GDAP1 mutations in CMT 4A in Italian families

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Abstract from J Neurol Neurosurg Psychiatry. 2004 Oct;75(10):1495-8.

A novel mutation of GDAP1 associated with Charcot-Marie-Tooth disease in

three Italian families: evidence for a founder effect.

Di E, Gulli R, Balestra P, Cassandrini D, Pigullo S, Doria-Lamba

L, Bado M, Schenone A, Ajmar F, Mandich P, Bellone E.

Department of Neuroscience, Ophthalmology and Genetics, Section of

Medical Genetics, University of Genova, c/o DIMI - Viale Benedetto XV, 6

16132 Genova, Italy.

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.