Hereditary Motor Sensory Neuropathies (Charcot–Marie–Tooth Disease)

Key genes: PMP22 duplication, mutations of MPZ, LITAF/SIMPLE, EGR2, NEFL
CMT1X (X-linked)
Key gene: GJB1HMSN2 (dominant axonal): median or ulnar motor conduction velocity >38 m/sAD-CMT2A–N
Some key genes: MFN2, KIF1B, RAB7, TRPV4, GARS, NEFL, HSPB1 and -8, MPZ, DNM2, YARS, BSCL2
AR-CMT2 (very rare):
Some involve lamin A/C, GDAP1HMSN3: Déjérine–Sottas syndrome/congenital hypomyelinating neuropathy – severe early onset, conduction velocity <10 m/sHMSN3 or CMT3
Key genes: point mutations in PMP22, MPZ, EGR2, PRXHMSN4: recessive demyelinatingCMT4A-J
More common genes include: GDAP1 (CMT4A), SH3TC2 (CMT4C), PRX (CMT4F)HMSN5: dominant axonal neuropathy with spastic paraparesisMFN2 and BSCL2 mutations account for some patientsHMSN6: axonal neuropathy with optic atrophyMFN2 mutations account for some patientsHMSN7: axonal neuropathy with retinitis pigmentosa?Other, e.g. tomaculous neuropathyHNPP
PMP22 deletion, point mutations

AD, autosomal dominant; AR, autosomal recessive; BSCL2, Berardinelli–Seip congenital lipodystrophy 2; CMT, Charcot–Marie–Tooth disease; DNM2, dynamin 2; EGR2, early growth response protein 2; GARS, glycyl-tRNA synthetase; GDAP1 ganglioside-induced differentiation-associated protein 1; GJB1; gap junction beta-1 protein; HMSN, hereditary motor sensory neuropathy; HNPP, hereditary neuropathy with liability to pressure palsies; HSP, heat shock protein; KIF1B, kinesin family member 1B; LITAF, lipopolysaccharide-induced tumor necrosis factor-α factor; MFN2, itofusin-2; MPZ, myelin p zero gene; NEFL, neurofilament light polypeptide; PMP22, peripheral myelin protein 22 gene; PRX periaxin; SH3TC2 SH3 domain and tetratricopeptide repeats 2; TRPV4, transient receptor potential cation channel, subfamily V, member 4; YARS, tyrosyl-tRNA synthetase.

Specific CMT Neuropathies and HNPP (Table 21.3)


CMT1A is the most common CMT, accounting for 70–90% of CMT1 and 50% of all CMT. It is caused by duplication of a 1.5-Mb fragment on chromosome 17p.11 which includes the peripheral myelin protein 22 (PMP22) gene. PMP22 overexpression underlies development of CMT1A. New duplication of PMP22 (resul­ting in sporadic CMT), accounts for 10% of CMT1A. Patients usually present with a “classic CMT disease phenotype” beginning in the first two decades. Longevity is normal, but disease severity variable. Affected individuals commonly require bracing or other gait-assistive devices, but rarely become wheelchair bound. Occasional patients develop scoliosis, upper extremity postural tremor, or hearing and respiratory impairment. Nerve conduction studies (NCSs) disclose a demyelinating neuropathy, with upper limb motor NCVs that are almost invariably between 10 and 38 m/s, with uniform slowing.

CMT1B is due to mutations in the myelin protein zero gene (MPZ), located on chromosome 1 and accounts for about 5% of CMT1. It is essential for the normal structure and function of myelin. Over 120 MPZ point mutations have been associated with CMT. Patients can present with a “classic CMT disease phenotype”, but are more likely to have either a severe earlier onset form with delayed ambulation and NCV <10 m/s (HSMNIII) or adult onset with variable NCV slowing.

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MPZ mutations can manifest with a varying phenotype:

  • CMT1B: early onset of a “classic CMT phenotype”
  • HMSN III (DSN-CHN): infantile or early childhood onset, most severe form of CMT, very slow nerve conduction velocities (<10 m/s)
  • CMT2I/J: late-onset CMT2, can be severe; pupillary abnormalities, deafness, and dysphagia possible
  • Dominant intermediate CMT: variable severity.

