Type 4A/Type 2 Research from Spain

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Abstract from Brain. 2003 Jun 23

Clinical, electrophysiological and morphological findings of

Charcot-Marie-Tooth neuropathy with vocal cord palsy and mutations in

the GDAP1 gene.

Sevilla T, Cuesta A, Chumillas MJ, Mayordomo F, Pedrola L, Palau F,

Vilchez JJ.

Department of Neurology, University Hospital La Fe, Valencia, Spain.

Three Spanish families with an autosomal recessive severe hereditary

motor and sensory neuropathy, showing mutations in the

ganglioside-induced-differentiation-associated protein 1 (GDAP1) gene in

the Charcot-Marie-Tooth (CMT) type 4A locus were studied. The disorder

started in the neonatal period or early infancy with weakness and

wasting of the feet and, subsequently, involvement of the hands, causing

severe disability. By the late teens, some patients developed a hoarse

voice and vocal cord paresis. Peripheral motor nerve conduction velocity

(MNCV) could not be measured in many cases because of the absence of

muscle response due to distal atrophy. However, latencies to proximal

muscles were in the normal range; median MNCV was >40 m/s in those cases

in which it could be measured. Sural nerve biopsy from two patients

showed a pronounced depletion of myelinated fibres, regenerative

clusters and signs of axonal atrophy. Additionally, a small proportion

of thin myelinated fibres and proliferation of Schwann cells forming

onion bulb structures were also found. Unmyelinated fibre

population was markedly increased. These findings are indicative of a

predominant axonal degeneration with some demyelinating features.

These Spanish families share in the severe CMT clinical phenotype with

some Tunisian families who also presented mutations in the GDAP1 gene

and to which the CMT4A locus was originally assigned. However, our

families differ in the presence of laryngeal involvement and values of

MNCV and pathological features are more in line with CMT2 type. The

possibility that GDAP1 gene mutations could be expressed under different

phenotypes is a question to be resolved.