Hereditary Neuropathies

Motor and sensory neuropathies

Charcot-Marie-Tooth disease is the most common form of hereditary neuropathy. There are 3 main types (CMT1, CMT2, and CMT3), all begin in childhood. Some less common types begin at birth and result in greater disability.

CMT1 and CMT2 (varieties of Charcot-Marie-Tooth disease, also called peroneal muscular atrophy) are the most common; they are usually autosomal dominant disorders but, rarely, can be recessive or X-linked. Type I results from a duplication (extra copy) or deletion of the peripheral myelin protein-22 gene (PMP22), located on the short arm of chromosome 17; it accounts for 70 to 80% of CMT1 cases (1).

CMT1 and CMT2 are characterized by weakness and atrophy, primarily in peroneal and distal leg muscles. Patients often have a family history of neuropathy. The natural history varies: some patients are asymptomatic and have only slowed conduction velocities (detected on nerve conduction studies); others are more severely affected.

Patients with CMT1 may present in middle childhood with footdrop and slowly progressive distal muscle atrophy, causing stork leg deformity. Intrinsic muscle wasting in the hands begins later. Vibration, pain, and temperature sensation decrease in a stocking-glove pattern. Deep tendon reflexes are absent. High pedal arches or hammertoes may be the only signs in family members who are carriers. Nerve conduction velocities are slow, and distal latencies are prolonged. Segmental demyelination and remyelination occur. Enlarged peripheral nerves may be palpated. The disease progresses slowly and does not affect lifespan. In 1 subtype, males have severe symptoms, and females have mild symptoms or may be unaffected.

The genetics of CMT2 are less clear. One study found that CMT2 accounts for 12 to almost 36% of all CMT cases (2); pathogenic mutations have been identified in only about 25% of patients, with many subtypes. CMT2A is the most common CMT2 phenotype, most often due to a mutation in the gene that encodes mitochondrial fusion protein mitofusin-2 (MFN2). CMT2A is usually an autosomal dominant disorder. It evolves slowly; weakness usually develops later in life. Patients have relatively normal nerve conduction velocities but low amplitude sensory nerve action potentials and compound muscle action potentials. Biopsies detect axonal (wallerian) degeneration.

CMT3 (also known as Dejerine-Sottas disease) is a rare congenital hypomyelinating neuropathy, which can be an autosomal dominant or a recessive disorder with mutations in several genes, including PMP22, MPZ, and EGR2. It begins in childhood with progressive weakness and sensory loss and absent deep tendon reflexes. Although initially it resembles Charcot-Marie-Tooth disease, the motor weakness progresses more quickly. Demyelination and remyelination occur, producing enlarged peripheral nerves and onion bulbs, detected by nerve biopsy.

Hereditary sensory and autonomic neuropathy (HSAN)

Hereditary sensory and autonomic neuropathies are rare. Eight main types have been described. HSAN1 is the most common subtype, caused by a missense mutation in SPTLC1 or SPTLC2 genes.

Loss of distal pain and temperature sensation is more prominent than loss of vibratory and position sense. The main complication is foot mutilation due to pain insensitivity, resulting in a high risk of infections and osteomyelitis. Autonomic symptoms include heart rate and blood pressure variability, abnormal sweating, and gastrointestinal disorders (dysmotility). Distal motor weakness is also common (3).

References

1. 1. Gutmann L, Shy M. Update on Charcot–Marie–Tooth disease. Curr Opin Neurol. 28 (5):462–467, 2015. doi: 10.1097/WCO.0000000000000237

2. 2. Barreto LCLS, Oliveira FS, Nunes PS, et al. Epidemiologic study of Charcot-Marie-Tooth disease: A systematic review. Neuroepidemiology. 46 (3):157–165, 2016. doi: 10.1159/000443706

3. 3. Hayes LH, Sadjadi R. Hereditary Neuropathies. Continuum (Minneap Minn). 2023;29(5):1514-1537. doi:10.1212/CON.0000000000001339