issues, I have my legs). My dad would have never been suspected of it had I not been diagnosed. However, CMT did not skip a generation from my grandfather to me. Investigative medicine showed that my dad did have it, even though his was exceedingly dismissively mild. CMT 1A is autosomal dominant. If you have the one copy of the CMT causing mutation, you then have the associated CMT. Symptom onset, rate of progression, severity, etc., become the question, and it is a question of when, not if. My dad had the 1A causing mutation. Despite no outwardly clinical symptoms of CMT, his nerve conduction characteristics were textbook 1A. For whatever reasons there might have been, he never developed anything CMT-consistent beyond nerve conduction characteristics. Despite an otherwise absence of symptoms, he had CMT. CMT did not skip, because CMT does not skip. What if both parents of a CMTer absolutely do not have CMT, but a grandparent absolutely does? Surely, then, CMT skipped a generation, right? CMT, in this situation still has not skipped a generation. The De Novo Conundrum CMT is inheritable. This much is a given. However, CMT does not have to be inherited in order to have CMT. When there is no genetically established family history, that is, the CMTer did not inherit their CMT causing mutation from a parent (or from both parents in cases of autosomal recessive CMT), the CMTer's CMT is referred to as a de novo (new) case. A de novo case is one in which the underlying causative gene mutation occurred spontaneously without having been inherited. A CMTer whose CMT is a de novo case passes on their CMT causing mutation according to the inheritance pattern of the mutation: autosomal dominant, autosomal recessive, X-Linked dominant, or X-Linked recessive. How does this apply to the notion of CMT skipping a generation? Hypothetically, Grandpa Bob has CMT. Dad (Tom) does not. However, Tom's son, Bill, does. Tom's wife, Cathy, does not have CMT. Tom and Cathy do not have CMT, but their son, Bill, does. Because Tom's dad, Grandpa Bob, has CMT, it obviously skipped a generation, right? No, the CMT did not skip a generation. Why not? Situation One Bill was diagnosed with CMT when he was 20 years old. He received genetic confirmation of the CMT1B causing autosomal dominant mutation in his MPZ gene at 21. Grandpa Bob had received genetic confirmation of his CMT years ago. Tom never showed any signs of CMT, so he was never evaluated. With Bill's genetic confirmation, both Tom and Cathy get tested. Neither of them have Bill's CMT causing genetic mutation. Low and behold, Bill has the same mutation that Grandpa Bob has though. This is proof that CMT skipped a generation, right? No, it did not skip a generation. Although Bill has the same CMT1B causing mutation as Grandpa Bob, Tom does not. Because Tom does not have the mutation, he could not have and did not pass it on to Bill. Bill's CMT1B causing mutation, instead, and albeit the same mutation as Grandpa Bob, is a de novo occurrence, having occurred spontaneously at conception. The chances of this happening are exceedingly rare, but never zero. Situation Two Grandpa Bob has an autosomal recessive type of CMT, we'll say CMT2A2B, and he has genetic confirmation of the responsible compound heterozygous mutation in his MFN2 gene. His son, Tom, has no signs of CMT, and was never tested. However, Tom's son, Bill, is diagnosed with CMT, and then genetically confirmed to have, coincidentally, the same compound heterozygous mutations in his MFN2 gene as Grandpa Bob. Obviously, CMT skipped a generation, right? No, CMT did not skip a generation. After Bill received genetic confirmation of CMT2A2B, Tom and Cathy were tested. It turns out that Tom has in his MFN2 gene one mutation of the two needed to cause CMT2A2B, and Cathy has the second in her two MFN2 gene copies. It's a safe bet that Tom inherited his copy from his dad, Grandpa Bob. Because Tom has only one of the needed mutations that, when there is both in the same person cause CMT, he does not have CMT. Cathy, also, with only one of the needed mutations in her MFN2 gene, does not have CMT. But, because Tom has one of the mutations, but not CMT, CMT skipped a generation because Grandpa Bob and Bill both have CMT, right? No, CMT did not skip a generation. Bill has CMT2A2B because he inherited one of his two CMT causing mutations from his dad, Tom, and the other from his mom, Cathy. Unbeknownst to everybody, both Tom and Cathy were "carriers" not of CMT, but of one copy each of a mutation, that when both are present in the same person, causes CMT2A2B. Tom and Cathy each having only one of the 2A2B causing mutations in their MFN2 genes do not and cannot have CMT. Bill, though, having both copies, has CMT2A2B. Because Tom and Cathy each have just one of the mutations, there was a 25% chance that Bill would inherit both copies, and then have the associated CMT. Grandpa Bob’s MFN2 gene has a mutation in each of the gene’s two copies. Grandpa Bob randomly passed on one of his two MFN2 copies to Tom. Because both copies of Grandpa Bob’s MFN2 gene have a mutation, the copy that Tom inherited from Grandpa Bob has one of the two mutations needed to cause CMT2A2B. Tom’s mom had no mutations in her MFN2 gene, so Tom’s other copy, which was inherited from his mom, has no mutation. Hence, Tom does not have CMT2A2B. Neither of Cathy’s parents had CMT, so it is decided that Cathy’s only MFN2 mutation copy was a de novo occurrence for her. With the genetics and inheritance patterns of the genetics that, together, dictate the CMT family situation of Grandpa Bob, Tom, Cathy, and Bill, we can see how and why CMT did not skip from Grandpa Bob, over Tom’s generation, and land with Bill. Once we look beneath the hood, and examine the details, we see that the genetic patterns of CMT do not permit CMT to skip a generation. X-Linked CMT perhaps provides the best argument supporting the notion that CMT can skip a generation. However, much like our example of Bill’s family, there is a reasonable explanation for what transpires. The X-Linked Conundrum X-Linked CMT gets its name from the genes that cause it. Each of the genes that cause X-Linked CMT live on the X-chromosome. The X-chromosome is one of two chromosomes that determine gender—the other is the Y-chromosome. Together, the X and Y chromosomes are called the sex chromosomes. Females have two X-chromosomes. Males have one X-chromosome and one Y-chromosome. Because of this, unlike all the other types of CMT, gender plays a role in X-Linked CMT, in both inheritance and in reported disease severity. X-Linked CMT can be either dominant or recessive in inheritance, and these are termed X-Linked dominant and X-Linked recessive. Like autosomal dominant, X-linked dominant types of CMT need only one copy of a gene mutation in order to cause the associated CMT; and, like autosomal recessive CMT, X-Linked recessive needs two, but with an exception. Dominant is still dominant, and recessive is still recessive. The difference is only with the gene living on the X-chromosome vs the associated gene living on one of the numbered chromosomes. Gender plays a role in inheritance and reported disease severity in X-Linked CMT because of the number of X-chromosomes females have compared to males. Females have two X-chromosomes and males have one. Females inherit one of their X-chromosomes from their mom, and one from their dad. Males inherit one X-chromosome from their mom, and they inherit their Y-chromosome from their dad. Females, because they have two X-chromosomes, can only pass on an X-chromosome to each of their children. The one of her two X-chromosomes that gets passed on is completely randomized. Her children’s dad will pass on either his one X-chromosome or his one Y-chromosome. When he passes on his one X-chromosome, the children are female. When the dad passes on his Y-chromosome, the children are male. Because of this gender-determining combination, there can be no male-to-male inheritance of X-Linked CMT. When a male has X-Linked CMT, he cannot pass it onto any of his sons because he passes on only his Y-chromosome to his sons, and not his X-chromosome, without exception. However, when a male has X-Linked CMT, he will pass it on to every daughter because he passes on his X-chromosome, and all the genes living on his X-chromosome, to every daughter, without exception. What I mean here by including “without exception” refers only to the Y-chromosome being passed onto to his sons, and the X-chromosomes being passed onto his daughters. The CMT part gets tricky and is different for males than it is for females. For all intent and purpose, for females, the rules that govern X-linked dominant and X-Linked recessive CMT inheritance are the exact same as those regarding autosomal dominant and autosomal recessive. When a female has an X-Linked dominant CMT (X1 or x6), the associated gene has a mutation in only one of the two gene copies, just as in autosomal dominant types of CMT. When a female has an X-Linked recessive CMT (X2, X3, X4, or X5), both copies of the associated gene have a mutation, just as in autosomal recessive types of CMT. When a female has X1, only one of her two copies of her GJB1gene has a mutation. When a female has X6, only one of her two copies of PDK3 gene has a mutation. When a female has X2, X3, X4, or X5, then both copies of the associated gene have the responsible mutations. The rules are quite literally the same as autosomal dominant and autosomal recessive. When a female has an X-Linked dominant CMT, there is a 50/50 chance that she will pass it on to each of her children, regardless of gender, just as in autosomal dominant CMT. When a female has X-Linked recessive CMT, things change a little bit. When a female has X-Linked recessive CMT, let’s say X4 for example, both copies of her AIFM1 gene have a mutation. These two mutations, when together in the same person, causes CMTX4. She will randomly pass on one of her two AIFM1 gene copies, and its mutation, to each of her children. This is where the similarities to autosomal recessive end. When a female has X-Linked recessive CMT, both copies of her associated gene have the responsible mutation. She will pass on one copy of that associated gene and its mutation to each of her children. Her female children, inheriting this one copy, will not have the associated CMT unless they inherit the required second mutation from their dad or develop it spontaneously—de novo. Each of her male children, however, will have the associated CMT. This is where a lot of the confusion regarding X-Link CMT skipping a generation comes from. Despite recessive inferring that there must be two mutations, one in each of the two copies of the associated gene, when it comes to X-Linked recessive types of CMT, males can have it even though males have only one copy of the associated gene being that they have only one X-chromosome. A male who has an X-Linked recessive CMT cannot and will not pass it on to any son, but he will pass on his one copy of the associated gene, with its mutation, to every daughter. Like the daughter who receives the one copy from her mom who has an X-Linked recessive CMT, she won’t have the associated CMT. Rather, she’ll be a carrier of that mutation. Down the road, when she has children, she will have a 50/50 chance of passing on this mutation to each of her children. When the children are female and inherit this one copy of the recessive mutation, they will only be a carrier of the mutation. When the children are male and inherit this one copy of the recessive mutation, because they have only one X-chromosome, it is sufficient to cause the associate X-Linked recessive CMT. As confusing as all this X-Linked recessive stuff is, the CMT does not skip a generation. It all comes down to the mutations, how they are inherited, and how they affect females vs males. Adding to this X-Linked conundrum, males who have an X-Linked dominant type of CMT (X1or X6) tend to be far more severely affected than females who have X-Linked dominant CMT. This is thought to occur because females have a buffer, of sorts, with having a second X-chromosome ergo a second and unmutated copy of the associated gene. This, too, can give the appearance of CMT seemingly skipping a generation. But for the reason we’ve discussed, the CMT does not skip a generation. It’s All About the Mutations, and Not About The CMT CMT is not about genes, per se. Rather, CMT is about mutations in genes. I do submit that an argument can be made that if a gene has a mutation that causes CMT, that gene with that mutation is then a CMT gene. Regardless of which argument, because these genes are inherited, the genetic mutations that cause CMT are inheritable. Hence, CMT is inheritable. The notion that CMT can skip a generation infers that, by whatever mechanism, CMT selectively affects only some generations, but not others. This is not the case though. In order to have CMT, somebody must have the genetic mutation that causes the associated type of CMT. Genetic mutations cannot and do not skip a generation. If somebody does not have the CMT causing mutation (whether dominant or recessive, autosomal or X-Linked), they do not have CMT and they cannot pass it on—their children cannot inherit it from them. Regarding the mutations that cause CMT, when they are inherited, they are only inherited from a parent and not from any other family member. The mutations do not and cannot skip over a parent, nor do they come from an aunt, uncle, or cousin. The mutations that cause CMT are inheritable, but they are different and separate from heritable traits (inheritable traits, depending on author). There are other variables and considerations that have spurred the misconception that CMT can skip a generation. They are each along the same lines though. Each familial situation where CMT has seemingly skipped a generation can be phenotypically and genotypically explained. Sometimes those explanations are easy, and sometimes they are complex and confusing, but the scenarios can be explained.

