Charcot-Marie-Tooth Disease, Axonal, With Vocal Cord Paresis, Autosomal Recessive

A number sign (#) is used with this entry because of evidence that autosomal recessive axonal CMT with vocal cord paresis is caused by homozygous or compound heterozygous mutation in the GDAP1 gene (606598). Mutations in the same gene cause autosomal recessive demyelinating CMT4A (214400).

For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (118210).

Clinical Features

Cuesta et al. (2002) reported 3 families of Spanish ancestry with an autosomal recessive axonal CMT phenotype associated with hoarse voice and vocal cord paresis. The clinical picture was characterized by onset in childhood of weakness and hand and foot wasting, leading to disability by the end of the first decade and necessitating wheelchair use (Sevilla et al., 2001). Sensory nerve action potentials were decreased or absent in all affected individuals. Sural nerve biopsies of 2 probands showed loss of myelinated fibers and axonal degeneration, with no signs of demyelination and remyelination. Sevilla et al. (2003) provided a more detailed clinical description of the 3 families reported by Cuesta et al. (2002). All 9 affected patients had disease onset in the neonatal period or before the age of 2 years. All patients showed severe distal muscle weakness and atrophy of the upper and lower limbs, often classified as paralysis. All patients had severe sensory loss in the hands, including pinprick, vibration, and touch, with additional loss of vibratory sense in the feet. All had absent reflexes. Spinal deformities, pes cavus, claw hands, and contractures were also present. Motor nerve conduction velocities, when present, were within the normal range. Sural nerve biopsies showed marked loss of myelinated fibers, axonal degeneration and regeneration, and occasional onion bulb formations.

Molecular Genetics

In 3 Spanish families with autosomal recessive axonal neuropathy, Cuesta et al. (2002) identified mutations in the GDAP1 gene (see, e.g., 606598.0004). Thus, mutations in GDAP1 are associated with both axonal and demyelinating phenotypes, as has been reported for the MPZ gene (159440) (Vance, 2000).