CMT Types & Subtypes
Genetically, CMT is a collection of 155 unique conditions that are caused by mutations in any one of 120 genes, and these numbers are growing. Stripped down to its very core, CMT is CMT, and each subtype name represents the name of the underlying genetic cause. When a scientist discovers a new CMT genetic cause—a CMT-causing gene mutation, they name this discovery. The name given becomes a CMT subtype name. The CMT name given to a new genetic discovery is based on several criteria, and the type categories define these criteria. The scientist(s) who make the discovery have the distinct honor of deciding its CMT name, and the type category criteria guide the scientist(s) in the name choice.
CMT as a Name and as an Acronym
CMT, as a disease name, is an acronym that represents the names of the three doctors who first described it in 1886: Jean-Martin Charcot (1825-1893), Pierre Marie (1853-1940), and Howard Henry Tooth (1856-1925). This acronym, however, has grown into an umbrella term that represents many different inherited sensory and/or motor neuropathies. The many different inherited neuropathies that encompass CMT are comprised of the acronyms that represent the types, and each are but a category into which CMT subtypes are sorted by scientists for ease of organization. The 14 type categories that CMT subtypes are sorted into are: CMT Type 1 (CMT1), CMT Type 2 (CMT2), CMT Type 4 (CMT4), X-Linked CMT (CMTX), Dominant Intermediate CMT (CMTDI), Recessive Intermediate CMT (CMTRI), Distal Hereditary Motor Neuropathy (dHMN), Distal Spinal Muscular Atrophy (dSMA), Giant Axonal Neuropathy (GAN), Hereditary Motor and Sensory Neuropathy (HMSN), Hereditary Sensory and Autonomic Neuropathy (HSAN), Hereditary Sensory Neuropathy (HSN), Lower Extremity Predominant Spinal Muscular Atrophy (SMA-LEP), and one known as [Gene Name]-CMT that is stated as, “[Gene Name]-associated CMT,” as in “SORD1-associated CMT.”
CMT Type Category Definitions
These are the 14 categories that represent the CMT Types. The criteria given for each are how scientists determine the name of a new CMT subtype when they discover a new CMT cause. In a sense, this is how CMT subtypes are sorted.
CMT4 subtypes are a demyelinating neuropathy and are autosomal recessive in inheritance.
CMTX subtypes are each X-Linked in Inheritance.
CMTDI subtypes are an intermediate neuropathy and are autosomal dominant in inheritance.
CMTRI subtypes are an intermediate neuropathy—nerve conduction profile overlaps demyelinating CMT and axonal CMT and are autosomal recessive in inheritance.
dHMN subtypes are a motor neuropathy affecting primarily the most distal points, affect primarily motor neurons, have little to no sensory nerve involvement, are an axonal neuropathy, and are either autosomal dominant or autosomal recessive in inheritance.
dSMA subtypes are a motor neuropathy affecting primarily the most distal points, affect primarily motor neurons, have little to no sensory nerve involvement, and dSMA is synonymous with dHMN. dSMA subtypes are either an axonal or intermediate neuropathy and they are either autosomal recessive or X-Linked recessive in inheritance.
GAN subtypes affect the central nervous system and the peripheral nervous system and are an axonal neuropathy. GAN has two subtypes. GAN-1 is autosomal recessive in inheritance, and GAN-2 is autosomal dominant in inheritance.
HMSN subtypes affect both motor and sensory nerves, the acronym has been historically used to represent CMT as a whole, and this acronym is preferred over CMT by many. Currently, six subtypes are known only by their HMSN name. Each are an axonal neuropathy and are either autosomal dominant or autosomal recessive in inheritance.
HSAN subtypes affect primarily the sensory nerves and the autonomic nerves, have little to no motor nerve involvement, are an axonal neuropathy, and are either autosomal dominant or autosomal recessive in inheritance.
HSN subtypes affect primarily the sensory nerves, have little to no motor nerve involvement, are an axonal neuropathy, and are either autosomal dominant or autosomal recessive in inheritance.
SMA-LEP subtypes are a motor neuropathy affecting primarily the lower extremities, affect primarily motor neurons, have little to no sensory nerve involvement, are an axonal neuropathy, and are autosomal dominant in inheritance.
[Gene Name]-CMT subtypes are known only by their CMT-associated gene name. These subtypes are either a demyelinating neuropathy or an axonal neuropathy; and are either autosomal dominant, autosomal recessive, or X-Linked dominant in inheritance.
Not Every CMT-Associated Gene Mutation is a CMT-Causing Mutation
CMT is caused by mutations in genes. Genes that have CMT-causing mutations are known as CMT-associated genes. More importantly, not every mutation in a CMT-associated gene causes CMT, and there are several notable examples. Many different and unique mutations in the MFN2 gene cause CMT. Some mutations cause CMT2A, some cause CMT2A2B, some cause CMT2B4, some cause HMSN6A, and others cause nothing at all—benign mutations that are harmless. Over 400 different mutations in the GJB1 gene cause CMTX1, while other mutations in this gene are harmless.
We normally have two copies of every gene, with very few exceptions. A duplication of one copy of the PMP22 gene causes CMT1A. A deletion of one copy of this gene causes the CMT subtype HNPP. Yet, mutations within the PMP22 gene, rather than a gene duplication or deletion, cause CMT1E, and different mutations from these CMT1E causing mutations can also cause HNPP.
These each perfectly illustrate that CMT is about the exact mutation of the gene, and not just the presence of a mutation. Having a mutation in a CMT-associated gene does not necessarily mean the mutation is causing the CMT—the mutation itself might be benign and harmless, with the CMT having a different cause with a different gene. There might even be a hidden cause yet to be discovered.
Introducing The Cryptid Sloth's CMT-Associated Genes Database
The Cryptid Sloth offers the most comprehensive searchable public database of CMT-associated genes and their related subtypes that is available. Every effort has been made to include the most up-to-date information on CMT-associated gene discovery and named subtypes. Using the search tools, you can easily search by type, by inheritance, by neuropathy, or by any combination of these options. You can even search by gene for the subtypes associated with that gene.
Our own Kenneth Raymond built this searchable database for his groundbreaking book, CMT-Associated Genes and Their Related Subtypes: The Definitive Guide, 1St Edition, and the database is now available here for all to use. This CMT genetics guide for the CMTer and the practicing physician alike is available for free from the Charcot-Marie-Tooth Association as an eBook download on the CMTA website.
This database does not include symptom overviews and profiles. Rather, this database contains subtype specific information relating to the genetics of CMT, i.e. each named subtype, each discovered CMT-associated gene, the manner in which each subtype is inherited (the inheritance pattern), the chromosome each CMT-associated gene lives on, each subtype’s neuropathy type, etc.—comprehensive information that is difficult to find elsewhere, but is the most basic of CMT information. The What is CMT page is where you’ll find an overview of CMT symptoms.