I am a CMTer and I was recently diagnosed with A-Fib. First and foremost, I’m not trying to establish nor suggest a claim that cardiac problems, especially cardiac conduction abnormalities, are caused by CMT, or that they are not. I only want to share my experience so far, what I’ve learned so far, and I want to some insight from my cardiologist on my individual situation. Cardiac involvement in CMT is one of those controversial subjects. There’s plenty of anecdotal evidence, but there’s not much in published literature. There was a study in 1979 (it’s usually the first search return in Google) that suggests a connection between cardiac conduction abnormalities and especially 1A. There hasn’t been much of anything to support or refute since. There are some occasional mentions of cardiac involvement in CMT peppered in literature, but even then it’s only a small blip of a mention, without much discussion of findings. Sometimes, these mentions attempt to link certain subtypes (via using CMT associated gene mutations), but still don’t really provide much of a finding discussion, if any at all. Cardiac involvement in CMT is an area that needs a lot more work. Time will tell, as we learn more, if there’s a definitive connection, or not. But, the topic needs more in-depth study. So, You See, What Happened Was… I had a bilateral tonsillectomy in September 2020, and at the age of 47. The surgery was on a Monday, and the surgery was smooth and uneventful. The anesthesiologist opted for a non-neuromuscular blocking med for the general anesthesia. He used what he said was a somewhat newer med that has almost instant reversal properties. The name, however, escapes me. I rolled into the OR about 8AM. I was awake, alert, and communicating in post-op at 9AM. Smooth and uneventful. The plan was to stay overnight, and in ICU at University of Michigan Hospital, because of my complex neuromuscular respiratory history and current overall respiratory condition. Because anesthesia was able to avoid neuromuscular blocking, I extubated in a snap with no issues, and I was moved into the ICU step-down unit. Again, though, only as a precaution. I was in my room by 1PM, and everything was still smooth and uneventful. That would change. About 730PM, everybody on the floor seemed like they were as bored as could be. I couldn’t have that, and I wanted to help them to not be bored. All of a sudden, without warning of any kind, I started throwing up. It caught me by total surprise. I was wired for sight and sound, so before I could hit the call button to let my nurse know what had just happened, every staff member on the floor was busting through my door. I had set off the monitors at the nursing station, and they jumped in like I was having a massive heart attack. But, a heart attack is not what was happening. My little charade to end the boredom turned into an Atrial Fibrillation event. I had never experienced A-Fib. I’ve never been a cardiac patient. Knock on wood, I’ve been able to maintain good cardiovascular health. This A-Fib thing was completely new for me. Two EKGs, in-room monitor, and a 2D Echo all concur that it is A-Fib. With a resting heart rate of an erratic 120 – 160, they started pushing Cardizem in the IV to control it. The Cardizem helped, after a couple of hours, to keep my heart rate around 100 for most of the night. By the time the 2D Echo was taking place the following morning, my resting heart rate was hovering around 120, and only slightly erratic. I was still in A-Fib. The preferred treatment for A-Fib is to manage the rhythm. However, instead, they were managing the heart rate with me. Why? Rhythm control requires the use of blood thinners, and I wasn’t even 48 hours post-op. Blood thinners post-op can be a bad thing, especially with tonsillectomy. Why is rhythm control with A-Fib important though? A-Fib, or Atrial Fibrillation, is a condition in which the top half of the heart (the atrial chambers) beats fast and erratically (fibrillate) while the lower half (the ventricle chambers) beats normally. A-Fib has many different causes, including sleep apnea. Of course, being a CMTer who has sleep apnea at the hands of my CMT, I’m in a higher risk category. During A-Fib, blood doesn’t flow through the atrial chambers normally. Instead, it can kind of swish and can even become static (staying still). When blood becomes static, it can coagulate and form a clot. This clot can travel and cause a stroke. Because of this, A-Fib is preferably combated by managing the rhythm from erratic to a constant rhythm, and blood thinners are a part of the therapy. I was precluded from blood thinners for at least 14 days post-op. So, inpatient cardiology opted for rate control. Fortunately, I am in the lowest risk category for stroke, and that provides some comfort in the approach. As luck would have it, while on rate control, I spontaneously converted back to normal sinus rhythm overnight Tuesday into Wednesday morning. I woke Wednesday morning with no A-Fib. This bodes well considering I couldn’t be on blood thinners at that time. What caused my A-Fib though? It All Started When… I have CMT1A. For years, going back to at least the mid-90s, I’ve had little transient bouts of cardiac arrhythmia that show up without warning, and disappear that quickly. They’ve never been explained; and, not for lack of trying, they’ve never been captured via monitoring. With the event that started that day-of-tonsillectomy Monday evening, the cardiology team was confident that all of it has been A-Fib all along. Ok, so, I’d be remiss if I didn’t ask: is there a connection between CMT and cardiac conduction abnormalities, and specifically 1A? The answer was an interesting conversation with the inpatient team. By the time I asked the question, the lead cardiologist had already looked into it. They seemed surprised that I asked. Their surprise might have been in how I asked. “Because I have CMT1A, are there any known or suggested connections that you are aware of that establishes a quantitative correlation between not just CMT1A, but CMT as a whole?,” is probably not something that most physicians get from any of their patients. I can see how one might be caught off guard a touch. Yes, I really do talk like that with my doctors. I’m an odd one. The cardiologist let me know that she found only a mention of a couple of gene mutations that might have something involved, and she said she wasn’t sure if I had those mutations. Well, lucky for her, her team, and me, I know my underlying causative mutation. I let the team know that my 1A is caused by a duplication of the PMP22 gene, and I asked the cardiologist if she recalled the mutations mentioned in the literature she found. She didn’t recall, but she offered to pull everything up on the in-room computer. Now we’re talking my language. She opened up the database provided to the physicians at University of Michigan Hospital. She pulled up the search results. The results indicated a paper that made a blip of a mention of cardiac something in CMT caused by a mutation in DYNC1H1, and another blip of a mention about cardiac something in CMT caused by a mutation in the RAB7 gene. The cardiologist team had no idea what any of that meant, but I was able to let them know that those references were to CMT2O and CMT2B, respectively. They were surprised, again, but I’m not a normal patient in any sense. There were no descriptions of what any connection was nor what any cardiac symptom was. It raised more questions that it gave answers. The cardiologist also pointed to the study from 1979 that I mentioned earlier. This paper establishes a possible connection in a small group of 1A CMTers (68 CMTers with 1A) to cardiac conduction abnormalities. My cardiology team says that, while the findings are interesting, there are several flaws in the underlying data and inaccuracies in the report narrative. They also noted that it is a very old study and there is nothing in the published literature to support or to refute the study. They are not the first ones to tell me this about the particular study. In the end, the inpatient cardiology team couldn’t make an established connection between any type of CMT and cardiac conduction abnormalities. I was discharged in normal sinus rhythm, and with a Cardizem script until follow-up with outpatient cardiology. Fast-forward to early December. The Current Sitch Since hospital discharge in September, while taking the med for rate management, and nothing else for the A-Fib, things have been fun. A-Fib is just one of those fun things. Yeah, let’s go with fun. A-fib is fun. I’ve been having several episodes a week, but nothing that hangs around for more than an hour, and most have been less than 15 minutes. I finally saw my new cardiologist the first week of December, approximately ten weeks since my A-Fib event while inpatient. I know you all know the doc was not getting out of there without doing an in-depth Q&A with me, that I wasn’t going to give them an opportunity to quietly slip away. So, me being me, I asked if he knew of any specific connection between my 1A and cardiac conduction abnormalities such as A-Fib, especially given the expression of PMP22 in cardiac tissue. The response was thorough, and we had an enjoyable conversation. According to my cardiologist, as my A-Fib pertains to me, “in theory, there might be a connection, but I’d have to cut you open, grab a chunk of heart muscle, and put it under a microscope; and I’m just not going to do that.” The cardiologist went on to explain that PMP22, the gene that is duplicated thereby causing 1A, is also expressed in cardiac muscle and in the nerves that control the heart and the rest of the cardiovascular system. He explained that although the gene is expressed in those anatomies, the gene’s function there is not understood. He further explained that it’s possible that the same type of pathology in peripheral nerve myelin that’s caused by an over expression of the PMP22 gene could take place wherever the gene is expressed. My cardiologist repeatedly emphasized that cardiac conduction involvement in CMT and especially in my 1A, if any, is not known or understood. He concluded that if there is a connection, at this point in time, treatment options and decisions would be the same as if there isn’t a connection. My cardiologist also feels that all of my little episodes of arrhythmia over the years have been A-Fib events. He also cautioned that A-fib is quite common, and that I have at least one very common risk factor: sleep apnea. I’m not a physician or a clinician. I have no formal medical training. I do have a decently firm grasp on a lot of things related to CMT though. My tonsils were removed because of my CMT induced respiratory issues. In the process, boom, A-Fib. Does this mean that my CMT caused my A-Fib? I don’t know. I only know that I had, in the very least, the same chances to develop A-Fib as a non-CMTer. There isn’t much in published literature about CMT and cardiac conduction issues, but there is a lot of anecdotal evidence in the CMTer community. The disparage between anecdotal evidence and quantitative scientific evidence leaves this as a controversial subject. The consensus of the CMT expert community is that there is no established connection. From a patient perspective, the controversial nature of this subject suggests that much more research needs to happen in this area. A-Fib is an electrical problem in the heart tissue. There is no indication that my cardiac muscle is weakened or otherwise diseased at the hands of my CMT, or at the hands of anything else. For all intent and purpose, my A-Fib is a stand-alone issue, until proven otherwise.

