Charcot-Marie-Tooth disease (CMT), the broadest and most common disease class among the hereditary motor and sensory neuropathies (HMSNs), is a slowly progressive neurologic disease caused by dysfunction of the peripheral nerves with secondary muscle wasting, weakness, and sensory loss in a distal distribution. It is a distal symmetric polyneuropathy (DSP). DSP evidence-based medicine practice guidelines for laboratory and genetic testing have been established.
The disease is extremely heterogeneous both clinically and genetically (Table 132-1).
Electrophysiologic studies enable a distinction between the two major forms: (i) demyelinating (CMT1), with symmetrically slowed nerve conduction velocity (NCV); and (ii) axonal (CMT2), which is associated with normal nerve conduction velocity (NCV) but reduced compound muscle action potentials.
CMT can be observed as an autosomal dominant, autosomal recessive, or X-linked trait, predominately depending on the locus or gene involved. Many sporadic cases occur as a result of new mutation.
Thirty-six different genetic loci have been linked to CMT; for 30 of these loci, specific genes have been identified.
CMT subtypes are assigned broad designations based on nerve pathology and inheritance pattern: CMT1 = dominant, demyelinating; CMT4 = recessive, demyelinating; CMT2 = axonal; dominant, intermediate CMT (CMTDI) = dominant, mixed demyelinating and axonal; recessive, intermediate CMT (CMTRI) = recessive, mixed demyelinating and axonal; CMTX = X-linked. Within each class, specific designations are assigned for each separate gene or locus involved.
The most prevalent form of CMT disease, CMT1A, is caused in the vast majority of cases by copy-number gain of the PMP22 gene and results from the CMT1A duplication and a gene dosage effect.
A deletion reciprocal to the CMT1A duplication results in hereditary neuropathy with liability to pressure palsies (HNPP), a milder condition characterized by recurrent episodes of nerve palsies at sites of compression.
Acquired neuropathies associated with chronic disorders, including diabetes mellitus, vitamin deficiencies, and chronic infections (eg, HIV), paraneoplastic neuropathy, and iatrogenic causes (ie, side effect of chemotherapy; note that vincristine can cause a severe and sometimes lethal neuropathy in patients with CMT).
Other hereditary disorders with a neuropathic component, including other HMSNs, hereditary sensory and autonomic neuropathies (HSANs), distal hereditary motor neuropathy, etc.
Other conditions, such as myopathies, muscular dystrophy, amyotrophic lateral sclerosis (ALS), mitochondrial disorders, and many others.
Table 132-1Genetic Differential Diagnosis |Favorite Table|Download (.pdf) Table 132-1 Genetic Differential Diagnosis
|Syndrome ||OMIM ID ||Gene Symbol ||Inheritancea ||Unique Associated Findings |
|CMT1A ||#118220 ||PMP22 ||AD || |
|CMT1B ||#118200 ||MPZ ||AD || |
|CMT1C ||#601098 ||LITAF (SIMPLE) ||AD || |
|CMT1D ||#607678 ||EGR2 ||AD || |
|CMT1E ||#118300 ||PMP22 ||AD ||Sensorineural deafness |
|CMT1F ||#607734 ||NEFL ||AD, AR ||Early onset |
|CMT2A ||#609260 ||MFN2 ||AD, AR || |
|CMT2B ||#600882 ||RAB7A ||AD ||Notable sensory loss |
|CMT2B1 ||#605588 ||LMNA ||AR || |
|CMT2B2 ||#605589 ||MED25 ||AR || |
|CMT2C ||#606071 ||TRPV4 ||AD ||Vocal cord paresis, respiratory involvement |
|CMT2D ||#601472 ||GARS ||AD ||Involvement of hands more severe than of feet |
|CMT2E ||#607684 ||NEFL ||AD || |
|CMT2F ||#606595 ||HSPB1 ||AD || |
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