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  Disease summary:

  
  
  
  
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    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.

    
    
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    The disease is extremely heterogeneous both clinically and genetically (Table 132-1).

    
    
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    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.

  
  
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  Hereditary basis:

  
  
  
  
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    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.

    
    
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    Thirty-six different genetic loci have been linked to CMT; for 30 of these loci, specific genes have been identified.

    
    
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    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.

    
    
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    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.

    
    
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    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.

  
  
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  Differential diagnosis:

  
  
  
  
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    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).

    
    
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    Other hereditary disorders with a neuropathic component, including other HMSNs, hereditary sensory and autonomic neuropathies (HSANs), distal hereditary motor neuropathy, etc.

    
    
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    Other conditions, such as myopathies, muscular dystrophy, amyotrophic lateral sclerosis (ALS), mitochondrial disorders, and many others.

Diagnostic Criteria

Electrophysiologic studies: Symmetrically slowed NCVs of less than 38 m/s (normal value >45 m/s) indicates demyelinating CMT (CMT1; ~60%-70% of patients), while normal or slightly slowed NCVs with reduced compound muscle action potentials are features of axonal CMT (CMT2; ~20%-40% of patients).

Histopathologic evaluation of the sural nerve: Segmental demyelination and remyelination (onion bulb formation) in CMT1; normal myelin but reduced number of nerve fibers in CMT2.

Clinical characteristics

CMT disease: Peripheral muscle weakness in lower and upper extremities, foot deformities, hammer toes, steppage gait, claw hand, hypo- or areflexia, sensory loss. Subtypes which have been studied appear to be highly penetrant. Age of symptom onset is variable, but usually occurs in the first or second decade of life. Most individuals with CMT1 walk without significant disability past middle age and a few (<5%) become wheelchair dependent.

HNPP: Nerve palsies following nerve compression. Focal thickening of myelin sheath (tomacula) on pathologic examination. Penetrance is unknown.