CPAP Is the First Choice of Physicians When Treating Obstructive Sleep Apnea, But CPAP Often is an Incorrect Therapy Option in Charcot Marie Tooth Disease Sleep disorders in the general population are common. The American Sleep Association estimates that 50 – 70 million adults in the US have a sleep disorder, with 25 million having Obstructive Sleep Apnea (OSA). A much less common type of sleep apnea, called Central Sleep Apnea (CSA), affects less than 10% of people who experience Sleep Disordered Breathing (SDB). The go-to therapy for OSA and CSA is CPAP. CPAP is an acronym for Continuous Positive Airway Pressure. CPAP provides a constant supply of low-pressure air that keeps the airway open so that breathing does not stop. However, CPAP is contraindicated in Charcot Marie Tooth disease. Why is CPAP bad for a CMTer, and what are the options? To answer those questions, we must dig a little deeper. Under Pressure Sleep Disordered Breathing—a collection of sleep disorders characterized by irregular breathing while asleep, is common in the general population. Research suggests that CMTers might bear a predisposition to SDB. A study first published in 2007 established that especially CMT1A has a predisposition to OSA. Dziewas, et al. note in the study that, “pathophysiologically, one may assume that CMT1 related pharyngeal neuropathy increases the collapsibility of the upper airway which in turn leads to recurring obstructive respiratory events.” Treating SDB is straightforward in the general population. Basically, throw a bunch of air into the collapsing throat, and you are good to go. Neuromuscular disease, including CMT, however, presents additional challenges. CMT experts and researchers hold that respiratory involvement outside of SDB conditions in CMT is rare. There is not much data depicting the prevalence of respiratory involvement in CMT. Anecdotal evidence disagrees with published literature. One must only look as far as social media CMTer communities to see the overwhelming number of personal stories about respiratory issues endured by CMTers, enduring often without treatment. This disparage between anecdote and expert consensus leaves CMT caused respiratory involvement a controversial topic. Nearly all CMTers who talk about experiencing respiratory impairment also talk about having SDB, be it OSA or CSA, with OSA being the most common. A good indicator of respiratory involvement as it pertains to the treatment of SDB in CMT is the CMTer’s response to the first line of therapy—CPAP. In an oversimplified explanation of CPAP therapy, a machine outputs air at a specified pressure, through a hose connected to a mask. The unit of measure for this is centimeters of water pressure, or cmH2O. This pressure is exceptionally low. To give it some perspective, 1 psi is equal to 70.3 cmH2O, and maximum CPAP pressure is 25 cmH2O. Even at CPAP maximum pressure capability, the equivalent is only 0.35 psi. As a therapy for OSA, the continuous pressure output of CPAP forces the airway to stay open during inspiration (inhale) and expiration (exhale). The pressure remains the same for expiration as it is for inspiration. Even though CPAP pressure output is low, the continuous pressure can cause respiration difficulty in CMT, and especially during expiration. When difficulty is present, it is rooted in respiratory muscle weakness. CMT does not cause disease in lung tissue. Rather, when there is respiratory involvement, the involvement is the result of the CMT disease process in the peripheral nerves that control the respiratory muscles. Just as CMT causes weakness in the muscles controlled by the motor nerves, CMT can also cause weakness in the muscles controlled by the somatic nerves that control breathing, i.e. the phrenic nerves and the intercostal nerves. Respiration occurs because of muscle contractions. To inhale, the diaphragm contracts and moves downward. This downward motion creates a low-pressure area in the chest. Because pressure moves from a high-pressure to a low-pressure, and because the inside of the chest now has a lower pressure than what is outside the body, air rushes in to fill the lungs. To facilitate the lungs filling completely, the intercostal muscles of the rib cage contract, thereby expanding the chest. Once we have taken in as full of a breath as we can, the respiratory muscles contract in the opposite direction, forcing out the air from the lungs. This, of course, is an oversimplified explanation of respiration, but it is how the respiratory pump works. When a CMTer has respiratory muscle weakness, it can be difficult to take in a full breath. Likewise, it can be difficult to exhale completely. When the respiratory muscles are weak because CMT has affected the nerves that control them, a CMTer might not have adequate muscle strength to get a full breath and/or to fully exhale. This creates a condition called hypoventilation. Barring any lung tissue disease that the CMTer might also have, oxygenation typically remains normal. However, an inability to fully exhale can lead to hypercapnia— an excessive level of CO2 in the body. Every breath we take results in a gas exchange in the lungs. The lungs transfer oxygen into the blood stream during each inhale, and the lungs transfer carbon dioxide from the blood stream, expelling it with every exhale. This is an efficient process when everything is running as it should. When the respiratory muscles become weakened by CMT, a CMTer might not have the ability to take in a full breath. The most that a person can exhale with each breath is equal to the air volume that the person inhaled. If a CMTer cannot get a full enough breath to facilitate an adequate expiration volume of air that the lungs need for adequately filtering out CO2, CO2 will start to build up in the system. Adding to this dilemma, if a CMTer cannot then fully empty the lungs before taking the next breath, the CO2 left behind goes back into the bloodstream, thereby causing CO2 levels to rise. SDB leads to hypoventilation and the build-up of CO2 also. Treat Me Right, Doc Sleep Disordered Breathing, such as OSA and CSA, causes hypoventilation. Hypoventilation leads to excessive CO2 in the body. SDB causes hypoventilation by causing a disruption in regular breathing. SDB disrupts breathing via obstructing the airway (OSA), via a disruption in the communication channels between the brain and the respiratory system (CSA), or sometimes via a combination of both. To treat the conditions, physicians use CPAP. Typically, by keeping the airway open with CPAP, breathing during sleep is managed well. What happens when there is a neuromuscular component such as respiratory muscle weakness caused by CMT? Obstructive Sleep Apnea is quite common in CMT. Research shows a predisposition to OSA in at least some types of CMT. CPAP is the first line of defense physicians deploy for treating Sleep Disordered Breathing, including OSA. However, according to Dr. Ashraf Elsayegh, MD, FCCP, Pulmonary/Critical Care, Cedars-Sinai Medical Center, CPAP is not recommended in neuromuscular disease. Despite its low-pressure, a CMTer can have difficulty exhaling against the continuous pressure of CPAP. This difficulty can fatigue the respiratory muscles. Respiratory muscle fatigue induced by CPAP can lead to hypoventilation; and of course, hypoventilation can lead to the build-up of CO2 in the body. CPAP induced hypoventilation is counterintuitive to the objective of CPAP therapy. Not only can CPAP not effectively treat SDB for a CMTer, CPAP can worsen the effects of SDB, at the hands of CPAP induced hypoventilation. If CPAP is out of the question, what are the options? When a CMTer has a Sleep Disordered Breathing condition, CPAP is not the best option. When a CMTer also has respiratory muscle weakness, an SDB can be even more difficult to treat. An option that physicians sometime use is BiPap therapy. BiPap is the acronym for Bi-level Positive Airway Pressure. BiPap is like CPAP, but BiPap allows for a different and often lower expiration pressure. There are clear advantages for the CMTer with BiPap. However, the consensus is that Noninvasive Ventilation (NIV) is the best option for CMTers. What is NIV? Noninvasive ventilation sounds scary, sure, but it is just supercharged BiPap, but with a twist. Noninvasive ventilation is a type of respiratory therapy that provides ventilation (respiratory) support, noninvasively. Conversely, invasive ventilation is mechanical ventilation support via intubation or via a surgical tracheotomy. NIV, much in the same way as CPAP, consists of a small tabletop machine that delivers air to a mask via a hose. Where NIV excels is the capability to provide volume support in addition to pressure therapy. Continuous Positive Airway Pressure is a limited therapy. CPAP can successfully keep an obstructed airway open, but the rest of the respiratory system must function at peak. If there is any kind of deficiency, like even minimal respiratory muscle weakness that can be present in CMT, for example, CPAP often will not succeed in achieving therapy goals. BiPap therapy can provide an advantage over CPAP by allowing for a lower expiration pressure, but that is where BiPap reaches its therapeutic limit. Neither CPAP nor BiPap have the capability to treat the variability in respiration that a CMTer can have. NIV picks up where CPAP and BiPap leave off. Exceeding the Limitations Noninvasive ventilation exceeds the capabilities of CPAP and BiPap by having the ability to provide pressure support, to automatically adjust in real-time to the respiratory needs of the patient, and to provide volume support. NIV pressure therapy can function like BiPap insofar as NIV can use two different pressures—one for inspiration, and a lower one for expiration. However, NIV can automatically vary the delivered pressure according to respiratory demand, and NIV can make that adjustment in real-time. Where NIV really takes off is with volume support. In addition to pressure support, noninvasive ventilation can provide volume support. As NIV pertains to CMT, the consensus is that NIV with volume support is the best option for a CMTer who is experiencing Sleep Disordered Breathing, and is the best option for a CMTer who is experiencing respiratory muscle weakness caused by their CMT. What is volume support? Noninvasive ventilation provides volume support via a capability called Average Volume Assured Pressure Support, or AVAPS for short. NIV pressure support uses pressure to keep the airway open, and AVAPS uses volume to ensure that each breath is consistent and maximized. Like CPAP, the pressures are extremely low, and measured in cmH2O. The unit of measure for volume is cubic centimeters (cc) or milliliters (mL). Cubic centimeters and millimeters are interchangeable with one another. So, how does this work? Average Volume Assured Pressure Support delivers a volume of air that is equal to the total lung volume of the patient, plus a little extra to allow for any leakage at the mask seal, and the volume is delivered within a specified duration of time, consistently with each breath. The lung volume, represented as Tidal Volume, tL, is determined during a test called a Pulmonary Function Test, or PFT. Although the pressure delivered by NIV might vary depending on respiratory demand, delivered volume will remain unchanged. I use NIV with AVAPS because I have respiratory muscle weakness caused by my CMT1A. I will use my machine set-up to explain the parameters. Noninvasive ventilation uses many parameters to treat respiratory conditions. AVAPS adds an additional set of complex parameters. My NIV has been a game changer for me. I have respiratory muscle weakness caused by my CMT. I also have Obstructive Sleep Apnea, and I have Central Sleep apnea. My physician at the time started me on CPAP therapy. I had a tough time exhaling against the pressure of CPAP, and my symptoms of SDB worsened, especially the morning headaches. After a physician change, and with my measured CO2 high enough in the middle of the day to qualify as hypercapnia, the new physician switched me to NIV with AVAPS. The machine set-up is complex, but there are a handful of parameters that are straightforward. My noninvasive ventilator is set-up to treat my Sleep Disordered Breathing conditions, and to also treat the neuromuscular respiratory weakness that my CMT causes. The pressure support half of my NIV treats the SDB conditions, and the AVAPS half treats the respiratory muscle weakness. Remember that I mentioned that NIV pressures can vary? My pressure parameters are set to have a minimum inspiratory pressure of 10 cmH2O and a maximum inspiratory pressure of 25 cmH2O. The pressure drops to 7 cmH2O for expiration. While expiration pressure does not vary, inspiration pressure will adjust up and down, in real-time, as the machine determines I need based on my actual breathing. My AVAPS parameters have my tidal volume set at 500 mL. This number is equal to my total lung volume, plus 150 mL to allow for any loss between the machine and my lungs. AVAPS delivers this 500 mL in 1.2 seconds with each breath. The 1.2 seconds is based on my actual PFT measured average inspiration time. AVAPS is set to deliver 12 breathes per minute. The breathes per minute is based on the average for my height, weight, and age. There are many other parameters used in my NIV, but these are the important ones. Noninvasive ventilation pressure support provides a critical therapy for CMTers who are experiencing Sleep Disordered Breathing conditions. NIV with AVAPS provides an even more critical therapy for CMTers who experience even minimal respiratory muscle weakness. The volume support provided by AVAPS capabilities allows for the respiratory muscles to get a break by creating an opportunity for the muscles to not have to work as hard to facilitate breathing. The break that AVAPS can provide lessens the muscle workload, thereby lessening the opportunity for respiratory muscle fatigue. Why are these things important? In Sleep We Trust Successfully treating Sleep Disordered Breathing conditions is vital to overall health. Treating SDB can reduce the risk of developing heart disease such as congestive heart failure, coronary artery disease, and cardiac arrhythmias. Treating SDB can reduce the risk of stroke, diabetes, and obesity. Treating SDB can improve cognitive function, emotional health, and general mood. Successfully treating SDB conditions can even improve the neuropathy experienced by CMTers. Restorative sleep is critically important. SDB interrupts restorative sleep. The short-term and long-term health consequences can be significant. Lost sleep is forever gone, for there is no catching up on sleep. The longer it takes to successfully treat SDB conditions, the more severe the overall health problems can become. There are several options available for treating Sleep Disordered Breathing in CMT. While the consensus is that NIV with AVAPS is the best option for CMTers, the therapeutic choice is up to the physician. It all comes down to what the individual patient needs. For some CMTers, CPAP is the perfect choice. For others, BiPap is the best option. Yet, for others, NIV with AVAPS is the needed therapy. What works for one, might not work for the other. If you are using a particular therapy but it is not achieving what you need it to, talk to your physician. There are options available. The sooner your condition becomes managed well, the better your overall health, and CMT condition, will be.

