Hereditary Motor and Sensory Neuropathy Advanced Subtypes

Hereditary motor and sensory neuropathies (HMSN), also known as Charcot-Marie-Tooth (CMT) disease, are a heterogeneous group of inherited peripheral neuropathies with prevalence 1:2500. Classification combines clinical phenotype, electrophysiology (median motor conduction velocity), inheritance pattern, and genetic testing.

Major subtypes include CMT1 (autosomal dominant demyelinating, MCV <38 m/s, PMP22 duplication in 70% of CMT1A), CMT2 (autosomal dominant axonal, MCV >38, MFN2 most common in CMT2A), CMT4 (autosomal recessive demyelinating, severe early-onset, GDAP1 and others), CMTX (X-linked, GJB1 connexin-32 most common), and intermediate forms. Advanced testing includes whole-exome sequencing, copy number variant analysis, and skin biopsy with epidermal nerve fiber density.

Clinical management requires multidisciplinary care: physical therapy and orthotic management for foot drop and ankle instability, custom shoes and ankle-foot orthoses, surgical correction for fixed deformities (Steindler stripping, triple arthrodesis), pain management for neuropathic pain, vocal cord and respiratory monitoring in advanced cases, cardiac evaluation in CMT1 with arrhythmia risk, and avoidance of neurotoxic medications (vincristine, cisplatin, taxanes). Emerging therapies include PMP22-targeted antisense oligonucleotides, gene therapy clinical trials for CMT1A and CMT4, and small molecule drugs targeting Schwann cell metabolism. Genetic counseling and pre-implantation genetic diagnosis offered to affected families.