Charcot-Marie-Tooth and Other Inherited Neuropathies
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- Charcot-Marie-Tooth (CMT) and hereditary neuropathies are genetically heterogeneous disorders primarily affecting peripheral nerves in a length-dependent pattern with symmetrical motor greater than sensory manifestations in most cases.
- Onset is typically in childhood, adolescence, or young adulthood.
- Categorized by pathophysiology, inheritance pattern, and genotype; type 1 is characterized by a disruption in myelin formation, and type 2 is due to disruption of axonal integrity.
- OMIM has 64 entries in its phenotypic series for CMT disease.
- Autosomal dominant
- CMT1 subtypes A to F
- CMT2 subtypes A to L
- CMT3/Dejerine-Sottas disease (severe congenital)
- X-linked dominant: CMTX
- Autosomal recessive (rare): CMT4
- Mitochondrial disorders with neuropathy
- Neuropathy, ataxia, and retinitis pigmentosa (NARP)
- Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)
- Hereditary neuropathy with liability to pressure palsies (HNPP)
- Axonal neuropathies
- Giant axonal neuropathy (GAN)
- Hereditary neuralgic amyotrophy (HNA with predilection for the brachial plexus)
- Hereditary sensory and autonomic neuropathies (HSANs; rare): HSAN1; HSAN2 (Morvan disease); HSAN3 (familial dysautonomia); HSAN4 (anhidrotic sensory neuropathy)
CMT: 1/2,500 to 1/3,300
- CMT1: 70% of all CMT disorders, CMT1A is the most common making up 80% followed by type 1B, which accounts for 10%.
- 20% of patients with undiagnosed polyneuropathy presenting to a neurologist have CMT1A.
- CMTX is 10% of all CMT.
- CMT2 is 30% of all CMT. CMT2A2 is the most common subtype (20%).
Etiology and Pathophysiology
- CMT is a spectrum of disorders caused by ~1,000 different genetic mutations in >80 different genes (1).
- Peripheral myelin protein 22 (PMP22) is responsible for the formation of compact myelin.
- Duplication of the gene (increased PMP dosage) results in the CMT1A phenotype.
- Deletion results in the HNPP phenotype.
- Mitofusin 2 (MFN2) determines structure and morphology of mitochondria.
- Mutation present in 20% of CMT2
- Myelin protein zero (MPZ or P0) compacts myelin; mutations present as different phenotypes (CMT1B, DSD, CHN, and CMT2)
- Gap junction protein, β-1 gene (GJB1, connexin 32)
- Gap junction protein found in noncompact myelin forms a gap junction to facilitate the movement of metabolites and ions through myelin.
- Mutation present in 90% of CMTX
- Vast majority are autosomal dominant inheritance.
- X-linked dominant (codominant) is second most common inheritance pattern: females less severely affected than male family members
- Autosomal recessive inheritance is rare and occurs typically in isolated populations with consanguinity. Mitochondrial or maternal inheritance is rare, usually associated with involvement of other organ systems.
- Positive family history of neuropathy
- Foot and hand deformities (e.g., pes cavus, hammer toes, claw hand)
- Frequent ankle sprain, tripping, gait difficulties, distal weakness and sensory loss
Most inherited neuropathies are highly penetrant; treatment is supportive.
Commonly Associated Conditions
- Foot deformities, heel-cord shortening, contractures, muscle wasting, osteoarthritis, scoliosis
- Hearing loss
- Optic atrophy (CMT2A, CMTX5), retinopathy
- Vocal cord and phrenic nerve involvement (CMT2C)
- Restrictive airway disease and sleep apnea with phrenic nerve involvement