Researchers Have Identified a Variant in the SORD Gene That Is Believed to be The Most Frequent Cause of Recessive Axon-Related Charcot Marie Tooth disease, and It Might be Treatable Researchers at the University of Miami, led by Dr. Stephen Züchner, report that they have discovered a gene mutation that is the cause of a recessive subtype of Charcot Marie Tooth disease. This mutation is believed to be the cause of the most common recessive axon-related subtype of CMT, whose underlying genetic cause had not yet been identified. This study was substantially supported by the Inherited Neuropathies Consortium. Their findings were published in Nature Genetics. Researchers were able to query a database of 1,100 CMTers who had undergone Whole-Exome Sequencing (WES) and/or Whole-Genome Sequencing (WGS). From that group, they identified 48 CMTers from 38 families whose genetic cause had not yet been identified, who all demonstrate an axon-related subtype on Nerve Conduction Study (NCS), who all demonstrate a recessive inheritance pattern, and who were all carrying the same homozygous variant in SORD. SORD is the name/gene symbol given to the Sorbitol Dehydrogenase 1 gene. SORD (OMIM - 182500) is an enzyme that catalyzes the interconversion of polyols and their corresponding ketoses, and, together with aldose reductase (ALDR1; OMIM - 103880), makes up the sorbitol pathway that is believed to play an important role in the development of diabetic neuropathy and diabetic complications. The first reaction of the pathway (also called the polyol pathway) is the reduction of glucose to sorbitol by ALDR1 with NADPH (OMIM - 300225) as the cofactor. SORD then oxidizes the sorbitol to fructose using NAD(+) cofactor. Whoa! That's a mouthful! What does it mean though? SORD is responsible for converting sorbitol to fructose through a two-step process. It does this via a pathway that is implicated in diabetic neuropathy. Researchers found that, when the c.757delG (p.Ala253GlnfsTer27) variant is present in SORD, there is a complete loss of SORD protein and an increased level of sorbitol within a cell. Researchers also discovered that blood levels of fasting sorbitol were significantly increased. Each of the 48 CMTers who were found to have this variant in SORD, have a CMT disease presentation that is consistent with an axon-related subtype of CMT. Researchers were able to reproduce these findings in the lab, using a fly model. Dr. Züchner and his team were able to demonstrate in the fly model that treatment with a class of drug called, aldose reductase inhibitor, normalized sorbitol levels within the cell.Disease phenotype was also improved after treatment with the drug. Two drugs were evaluated, Epalrestat and Renirestat, and both gave the same results. Epalrestat is a drug available in several countries and is used to treat complications from diabetes. Renistat is currently in late stages of a clinical trial assessing its possible use as a treatment for complications from diabetes. Researchers suggest that the subtype of CMT caused by the newly identified variant in SORD might be treatable with an aldose reductase inhibitor such as Epalrestat. Approximately 90% CMTers with a demyelinating (CMT1) subtype have a genetic confirmation. Conversely, approximately 20% to 30% of CMTers with an axon-related (CMT2) subtype receive a genetic confirmation. As many as 70% of CMT2 cases are a de novo case. Because of this, identifying the underlying CMT-causing gene mutation remains difficult. This also explains the disparage between understanding the genetic causes of the CMT1 subtypes and the CMT2 subtypes. The new variant identification in SORD as being the cause of a recessive axon-related (CMT2) could serve to bridge this gap of disparity. The researchers were able to determine that the homozygous c.757delG (p.Ala253GlnfsTer27) variant in SORD is present in ~3 per 1,000 individuals. This discovery means that this variant is potentially responsible for more than 60,000 CMT cases worldwide, with 3,000 to 5,000 cases being in the US. This would make the subtype caused by this SORD variant to be the most common recessive subtype of CMT. The researchers have not yet assigned a name to the subtype caused by this variant. This is a testament as to how new this reported discovery is. Efforts are underway to identify undiagnosed CMTers who fit the recessive axon-related subtype profile and whose genetic cause has been elusive. The Charcot-Marie-Tooth Association, through voluntary enrollment in their Patients as Partners in Research initiative, is hoping to identify CMTer candidates for possible participation in a specialized study that is anticipated to be available within in the next several months through the University of Miami and the Inherited Neuropathies Consortium. While there are drugs that safely and effectively treat complications of diabetes where SORD is implicated, their safety and effectiveness in treating any subtype of CMT, and especially the subtype newly discovered to be caused by this recessive variant in SORD is not understood and has not been evaluated in a patient population. Therefore, extreme caution must be exercised in moving forward from this new discovery. What I find very interesting is that the drug, PXT-3003, that is in Phase III clinical trial, is being developed as a possible first ever treatment for CMT, and is specifically tested only for CMT1A - the most common subtype of CMT, has sorbitol as one of its constituent parts. Specifically, PXT-3003 is a fixed combination of low-dose (RS) Baclofen, Naltrexone Hydrochloride, and D-sorbitol. I find it fascinating that this Phase III Orphan-designated drug developed to potentially treat specifically CMT1A, contains D-sorbitol, and researchers have now discovered a variant in SORD that not only disrupts sorbitol's conversion to fructose, but also causes a recessive subtype of CMT. Truly fascinating. #charcotmarietoothdiseasenews #cmtnews #cmtgene #cmtgenediscovery charcotmarietoothdiseaseresearch #cmtresearch

PMP22 Gene Editing by CRISPR CaS9 Shows Reduction in PMP22 Expression in CMT1A Mice "We are already envisioning the possibilities that gene therapy holds for our community of 2.8 million people worldwide living with CMT." — John Svaren, PhD, Chair, CMTA Scientific Advisory Board Scientists are working on ways to directly target the gene defects that cause the various subtypes of Charcot Marie Tooth disease. They are using CRISPR CaS9 to perform genomic surgery in order to repair these gene defects. Ji-Su Lee, Jae Y Lee, Dong W Song, et al, demonstrated that a reduction in PMP22 gene expression, the gene responsible for causing CMT Type 1A, can be achieved in mice through the use of CRISPR CaS9. Their findings were reported in Nucleic Acids Research, Volume 48, Issue 1, 10 January 2020, Pages 130-140. Charcot Marie Tooth disease Type 1A, or what is referred to as CMT1A, is the most common subtype of CMT. According to the Charcot-Marie-Tooth Association, CMT1 represents approximately 55% of all CMT cases, and 1A represents approximately 66% of all CMT1 cases. CMT1A is understood to be caused by a duplication of the Peripheral Myelin Protein 22 (PMP22) gene. This gene encodes Schwann cells to initiate the production of peripheral nerve myelin. This gene duplication is referred to as an over-expression. This over-expression disrupts the tightly regulated peripheral nerve myelination process, thereby causing an over-production of peripheral myelin. This over-production impairs the peripheral nerve’s normal function. There have been previous studies and trials to reduce this over-expression. There was previously a large multi-continent clinical study to assess the effectiveness of high-dose Ascorbic Acid (Vitamin C) to reduce PMP22 expression, after there were some promising signs in a CMT1A mouse model. However, these lab findings did not translate well into the clinic setting as demonstrated by skin biopsy of treated patients in the study. Another previous study assessing progesterone antagonist as a means by which to reduce PMP22 expression also found that it was not a viable treatment. Both of these explored therapies can influence other cells and other biological processes. To eliminate these potential issues, why not target the specific gene? As it turns out, scientists have been working on ways to do exactly that. Recently, CRISPR CaS9 has been shown to have potential as a use in developing treatments and even cures in genetic disorders, including CMT. CRISPR CaS9 is a gene editing technology that allows scientists to target and edit specific genes, thereby potentially avoiding issues arising from therapies that could inadvertently affect off-target cells and processes. Ji-Su Lee, Jae Y Lee, Dong W Song, et al, demonstrated that, by using CRISPR CaS9 to target the over-expressed PMP22 gene in a CMT1A mouse model, a reduction in overall PMP22 expression can be achieved. The authors successfully demonstrated that, via targeted PMP22 TATA-box editing by CRISPR CaS9, PMP22 over-expression can be reduced, and their findings support that a reduction in PMP22 in CMT1A in the mouse model improves peripheral nerve conduction characteristics (peripheral nerve conduction characteristics are significantly impaired in CMT1A, causing a motor and sensory disease phenotype), and improves the overall disease severity caused by the over-expression of PMP22. The authors caution that one must be careful to not reduce PMP22 expression to the point of creating an under-expression that would be associated with/cause HNPP. HNPP is another subtype of CMT, and it is understood to be the genetic opposite of CMT1A insofar as HNPP is understood to be caused by a deletion of PMP22. Normally, there are two copies of the gene. In CMT1A, there is an extra copy; and in HNPP, there is only one copy. To safeguard against inducing an under-expression, the authors suggest that “in contrast to targeting protein coding sequence of PMP22, TATA-box editing may prevent unwanted effects from knocking down PMP22 expression too low.” TATA-box editing refers to editing the non-coding DNA - the TATA-box. Rather than targeting the coding sequence of PMP22, the authors targeted the non-coding sequence of the gene. In so doing, it is thought that a safeguard against unwanted coding transcriptions can be achieved. What does all of this mean for CMTers though? Researchers have now been able to demonstrate that, by reducing overall expression of PMP22 in CMT1A via direct gene targeting, an improvement in disease symptoms is possible. At the same time, researchers extrapolated that an increase in PMP22 expression can potentially achieve the same results for HNPP as does a reduction in over-expression for CMT1A. The study authors report that their results have the potential to carry over to the clinic, and they suggest that, because CRISPR CaS9 can directly edit a specific gene, there is a potential for a single dose therapy. While results thus far are only in a mouse model, it is a critical step in developing viable treatments and a potential cure for, in this study, CMT1A. Time will tell if these results will or can translate into potential therapies or a cure for all of the CMT subtypes. #charcotmarietoothdiseasenews #charcotmarietoothdisease #cmt1A #crisprcas9 #crispr #genetherapy #cmtgenetherapy #genomicsurgery