Note: CHN is congenital hypomyelinating neuropathy; DSN is Déjérine–Sottas neuropathies.

X-linked dominant CMT (CMT1X) is the second most common CMT (10% of all cases) and is associated with mutations in the gap junction protein beta-1 (GJB1) gene encoding connexin 32 which acts as a gap junction in compact myelin. Males present earlier and are usually more severely affected than females. Electrodiagnostic testing shows intermediate range NCV (25–45 m/s), with typically slower NCVs in affected males than females.

Hereditary Neuropathy with Liability to Pressure Palsies

HNPP is an AD disorder that is allelic with CMT1A, with 85–90% of cases due to a PMP22 gene deletion and in 10% to a PMP22 point mutation. It usually presents with recurrent painless neuropathies at compression sites (e.g. median neuropathy at the wrist, peroneal neuropathy at the knee). The focal neuropathies recover spontaneously, although fixed neuropathic deficits accrue over time. Incidental compression (e.g. leaning on an elbow, knee crossing, squatting, or positioning during surgery) can trigger the neuropathies. The focal neuropathies are typically superimposed on a mild, often asymptomatic underlying polyneuropathy. HNPP also predisposes to painless brachial plexopathies. Occasionally a fulminant presentation of HNPP has been described that resembles mononeuritis multiplex.

The electrophysiological pattern is one of a multifocal demyelinating neuropathy with particularly slowed motor and sensory distal latencies. Conduction block is seen at typical compression sites. Sural nerve biopsy (although rarely required for diagnosis) shows frequent focal myelin thickenings known as tomaculae. A lack of awareness of HNPP can lead to unnecessary nerve decompressions, treatment with immunosuppressive agents for misdiagnosed acquired inflammatory demyelinating polyneuropathy, or failure to take precautions to avoid external peripheral nerve compression.

CMT2 (Dominant Axonal CMT)

CMT2 represents 25–30% of all CMT, although it may be underdiagnosed because causative mutations are identified in only 30% of families. Mutations in the mitochondrial fusion protein, mitofusin 2 (MFN2), cause CMT2A and account for about 20% of CMT2 disease cases. MFN2 muta­tions typically are associated with childhood-onset CMT with distally dominant atrophy, weakness, and sensory loss in lower more than upper extremities. However. mild later onset or asymptomatic cases do occur. Some MFN2 mutations produce optic atrophy and CMT neuropathy (HMSN6), while others display a combination of axonal neuropathy and lower limb hyperreflexia (HMSN V) (see Table 21.3). It is unclear how MFN2 mutations produce CMT, but they result in abnormal mitochondrial fusion and disordered mitochondrial kinetics.

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Distinct phenotypes occur in CMT2 that are diagnostically helpful and direct genetic testing.

CMT2 disease Associated gene Clinical features
CMT2A MFN2 Classic CMT phenotype; optic atrophy or pyramidal tract signs frequently present
CMT2B RAB7 Prominent sensory loss, ulceromutilation
CMT2C TRPV4 Early onset vocal fold and diaphragm involvement, proximal weakness
CMT2D GARS/BSCL2 Upper limb and motor predominance
CMT2I/J MPZ Late onset; pupillary abnormalities; hearing loss, pain and possible dysphagia
CMT2H/K GDAP1 Early onset (<2 years); severe course; frequent vocal fold paralysis

BSCL2, Berardinelli–Seip congenital lipodystrophy 2; GARS, glycyl-tRNA synthetase; GDAP1, ganglioside-induced differentiation-associated protein; MFN2, mitofusin-2; MPZ, myelin protein zero; RAB7, small GTPase late endosomal protein; TRPV4, transient receptor potential cation channel, subfamily V, member 4.

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Jul 19, 2016 | Posted by in NEUROLOGY | Comments Off on Hereditary Motor Sensory Neuropathies (Charcot–Marie–Tooth Disease)
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