With a prevalence of 1 in 1500, Charcot-Marie-Tooth disease (CMT) is the most commonly inherited neuropathy. Subtype CMT-1A is caused by a duplication of a region on chromosome 17 encoding peripheralmyelin protein 22 (PMP22). Overexpression of PMP22 disrupts several signalling pathways and causes abnormal functioning of transcriptional regulatory mechanisms, resulting in demyelination of peripheral nerves, axonal degeneration, neurofilament phosphorylation, and increasing neurofilament densities manifest, ultimately provoking secondary axonal loss and atrophy. These changes decrease the nerve conduction velocity, causing symptoms such as muscle weakness, sensory loss, distal atrophy, and foot deformities which manifest during adolescence. The cellular mechanisms leading to this characteristic phenotype are disturbed myelin stoichiometry, toxic accumulation of protein aggregates, activation of autolysosomal degradation pathway, and dysfunction of purinoreceptor P2X7. Therapies aim to prevent the deterioration of axons by limiting the overexpression of PMP22 and inhibiting P2X7. Proposed therapy options include onapristone, ascorbic acid and neurotrophin 3.
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