Bracing in Charcot Marie Tooth Disease is A Bottoms-Up Approach with The Goal of Improving Mobility, Minimizing Trips & Falls, and Maximizing Quality of Life for the CMTer "There is no “CMT Orthosis” that will work for all patients with CMT. Within CMT as a diagnosis, there can be many, many varied presentations, each of which might require different approaches and orthosis designs." --Alicia Baxter CPO, University of Michigan Orthotics and Prosthetics Center Why AFOs? Well, first, what is AFO? AFO is mentioned a lot within the CMT realm, but what is it? AFO is an acronym for Ankle Foot Orthosis, and is pronounced A-F-O as standalone letters. Alright, then, what’s an orthosis? Orthosis is the mechanical correction of limb deformities or support of weak musculature by use of external mechanical bracing. So, by definition, an AFO is a mechanical device that is used to correct deformities of the foot and ankle. Some devices are used only for feet. These would be considered a foot orthosis. Any device that crosses the level of the ankle joint but stops below the knee is considered an AFO. As such, an ankle brace is also an AFO. There are some who also need knee bracing incorporated into their device. This device would be called a KAFO, for, as you guessed it, Knee Ankle Foot Orthosis. This article, however, focuses on AFOs. So, why, again, AFOs? The Nuts & Bolts Foot weakness and instability, plus ankle weakness and instability are exceedingly common in Charcot Marie Tooth disease. Progressive changes in the structure and alignment of the feet and ankles are common. However, the issues that are caused by the feet & ankle weakness and instability are as varied as the individual CMTer is unique. There are some commonalities across the spectrum though, because of the overall disease process. Standing and walking on the edges of the feet is very common in CMT. As this becomes the normal foot and ankle posture for the CMTer, the knees are forced to pitch in the opposite direction that the ankles pitch. In turn, this causes the hips to pitch, yet, again, in the opposite direction (opposite to the knees, but the same direction of the ankles). Because nothing with the human body is or happens perfectly symmetrical side-to-side, this action may cause the pelvis to shift/tilt to one side. This shifted pelvis can give the perception of one leg being disproportionately shorter than the other. Mechanically, as a result of a mechanical process, rather than anatomically, it is functionally shorter. The human body tries to compensate, and in turn, the lower back shifts. As the lower back (the lumbar spine) shifts to compensate for the legs, ankles, and feet being sketchy, the middle back (thoracic spine) shifts; and, then, the neck (cervical spine) shifts. A CMTer’s body is constantly working overtime just to maintain central and core neutral balance and centerline, and it all starts with the feet being out-of-neutral and the ankles shaky. When the foundation is shaky, and the feet and ankles are the foundation, all dependencies suffer. So, What’s Happening? There is a common and underappreciated presentation with CMT. This presentation is a dysfunction with proprioception. Proprioception is, essentially, knowing where our limbs are in space without looking at them. This is fundamental, as are many other things, to maintaining balance. Proprioception is often disrupted and reduced by CMT. We talked earlier about the weakening and mechanical changes that occur in CMT, but this decreased proprioception means CMT also causes sensation and balance disturbances. Throw in some of this proprioception deficiency on top of whack feet and ankles, and the Tibialis Anterior muscles, which control the feet, become unbalanced side-to-side and front-to-back, making them have to work even harder to maintain upright balance. This muscle imbalance can be easily visualized. Whether you are already in AFOs, or they are being entertained for you for the first time, this quick exercise will show exactly how your muscles are working to maintain balance. Tap a couple of helpers. You must have help. Do not do this by yourself. Period. The end. This is not open for debate. One of your helpers is somebody who can help steady you. The other is for making a quick video with their phone. Throw on a pair of shorts, don’t put on socks, and you’re ready to go. For comparison, have a non-CMTer do the same exercise afterwards, and make a video of what their lower leg muscles are doing. The results will be strikingly different. With your helper at your side, and your camera person at the ready, stand bare-footed, and in a normal standing orientation. You don’t have to do anything special. Now, raise both arms so that they’re level across your shoulders and pointing straight out. You have probably done this several times with your neurologist. As you look straight ahead, close your eyes, and just stand there. Your camera person should be recording what your lower legs, ankles, feet, and toes are doing. It’s best if they are filming you either from in front or behind you. You’ll most likely start to sway after just a couple of seconds. Your helper is there, at your side, to catch you if you sway too much. It only takes a few seconds of video footage to capture how everything is working, so you only need to do this for a few seconds. Again, do not try this alone, and do not do this so long that you fall. Do not hurt yourself while trying this. If you don’t have help, the risk to falling is not worth it, and I cannot stress this enough. Don’t do this by yourself. You probably didn’t feel what is going on while doing this short exercise. If you didn’t, it’s because it is your normal – you’re used to it. If you do feel what’s going on, you’re more in-tune than most. The video that was made will show that the muscles of your lower legs are in constant activation as they are trying to compensate for you not knowing where your limbs are in space. These muscles are just some of the muscles that are working overtime to keep the feet solidly planted. Keeping feet solidly planted in CMT is challenging for the body, to put it mildly. This is also a significant reason why the muscles of the lower legs get so fatigued and crampy for a CMTer. These muscles are always overworking, and they are overworking in addition to being weakened directly by CMT. AFOs can help to manage these issues. But, how? I’m glad you asked. Enough with The Wobbulations The primary goal of AFOs for a CMTer is to achieve a solid foundation via mechanical assistance to achieve a neutral foot posture thereby achieving an ideal weight distribution across the structure of the foot while also achieving an ideal heal-to-toe strike pattern when walking. Posture used here is not referring to sitting, standing, and walking with a straight back posture, as used to be drilled into us as a child. Rather, I use it here to refer specifically to how the feet function to support the body at rest and when in motion. As equally important, another primary objective is to stabilize the ankle both to prevent rolling the ankle and to prevent foot-drop (more on this in a moment). If the ankle is left alone to remain wobbly, then anything that is done to provide for foot neutrality is done in vain. Likewise, if an attempt is made to stabilize the ankle, but achieving a neutral foot posture is ignored, the work is for naught. The two go hand-in-hand. Once foot neutral posture and ankle stabilization is achieved, what happens? Well, there’s a domino-effect. Once the feet are held neutral and the ankles are stabilized, the body’s central alignment is more, well, central. Starting at the bottom—the foundation, and working upward through each joint, everything becomes more equally loaded and balanced. As an example, if you stand on the lateral (outside) edges of your feet, thereby stepping on the outside edges and rolling in as you walk, just as I do, your knees, like mine, are improperly loaded and pitch inwards. All of the ankle wobbulations (I made that word up, but you can use it all you like) cause the knees to also wobbulate. In turn, the hips wobbulate. When AFOs achieve a neutral foot posture and successfully stabilize the ankles, knee and hip wobbulations are minimized, and the AFOs, as a secondary process, achieve a more equal and balanced joint loading above the level of the AFOs. This benefit carries all the way up and through the spine, and all of those joints that were out of whack are now aligned how they should have been all along. Another benefit in the causative domino-effect is the potential for pain mitigation. There’s no question that there can be an insane amount of pain with CMT. The reasons for this are many. Part of the pain problem is caused by the feet and ankle issues that we’ve discussed. By using AFOs to manage these mechanical issues however, the pain that is caused by these issues has an opportunity to be reduced and maybe even controlled. I can speak to this from personal experience. My AFOs have significantly reduced my overall lower extremities pain level. My Magic Shoes Rock! I wear Allard BlueROCKER© AFOs, bilaterally. I wear custom orthotic inserts with them. Together, the appliances are my AFO system. My orthotic inserts are the mechanism by which my feet achieve a neutral posture. The BlueROCKERs©, together with my orthotic inserts, stabilize my ankles, and they manage another common CMT issue: the prolific trip-inducing bilateral foot-drop. My foot-drop is controlled via the rigid ankle of the BlueROCKERs©. This AFO has been a game-changer for me. What is foot-drop, though? Let me explain. Foot-drop is a condition where the front of the foot doesn’t fully “pick up” as you take a step while walking. If you visualize the mechanical process of walking, one foot is out in front and the other is trailing behind. When you move forward the foot that is trailing behind to take the next step, as the foot leaves the ground, a “normal” foot will “pick up” the front of the foot, tipping the toes upward as it swings through to be in position to take the next step. In “normal” walking, the foot will strike down on the heel, followed by the toes in a normal heel-to-toe rocking mechanical movement. Visualizing that same step again, but adding in foot-drop, rather than the foot properly picking up and tipping the front of the foot upwards, muscle weakness causes the front of the foot to drop downward. Often, with foot-drop, the toes will catch and cause a stumble, and sometimes a full trip and fall. AFOs can be used to correct for this by limiting the drop motion of the front of the foot, and sometimes eliminating the drop motion, depending on individual needs, and depending on the system that is selected to meet those needs. The orthotic inserts and the rigid ankle of the BlueROCKERs© work together, as a system, to mitigate my ankle wobbulations and to achieve a controlled heel-to-toe strike pattern while walking. This AFO system also achieves a more stable and solid foundation for supporting my body. Accomplishing this causes my muscles to not have to work as hard to maintain balance. Also, my AFO system achieves a more stable and balanced loading of my knees, hips, and spine. In so doing, my pain from mobility is reduced. This is an outcome measure that doesn’t get enough emphasis. Understanding the Biomechanics of CMT is Vital BlueROCKERs© with custom orthotic inserts work very well for me. I have worn this system for more than ten years. It took almost ten years to land in what I now use. The first orthotist I had did their best, but they didn’t fully appreciate the mechanics of how my CMT affected me. As such, early attempts were not successful. Of course, AFO technology then was nowhere near what it is now, twenty years later. The orthotist who put me in BlueROCKERs© with orthotics was amazing with CMT. The orthotist I now have, Alicia Foster CPO, at University of Michigan Orthotics and Prosthetics Center, who is also on the staff of the University of Michigan CMTA Center of Excellence, is an authority on AFOs and bracing in CMT. Alicia kept me in my system, and she stepped it up with how she makes my orthotic inserts. The one time I tried to suggest that I wanted a different AFO system, she stopped me and explained why what I had was perfect for me and my needs, and why the different system would have hindered my function more. This is why it is critically important for the orthotist to study how the CMTer moves, to study where the deficiencies are, and to make decisions based upon the individual CMTer’s unique needs. She determined that my system was optimal for me, that the system was achieving what I needed, and was so doing efficiently. You know what? She was right. However, my system may not be perfect for you. Only your orthotist, in working with you and your physician, as a team, can determine what your unique needs are. When a CMTer is meeting with an orthotist for AFO selection, Alicia says, “It’s important for patients to know that, while it is valuable to know about many different types of devices we have in our proverbial toolbox to treat different patients, there is not one device that works for “CMT” in and of itself. There is no “CMT Orthosis” that will work for all patients with CMT. Within CMT as a diagnosis, there can be many, many varied presentations, each of which might require different approaches and orthosis designs. There are some support groups on social media that are so valuable for “meeting” other patients with CMT and it is great to learn and share all the different devices that work for each other. But, just remember that each device type and design is determined by taking into account: Your specific clinical presentation (i.e. your range of motion at each joint, your strength of those joints in various planes of motion, and your level of impairment/frequency of falls). The environment in which you live and work (i.e. Do you have to traverse stairs? Uneven terrain? Multiple flooring types in either of those places? Do you live alone or have assistance either from a partner or caregiver?) Your hobbies or activities you’d like to return to. Then, once we’ve determined these needs, we can determine which type of orthosis design will likely work best for you. Within the design, we consider the available componentry, materials, and the properties of each. We strive to give patients the most motion and function while also keeping them safe and stable enough so their fall risk is minimized and stability is maximized while not “over-bracing” which could also have negative effects. It’s really the Goldilocks principle we use every day to give each person their optimal level of function and quality of life!” Having the right system for the individual is essential. Having an orthotist