Charcot-Marie-Tooth and Other Inherited Neuropathies

Description

• 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. Many experts believe that changes are needed in the classification of CMT (1).
• 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)

Epidemiology

Prevalence
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 (2).
• 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

Genetics

• 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.

Risk Factors

• 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

General Prevention

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
• Pain is frequent and may have strong impact. It may be neuropathic or biomechanical and is not well understood (3).