132: Charcot-Marie-Tooth Disease

Key Points

• Disease summary:

  • 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.

• Hereditary basis:

  • 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.

• Differential diagnosis:

  • 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.