who understands the needs of the CMTer is just as essential. As Alicia explained, there are so many variables that have to be considered for the individual CMTer, that there really is no one-device-fits-all. The AFO needs have to be tailored to individual needs if outcome expectations are to be maximized. With all the good that can come from wearing the correct AFO system, and there are a lot of systems out there, are there any downsides? For me, the short answer is no. Only good things come from wearing the proper AFOs. However, there are a few things that bear discussion for anybody who is new to AFOs, or who is about to be new to AFOs. Just for Kicks The biggest hurdle to overcome is footwear. Finding footwear that your AFOs will fit inside of is challenging at best. Finding footwear that is fashionable is even more difficult, especially if your job has a business attire requirement. On the other side of that, finding footwear that meets safety compliance for industrial, construction, skilled trades, etc. is as equally difficult. In the US, laws allow for accommodations so that AFOs can be worn in the workplace along with whatever footwear accommodates the AFOs, but this doesn’t solve the hassle of finding footwear that you like and fits the AFOs. For me, personally, footwear for my AFOs isn’t a big deal. Options are limited, but I’m a guy, and society is far more forgiving to me than to women. The website, Trend-Able, can be an invaluable resource for overcoming this footwear hurdle. My shoe size is a 9 ½ EEE without my AFOs. With my AFOs, I need a 10 ½ EEEE with a very tall toe box (the toe box, as you can probably picture, is the area of the shoe where the toes sit). My orthotic inserts add overall height, and the AFOs add width, especially from the strut. A 10 ½ EEEE is not a typical off-the-shelf size. If it is on the shelf, the toe box typically isn’t tall enough. However, a specialty shoe store will typically carry the size in something with a tall toe box. There are some online resources, too. Any 10 ½ EEEE I’ve gotten from New Balance© has a tall enough toe box. I currently wear Skechers© hiking shoes (not boots). I can easily get away with any style that fits. Not everybody can though. Your footwear needs when in your AFOs could very well be different than mine. You could require something that is larger than a one-size and one-width increase. You may not need something that much larger. The AFO system you require for your individual needs might even have the shoes incorporated into the system. The variables are many. Just as my footwear experience is unique to me, yours, too, will be unique to you. Another foreseeable issue that might be experienced is short-term soreness, joint pain, and lower back pain at first, especially if you’re brand new to AFOs. Patience and Communication is Paramount If you have just gotten into your first set of AFOs, it is reasonable to expect that things are going to hurt at first. This should subside as you get used to them. If you follow your orthotist’s break-in instructions to the letter, this soreness and pain will be minimized. While the AFOs need to be broken-in, the break-in period is more for your body to adjust to what your AFOs are doing. The same applies to the seasoned AFO pro. What causes this soreness and pain though? We’ve discussed in great detail how the body is affected by the poor foot posture, wobbulating ankles, knees, and hips that is a result of the disease process of CMT. Especially if you’ve never worn AFOs, your body is used to all of these bad mechanical processes that are your normal. These processes have taken a toll on you, too. Now, throw on some AFO’s that are going to tweak your foot into a neutral posture, that are going to minimize the side-to-side flexion that your ankles normally do, and is possibly going to help manage any foot-drop you might have going on, and your body is not going to know how to act at first, and things are going to be thrown out from what your normal alignment is. If you follow your orthotist’s break-in instructions to the letter, these impacts will be minimized, and you’ll be realizing the benefits of your AFOs in no time. There is a rare occasion that the AFOs you are put in just aren’t the right system for you. While this is rare, it can happen. This happened far more often twenty years ago than it happens in present day. Keeping an open communication with your orthotist is paramount to working through these kinds of issues. Often, the orthotist can make adjustments and/or modifications to your hardware so that the system does for you what it’s designed to do. Communication is paramount. Tossing them in the corner because they hurt, rather than discussing your concerns with your orthotist will not get you the benefit you need and deserve. Alicia reminds us to, "Try to not get discouraged. Most orthotists (if they’re in it for the right reasons) would rather you tell them when something is wrong because they want to help you; and they can’t help you if you don’t tell them what’s wrong. There are all KINDS of things they can do to improve the comfort and fit of your system and you are just as much a part of your medical team as your doctors and your orthotist.” And, if you break an AFO, and this does happen, an orthotist actually likes this – it means you’re wearing them. Don't be afraid of your AFOs! In Closing Why AFOs? Proper AFOs can dramatically improve mobility and ambulatory stability. The sooner the feet are maintained in a neutral posture, the more benefit the ankles, knees, hips, and spine will have. A drawback to myself not receiving a diagnosis until I was in my late twenties was that I didn’t have anything to help maintain neutral foot posture, even though I had a clear need for assistive devices from an early age. Because I wasn’t in any device for so long, my ankles, knees, hips, and lower back have suffered progressive joint changes that, had there been intervention years prior, may not have occurred. It should not have taken receiving a diagnosis for something to have been thought of. I am grateful to now have my AFOs, and I can’t imagine life without them. As with all things CMT, nothing is easy. There is only complexity. The biomechanics of CMT are especially complex. Working with somebody who understands this complexity and who has an astute eye to mechanical detail can change a CMTers life. It did mine, and it can yours as well. #charcotmarietoothdisease #charcotmarietoothdiseasenews #charcotmarietoothdiseaseawareness #cmt #cmtstrong #allard #bluerockers #cmtandbracing #cmtnews #cmtawareness #footdrop #cmtmobility

Life with Charcot-Marie-Tooth Disease and Neuromuscular Respiratory Failure When I was diagnosed with Charcot Marie Tooth Disease at 29, they said it was not life altering. I was fortunate to have as my physician the world’s foremost authority on the disease. Even he was adamant that the disease is not life-altering. It’s been 18 years since being diagnosed. While they still say that, despite all of the advances, the disease is not life-altering, life is exactly what the disease alters, and the disease changes everything. Everything. The most recent manifestation is my breathing and respiratory impairment. This one has completely changed life as I knew it. And, this is the one that ticks me off. Throw It All Away Throw out everything you know about breathing and respiratory issues. Conventional wisdom of respiratory issues does not apply to me or others like me. Let me explain how and why. My breathing is such that I run out of air easily in mid-sentence, and mid-word if I keep on pushing. I struggle to get a full breath, and I especially struggle to expel. The most remedial of tasks destroys my breathing, and it can take hours to recover. Laying down causes a significant reduction in my respiratory function. My voice gets weak quickly. This causes my articulation to disappear, and I can have difficulty having the muscle strength to form and speak words. This further erodes my breathing issues because my vocal cords essentially collapse, thereby affecting airflow. My CMT has caused CMT related respiratory failure, or what is referred to as neuromuscular respiratory failure. The mechanics of breathing, in a nutshell, are such that the diaphragm contracts and moves downward, causing a low-pressure area within the chest. Because air moves from high pressure to low pressure, and the pressure outside the chest is now higher than inside the chest, air moves in and fills the lungs. To facilitate the lungs filling and expanding, the intercostal muscles (the rib cage), contract and this expands the rib cage. We know this simply as inhaling, inhalation, or inspiration. To exhale, the intercostals and diaphragm relax, causing the air to be pushed out, and the abdominal muscles help. This is also referred to as expiration. The mechanism by which this takes place is referred to as the respiratory pump.This is an oversimplified explanation, but it’s essentially how breathing occurs. Conventional wisdom tells us that when we experience shortness-of-breath during exertion, physical activity, speaking, etc., the lungs and/or bronchial tree are/is trash, as in COPD or chronic bronchitis, for example. The solution is to hit the inhalers to open the inflamed/restricted/obstructed airways, and monitor O2/give O2 therapy as needed. Continue treatment and management, and move on. This is not the case though when neuromuscular disease is causing the respiratory failure. Breathing occurs because of the actions of muscles. All muscles do their thing at the command of the brain via motor neurons and nerves. The nervous system is made up of two structural components - the Central Nervous System (brain, brain stem, spinal cord) and the Peripheral Nervous System (every nerve that’s outside the spinal cord and brain, for the most part). The most important muscle for breathing, the diaphragm, is controlled by the phrenic nerve. Other components, such as larynx, pharynx, and ancillary respiratory muscles are controlled by branches of the vagus nerve, which is the longest cranial nerve. CMT affects these nerves, thereby affecting the breathing muscles. Charcot Marie Tooth Disease causes damage to the Peripheral Nervous System. I have CMT1A. The damage to the nerves that my subtype causes results in the speed at which signals travel through the nerves to be slowed. In my case, as is the typical with CMT1A, the speeds are 1/3 of normal (normal is understood to be between 50 and 60 meters/sec, mine is 19 m/sec). This reduction causes muscles to weaken and to atrophy, and this atrophy is progressive over time. What does all of this mean though? When the Lungs are Good Remember me saying to throw out the conventional wisdom? With me, my lungs and bronchial tree are top-notch. Test after test after test indicates and confirms that I have no signs of lung disease. Despite having been a smoker (I’m one-year totally clean), all tests indicate I dodged a bullet. My issues are that the muscles used for breathing are weakened, and they get weaker with use - the more/faster/harder I try to breath, the weaker the respiratory muscles get. Testing confirms this. Inhalers don’t fix it. O2 remains tip-top, and giving O2 would make things worse by causing oxygen induced hypercapnia. My shortness-of-breath does not cause coughing, like one would expect. My lungs and airways aren’t restricted - airway and/or lung restriction/obstruction is what causes the coughing with shortness-of-breath. When I’m having breathing difficulties, it’s because my muscles are weakened, they are tired (fatigable weakness), and they just can’t do their job. Conventional wisdom does not apply. My diaphragm is weak and does not move well. Because our bodies compensate automatically for impairments, my other breathing muscles are activated in ways that they normally would not be. But, they, too, are already weakened, and they get more weakened from the fatigability of operating in ways they normally wouldn’t. When my voice weakens, the muscles at the top of the airway that control the vocal cords and keep the airway open can’t do their job, and the vocal cords collapse, thereby closing off the airway. Inhalers do not fix this muscle problem. Because I frequently struggle to take a full breath, I can’t always accomplish a good enough gas exchange to filter out everything we need to expel, like CO2 and CO. We can only expel the volume we inhale. If my inspiratory volume is low, then I can’t expel enough volume for filtering CO2. This causes CO2 levels to rise, and can get kind of bad. O2 levels stay good though. When physical activity requires an increase in respiration rate, I don’t have the muscle strength and endurance to keep up with demand. Again, my lungs are top-notch, but the muscles used for breathing are not. Breathing becomes a huge struggle. Not because of restrictions/obstructions, but because the muscles can’t do their job properly. The only thing I can do about it is rest, or throw on the ventilator if it’s bad enough. And, it’s bad enough way