Autosomal dominant Charcot-Marie-Tooth disease type 2B

Autosomal dominant Charcot-Marie-Tooth disease type 2B (CMT2B) is a rare inherited peripheral neuropathy characterized primarily by a severe sensory neuropathy with prominent distal sensory loss, particularly affecting pain and temperature sensation in the feet and hands. It is also known as hereditary motor and sensory neuropathy type IIB (HMSN IIB). CMT2B is caused by mutations in the RAB7A gene on chromosome 3q21, which encodes a small GTPase involved in endosomal trafficking and autophagy. The disease predominantly affects the peripheral nervous system, with axonal degeneration being the primary pathological feature rather than demyelination. Clinically, CMT2B is distinguished from other CMT2 subtypes by its striking predisposition to distal ulcerations, infections, and osteomyelitis of the feet, frequently leading to toe and foot amputations. Patients typically present in the second or third decade of life with difficulty walking, foot deformities (such as pes cavus and hammer toes), and progressive distal muscle weakness and atrophy, predominantly in the lower limbs. The sensory loss is often severe and can lead to painless injuries and secondary complications including non-healing wounds. Motor involvement is variable but generally milder than the sensory component. Nerve conduction studies typically show reduced or absent sensory nerve action potentials with relatively preserved motor conduction velocities, consistent with an axonal neuropathy. There is currently no cure or disease-modifying therapy for CMT2B. Management is supportive and multidisciplinary, focusing on prevention of foot ulcers through meticulous foot care, appropriate footwear, and regular podiatric surveillance. Physical therapy and orthotic devices can help maintain mobility and prevent contractures. Surgical intervention may be necessary for severe foot deformities or non-healing ulcers. Genetic counseling is recommended for affected families given the autosomal dominant inheritance pattern, meaning each child of an affected individual has a 50% chance of inheriting the condition.

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