Charcot-Marie-Tooth Disease, Type 4A

Abstract

Peroneal muscular atrophy has been called Charcot-Marie-Tooth disease. Several genetic entities pertain to this disorder, both with autosomal dominant and autosomal recessive or X-linked pattern of inheritance. Electrophysiological studies suggested that the slowing of nerve conduction velocities distinguishes patients with a hypertrophic demyelinating form (CMT type 1) from patients with a neuronal form (CMT type 2). CMT4A is a severe, early-onset form of peripheral sensorimotor polyneuropathy characterized by severe motor retardation and progressive scoliosis. CMT4A is considered as the most frequent of all autosomal recessive forms of CMT. It was originally described in families from Tunisia but has since been reported in Europe (including Spain and Italy where founder mutations have been identified) and in Hispanic families from North America. Onset usually occurs in infancy with distal muscle weakness and foot atrophy, followed by proximal involvement and then distal weakness in the upper extremities and atrophy of the hands. Vocal cord paresis may also occur. CMT4A is caused by mutations in the GDAP1 gene (Table 73.1), which encodes an integral membrane protein of the outer mitochondrial membrane, expressed in the central and peripheral nervous system, particularly in Schwann cells. Mutations in the same gene have been associated with CMT4C4 (with axonal phenotype and vocal cord paralysis) and with a less severe later-onset autosomal dominant axonal form of CMT2K.