Abstract

Background: Mutations in a gene encoding a novel protein of unknown function—the ganglioside-induced differentiation-associated protein 1 gene (GDAP1)—are associated with the autosomal recessive Charcot-Marie-Tooth disease type 4A (CMT4A).

Objective: To investigate the role of GDAP1 mutations in causing autosomal recessive neuropathies in an Italian population.

Methods and results: 76 patients with severe early onset polyneuropathy and possible autosomal recessive inheritance were screened for mutations. A T>G transversion (c.347 T>G) at codon 116 (M116R) was detected in four affected subjects from three apparently unrelated families. All patients had early onset of disease with pronounced foot deformities and impaired walking. Neurophysiological studies showed an extremely variable expression. Sural nerve biopsies revealed signs of both de-remyelination and axonal impairment, the most prominent feature being a severe loss of larger fibres. Haplotype analysis of the GDAP1 locus demonstrated a common disease haplotype.

Conclusions: The association of the mutation with a common haplotype suggested a common ancestor.