more than I care for it to be. Why do these things tick me off though? Just Add Water There is no viable treatment or cure for CMT. There is only trying to manage its presentations. The disease is only progressive. Things will only get worse. There is no way to stop it. There’s no way to forecast or predict either. The variability in presentation amongst the patient population is mind boggling. A year ago, my breathing wasn’t too bad. Comparatively though, today, it’s a difference of night and day. There are many with CMT whose diaphragm is paralyzed, whether partially or fully. I’m fortunate that I still have some use of mine. How long before I lose it is anybody’s guess. What is this crap really like though? The only comparison I’ve come up with to accurately depict what the breathing issues feel like is a fairly simply one. Lay down flat on the floor with no pillow. Have somebody gently place on your chest a 32ct case of bottled water, and breathe normally. For most, this shouldn’t be too bad. Now, have your somebody gently place a second 32ct case of bottled water across your abdomen, and breathe normally. Most are going to be struggling a little within a couple of minutes. Lay there, until it gets a little bit difficult for you and you have to get the cases of water off of you in order to catch your breath. Now, imagine that those cases of water are always there, and that difficulty is always there, and gets worse with system demand. That is what my normal is. Now, imagine that that’s what it’s like when you’re standing, but then you lay down and add the cases of water. Things could always be worse. There are people who are significantly more severely affected than I am. However, that doesn’t mean that I have to like where I’m at with mine or that I have to be ok with where mine’s at. Because, you know what? I’m not. I hate it and it ticks me off. It’s rude and uncalled for. #charcotmarietoothdisease #cmt #cmt1a #cmtinducerespiratoryfailure #neuromuscularrespiratoryfailure

Today, you’re out bouncing, just doing what you do. It’s been a long week. Maybe you’re chilling on a park bench along the river. Maybe you’re on a hike in your local nature preserve. Whatever the case, you’re just out getting some you-time and unwinding before the week starts again. You’re fit. You’re healthy. You’re at your peak. You are the quintessential fit and healthy person. Fast-forward two weeks. You wake up with a fever, you’re mildly short-of-breath, you have a mild dry cough, and your joints feel like spikes are being driven through them. You check your temperature. Yep, 103. You’ve seen enough on your TV to know to make the call. Your doc has you go to your local hospital. They diagnose you with the Covid-19 infection, send you home with instructions to self-quarantine for the next two weeks, and tell you to come back if symptoms worsen. For the last two weeks, you were unaware that you had become infected, or that you even came into contact with anybody who was sick. During this time, you’ve been hitting the grocery store where nobody maintains a decent distance, except for checkout because of the tape lines on the floor. During this time, you’ve hit your corner store every day, where everybody knows they are immune to Covid-19. During this time, you’ve visited a few gas stations where everybody knows they’re immune, and where they stack up on each other while waiting in line. You never entertained the idea of “social distancing” because you’re not a “germaphobe” and because you don’t feel sick. You never entertained the notion of “social distancing” because none of this is real – it never happens to you, but only to others. Now that you’ve contracted Covid-19, you’re forced to stay home for a couple of weeks. You spend a few days on the couch feeling like crap. Your fever subsides. You’re a little coughy, but nothing you can’t handle. The body aches subside. You’re able to easily stay hydrated, so fatigue and lethargy subsides without much effort. After these few days, you’ve bounced right back because you’re healthy and bulletproof. You don’t understand what all the Covid-19 hoopla is about because you got through it with relative ease. You spend your last seven days of self-quarantine feeling well, complaining about how you’ve been unfairly held against your will, and complaining about all the fuss and commotion over a simple chest cold that was really no big deal. Your 80-year-old grandfather, who you visited in the two weeks before you were diagnosed, wasn’t so lucky. Grandpa Winston is oxygen dependent because of lung disease. He also has congestive heart failure. He doesn’t get out much, but he always loved having company, especially family. Shortly before you were diagnosed, you had stopped by to see him. You were carrying the virus, but you didn’t know it. You had helped him change his O2 line as you always do when you stop in. You shook hands and hugged as you were leaving, just as you always do. Then, during your second week of self-quarantine, Grandpa Winston falls very ill. Grandpa was taken to hospital and diagnosed with Covid-19. Because of his respiratory condition, the virus quickly wreaked havoc. Pneumonia quickly set in. Grandpa lost his Covid-19 fight the day before your self-quarantine ended. Grandpa wasn’t as lucky as you. You don’t understand how this could have happened since you got through it with relative ease. There’s no way Covid-19 caused this and there’s no way you could have given it to him. None of this makes any sense. I mean, you didn’t even visit him when you were sick. The hospital has to have messed up, right? During your two weeks before being diagnosed, after sneezing like you normally do, you were at your local gas station on a day off. You pumped gas after sneezing and before washing your hands. No biggie. You do this often, like everybody else. This is the norm. Your virus gets unknowingly transferred from your hand to the pump handle. A short time later, somebody else, Sally, on her way home from the pharmacy after picking up her kid’s prescription, uses the pump, and your virus transfers from the pump handle to her hand. Sally rubs her nose during the drive home because she had an itch, before washing her hands, and your virus transfer is now making its way into her lungs. Like you, Sally doesn’t know she’s had an exposure. When she gets home, she thoroughly washes her hands and does everything right, just in case. She has to. You see, Sally has a 4-year-old who has a condition that causes their muscles to barely be strong enough to breathe under normal conditions. This 4-year-old doesn’t have the strength to fight off any kind of a serious respiratory infection. They already struggle just to maintain normal breathing. Sally doesn’t know that she’s had an exposure from you. Within a week’s time, she transmits the virus to her compromised 4-year-old, because they live in the same house. Coincidentally, both Sally and her 4-year-old become sick at the same time, and are diagnosed on the same day as you, and at the same place. Sally’s 4-year-old is admitted to hospital and is quarantined in ICU because of their underlying respiratory impairment. Sally isn’t allowed contact because she, too, has Covid-19 that you unknowingly transmitted to her. Sally’s 4-year-old, on the 3rd day in ICU, develops what’s called, Acute Respiratory Distress Syndrome, or ARDS, and can no longer breathe on their own. Normally, the hospital would have put a ventilator on Sally’s 4-year-old to combat the ARDS. But, because the hospital is so overwhelmed by the Covid-19 outbreak, they don’t have a ventilator available. Sally’s 4-year-old died this 3rd day because Covid-19 caused them to stop breathing. They needed a ventilator that the hospital didn’t have. Sally wasn’t there. Sally wasn’t allowed to be there because she, too, had Covid-19. Sally’s 4-year-old died alone. Sally will recover from Covid-19 just as well and as easily as you did because Sally is just as fit and healthy as you. Sally’s 4-year-old, however, wasn’t so lucky, and Sally will never recover from that. None of the calls for social distancing are about you. None of the calls to stay home are about you. They are about the next person. They are about the person you don’t know. They are about the person you never come into contact with. They are about the person you will never meet. Grandpa Winston would not have died if you would have simply stayed home when you didn’t need to be out. Sally’s 4-year-old would not have died if you would have simply stayed home when you didn’t need to be out. None of this is about you. #socialdistance #socialdistancing #pandemic #covid19 #outbreak #stayhome #noneofthisisaboutyou #theonewhoyounevermet

Examining CMT-Related Speech and Vocal Cord Impairment Do you or a loved one have CMT? Are you or they experiencing voice or throat issues? If so, are the physicians scratching their heads because they can’t figure it out, or are they saying that nothing is wrong? Have the physicians said that there is no way that CMT can be causing any throat or voice issues? Whether you are experiencing these things, or a loved one is, but nobody can explain the why or the how, this story is for you. If a loved one is experiencing these things, and you’re trying to get a handle on what they are experiencing, this story is also for you. If you’re having voice and throat issues but can’t figure out how to explain them so that your physicians will pay attention to you, this story is for you. If you’re a CMTer who is just trying to learn more about this disease, this story is for you. Really though, this story is for everybody. But, what is this story, you ask? This is my personal story of the road trip to figuring out the root cause of my voice, vocals, and speech issues. It’s a journey spanning more than twenty years. Like most things with CMT, I was told along the way all kinds of crazy crap about what was actually causing my issues, including the prolific, “it’s all in your head, you are fine.” There is a real answer, it just took a long time to find it. I was diagnosed in 2002 at 27, and I was genetically confirmed with 1A a year later. Now, 18 years post diagnosis, I finally have a definitive explanation and understanding of what’s going on with my voice/vocals/speech. As with all things CMT, there can be only a complex answer. The short answer is that my issues are caused by my CMT. Root cause analysis, however, reveals a much more complex process at play. And, it’s one I hadn’t considered. You may be experiencing the same, but not have an explanation. If you’re not, this may help you if you do develop these issues down the road. So, What’s Happening? My voice gets weak quickly. I lose overall volume, my articulation can disappear, and I can have difficulty having the muscle strength to form and speak words. These issues worsen with use. My vocal cords and throat muscles essentially collapse, and this leaves my voice hoarse and it leaves my throat painfully sore. My voice/vocals/speech issues are such that they also affect my breathing. The larynx and throat muscles comprise the upper airway. Well, ok, the larynx technically sits atop the lower airway, but I’m including it here as an upper airway structure for argument’s sake, and because of its proximity to and inclusion in the biomechanics of what I have going on. When this musculature is affected by a neuromuscular disease process, such is that with CMT, breathing can be negatively impacted. Alright then, how is my breathing affected by my voice/vocals/speech issues? I’m glad you asked. Let me explain. Basically, it seems that earlier in life, relatively healthy people with CMT can overlook signs of compromised respiratory function which will start to cause more and more problems for them later. Better to recognize the symptoms and treat them early. My breathing is such that I run out of air easily in mid-sentence, and mid-word if I keep on pushing. I struggle to get a full breath, and I especially struggle to fully expel because of a weakened diaphragm. When my throat muscles and vocal cords collapse, air flow gets impeded, and I have to work harder to breathe. The most remedial of tasks destroys my breathing. The same destroys my voice, even if I haven’t been talking. It can take hours to recover, and sometimes days. What I described are all classic symptoms of bulbar muscle weakness and vocal cord paralysis. The bulbar muscles are the muscles of the throat and the mouth that are responsible for speech and swallowing. I also have transient swallowing issues, transient choking on air issues, and transient nasal regurgitation of liquids issues. These, too, are symptoms of bulbar muscle weakness. Bulbar muscle weakness and vocal cord paralysis are not unheard of in CMT. It can happen. How common it is in CMT is a topic of debate, but it can occur. Root Cause at Its Best Root cause analysis, especially in CMT, is vitally important. We already know that treating CMT is literally nothing more than putting a Band-Aid on something, and walking away. Change the Band-Aid as