Charcot-Marie-Tooth disease type 1

Charcot-Marie-Tooth disease type 1 (CMT1), also known as hereditary motor and sensory neuropathy type 1 (HMSN type 1) or demyelinating CMT, is a group of inherited peripheral neuropathies characterized by progressive demyelination of peripheral nerves. It is the most common subtype of Charcot-Marie-Tooth disease. CMT1 primarily affects the peripheral nervous system, leading to slowly progressive weakness and atrophy of the distal muscles, particularly in the feet, lower legs, hands, and forearms. The hallmark feature is reduced nerve conduction velocities (typically below 38 m/s in the median motor nerve), reflecting the underlying demyelinating pathology. Patients typically present in the first or second decade of life with difficulty walking, frequent tripping, and foot deformities such as high arches (pes cavus) and hammer toes. As the disease progresses, individuals may develop distal muscle wasting leading to the characteristic "inverted champagne bottle" appearance of the legs, steppage gait, and weakness in the hands affecting fine motor skills. Sensory loss in a stocking-glove distribution, decreased or absent deep tendon reflexes, and palpably enlarged peripheral nerves are also common findings. The severity of symptoms can vary considerably, even within the same family. CMT1 encompasses several genetic subtypes, the most common being CMT1A (caused by a duplication of the PMP22 gene on chromosome 17p), CMT1B (caused by mutations in the MPZ gene), CMT1C (LITAF gene), CMT1D (EGR2 gene), and others. There is currently no cure or disease-modifying therapy for CMT1. Management is supportive and multidisciplinary, including physical therapy to maintain muscle strength and flexibility, occupational therapy, orthotic devices such as ankle-foot orthoses (AFOs) to improve gait, pain management, and orthopedic surgery when needed for severe foot deformities. Several clinical trials investigating potential therapies, including PXT3003 and gene-based approaches, are ongoing.

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