needed; and lather, rinse, repeat. However, if we don’t take the time to perform the investigative medicine to understand what the root cause of something is, then we’re basically just throwing mom’s spaghetti at the wall, waiting for something to stick, and then arbitrarily throwing a Band-Aid on it. If we don’t understand what’s going on at its core, how can we choose the right Band-Aid? We can’t. We shouldn’t. I am a patient at the CMTA Center of Excellence CMT Clinic at the University of Michigan (Umich). Because of my CMT related respiratory issues, I am also a patient at the Umich Adult Assisted Ventilation Clinic, and I will transition to the forthcoming Umich Neuromuscular Pulmonology Clinic that will be ran in conjunction with Dr. Nowacek, who is the CMT clinic director. As of this past week, I’m a patient at the Umich Otolaryngology Clinic, because of my bulbar musculature issues. The ENT physician I saw, Dr. Kupfer, is a neuromuscular otolaryngologist, and, she’s a good one. This is where things get interesting. I have bulbar muscle weakness and vocal cord paralysis symptoms. There’s no disputing that. Bulbar muscle weakness and especially vocal cord paralysis can occur with CMT. It would make sense that I therefore have bulbar muscle weakness with vocal cord paralysis, and it would make further sense that, because I have CMT, my bulbar muscle weakness with vocal cord paralysis is caused by my CMT. I mean, it does make sense, right? A past physician, without investigation, relegated my bulbar musculature issues to my CMT diagnosis. It’s easy to decide that I have bulbar muscle involvement and vocal cord paralysis with my CMT. It’s simple. I have a CMT diagnosis already. No work involved. Move on. Next. Nothing is simple with CMT though, and this is why root cause analysis is so vitally important. It is true that my bulbar muscles are involved. Videokymography (the camera scope that goes in through the nose for live viewing of the throat and vocal cords) shows clear evidence of vocal cord and throat musculature fatiguability and fatigable weakness. Visualization evidence supports my complaints. Things are not as they seem though. We have to dig deeper, literally, to understand what’s actually causing my issues. My vocal cords are not paralyzed. My vocal cords, larynx muscles, and throat muscles, including the epiglottis, exhibit fatiguability and fatigable weakness that could be described as resulting in paresis (partial paralysis). They are so doing not necessarily because of CMT involvement in Cranial Nerves VII – XII (the nerves that control the bulbar muscles), but because of a biomechanical process referred to as Compensatory Activation. What is Compensatory Activation? I’m glad you asked. May I Offer Some Assistance? Compensatory Activation, in an oversimplified nutshell, is a process by which a muscle or a group of muscles become activated to perform a job that they normally would not do. They become activated to do this job because the muscle or muscles that normally do the job no longer function well, and these activated muscles are compensating for the loss of function in the correct muscle. Hence, Compensatory Activation. This isn’t reserved for only muscles though. A prime example of Compensatory Activation is how senses become heightened when we lose one of our senses. Somebody who is visually impaired tends to have heightened hearing, smell, and touch, and can feel and hear the movement of air from somebody waving at them. Somebody who is hearing impaired tends to have heightened peripheral sight and the ability to feel the air pressure of noises, like a baby’s cry in another room or a knock on a door. The other senses activate in order to compensate for the loss of function of another sense. Compensatory Activation. My bulbar muscle Compensatory Activation is occurring because my diaphragm is weakened by my CMT. Phrenic nerve involvement, ergo diaphragm weakness and paralysis, occurs significantly more frequently than physicians and clinicians are willing to admit. Published papers and tens of thousands of CMTer conflict with the narrative that respiratory involvement is exceedingly rare in CMT, or that it’s reserved for just a few ultra-rare subtypes. I am one of those who conflict with this conventional wisdom, and you might be, too. There’s A Thing About the Diaphragm The diaphragm is the principle muscle for breathing. It’s also the principle muscle for speech volume. Our vocal cords control pitch, our diaphragm controls volume. Phonation (the physical act of the vocal cords making sounds) occurs in part, in a nutshell, by air moving through and out of the larynx. The diaphragm is the principle muscle for moving this air. Because the larynx (the vocal cords) sits atop the trachea (the wind pipe) at the base of the throat, air passes through the vocal cords during inhalation and expiration. In a very complex coordination of bulbar musculature movements, we create articulation. In normal speech phonation, we use our diaphragm to push air through our vocal cords as we make our vocal cords vibrate against each other. The vocal cords make the sound, the air pushing through them determine how loud the sound is. A good visual representation of this volume control is a box fan with a bunch of streamers tied to the front of it. Metaphorically Speaking Grab any ole box fan. You can use an oscillating fan, too. Grab some paper or plastic party streamers and tie them to the front grill of the fan. The fan represents the diaphragm, and the streamers represent the vocal cords. Turn the fan on low. The air moving through the streamers creates a certain loudness (volume) within the streamers. Now, turn the fan speed up a notch. You’ll notice a change in the loudness of the streamers. Next, crank the fan speed to its highest setting, and notice the change in the loudness of the streamers. In this basic fan-and-streamers representation, the change in loudness is proportional to the change in how much air is being forced through the streamers. This is how we control our speech volume. The louder our voice, the more air we are forcing through our vocal cords. The more air we force through, the louder our voice. This is also how singers control their vocal volume, and how singers project their voice. Remember I said that we had to dig deeper to understand my bulbar musculature issues? Well, let’s dig deeper. Bulbars, Activate! The Compensatory Activation I am experiencing is occurring because my diaphragm is weakened. My bulbar muscles, including those of my larynx, are activating to compensate for my weakened diaphragm. They are activating to assist with the volume control of my voice, and this includes my vocal cords assisting with volume. Because these muscles aren’t normally responsible for these tasks, they get easily worn out. They exhibit fatiguability and fatigable weakness because they are performing tasks they aren’t supposed to, and are so doing additional to their normal function. The fatiguability and fatigable weakness exhibited by my bulbar musculature leads to a degree of paresis. As each component becomes affected by paresis, the remaining components work that much harder. As everything is working overtime in ways they normally don’t function, everything becomes inflamed. This inflammation causes painful hoarseness and painful soreness. These things are not occurring because my CMT has weakened my bulbar musculature as conventional wisdom would suggest. Rather, it’s happening because my CMT has weakened my diaphragm. Cool, right? But, wait, there’s more. I started to pay close attention to my voice in the summer of 2018. I learned during that summer that I can gauge how much I’ve over-done-it by how weakened my voice gets. I don’t have to have been talking a lot. Hell, I don’t have to have said a word. Any amount of physical activity, no matter how basic, can and does affect my voice. The more I do, the worse my voice gets. This has been going on for many years. I’m not sure when it started, but it predates my diagnoses and it’s been progressive. Why does this happen though? Why, Carly Beth, Why? My voice is weakened by physical activity, even when not having talked at all. This happens because of the Compensatory Activation occurring in my bulbar musculature that is compensating for my weakened diaphragm during breathing. The same muscles that are activating to assist with speech volume control are activating to also assist with breathing. They’re doing these two things while also working to perform their normal job. When all of these aggregate parts of the puzzle are pieced together, it’s easy to see why my throat muscles and my vocal cords get weak quickly, get worn out quickly, and get painfully sore quickly. It’s no wonder that with continued use and with continued exertion, I lose speech articulation, and can lose it to the point of not being able to physically form words. All of this was witnessed in real time via videokymography. The Big Reveal Root cause analysis revealed that yes, my throat and voice issues are related to my CMT. Root cause analysis further revealed that my bulbar muscle involvement is not a direct result of my CMT insofar as evidence does not at this time support that my issues are caused by any Cranial Nerves VII – XII involvement that might be present. Rather, my bulbar muscle involvement is indirect insofar as root cause analysis revealed that Compensatory Activation of my bulbar muscles is occurring. And, this Compensatory Activation is occurring because my CMT has weakened my diaphragm. Questions answered. My bulbar musculature is not directly weakened by my CMT. This is a plus. My bulbar musculature is not directly exhibiting CMT caused paresis or paralysis. This, too, is a plus. While my CMT does involve the bulbar muscles, they are involved indirectly at the behest of my diaphragm being directly weakened by my CMT. Knowing the intrinsic root cause of my bulbar musculature issues allows us to design a mitigation therapy that is properly tailored to the deficits I have rather than approaching the problem with conventional wisdom and applying techniques that could very well do more harm than good. The plan we arrived at via informed decision making upon identifying the root cause is to work with a neuromuscular speech pathologist, whom is also at Umich, to develop a speech therapy program that will help to maximize the efficient use of the muscle function I do have, while minimizing the abuse suffered by my Compensatory Activation. Remember Dr. Kupfer? She’s the neuromuscular ENT physician I mentioned earlier. Well, Dr. Kupfer knows what’s up. Dr. Kupfer suggested that, had she turfed me out to speech therapy without first investigating the true cause of my symptoms and complaints, her instructions to the speech pathologist would have been profoundly different. She feels that so doing without having first performed root cause investigatory medicine would have ended up causing more harm by making things worse than they already are. In Closing I’m not a physician or a clinician. I never try to diagnose myself, and I am certainly not qualified to diagnose anybody else, nor would I try. A few years ago, my CMT physician at the time, who I trust to this day even though they are no longer my physician, said that my bulbar musculature complaints and symptoms were consistent with bulbar muscle weakness and vocal cord paralysis, and that both are consistent with being caused by my CMT. They felt they didn’t need to pursue needless investigatory work, I was comfortable with how everything was explained, and it made sense to me. However, things have only gotten worse. With everything I have learned regarding CMT since then, the explanation for my bulbar muscle issues stopped making sense, and I started pushing for answers. I am very fortunate to have the physicians I have, and I am very fortunate to be plugged into the medical system that I am. Even being as fortunate as I am, none of these latest findings would be possible if it wasn’t for my tenacious self-advocacy, and that of my wife’s. Never be afraid to advocate for yourself. No matter the physician or clinician, push for answers when nothing makes sense. There is always an explanation. There is always an answer. Never accept otherwise. Ever. Nothing is easy or simple with CMT. There is only complexity. This disease affects everybody vastly differently, and even within the same family. If you’re having some of the same issues that I talk about in this story, but your physician is scratching their head because they can’t explain it, or they think you’re making it up, or it just doesn’t make sense, show them this story. The root cause of what I’m experiencing might be the inexplicable root cause of what you’re experiencing. If it’s not, don’t stop advocating, don’t stop pushing until you have your definitive answer. The answers are there, if somebody knows how to look, and if somebody understands what they are looking at. #cmt #cmtrespiratoryissues #cmt1a #cmta #respiratoryfailure #neuromuscularrespiratoryfailure