ARCMT2: phenotype-genotype correlations in 13 Moroccan families

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Brain. 2007 Mar 8

Autosomal recessive axonal Charcot-Marie-Tooth disease (ARCMT2):

phenotype-genotype correlations in 13 Moroccan families.

Bouhouche A, Birouk N, Azzedine H, Benomar A, Durosier G, Ente D,

Muriel MP, Ruberg M, Slassi I, Yahyaoui M, Dubourg O, Ouazzani R,

Leguern E.

Laboratoire de Neurogenetique, Service de Neurologie B, Hopital des

Specialites, Service de Neurophysiologie clinique, Hopital des

Specialites, Rabat, Service de Neurologie, Hopital Ibn Rochd,

Casablanca, Morocco, UMR679 INSERM - Universite Paris VI (Pierre et

Marie Curie), Hopital de la Pitie-Salpetriere, Laboratoire de

Neuropathologie Escourolle, Hopital de la Pitie-Salpetriere,

AP-HP and Laboratoire de neurogenetique moleculaire et cellulaire,

Departement de genetique, cytogenetique et embryologie, Hopital de

la Pitie-Salpetriere, Paris, France.

Charcot-Marie-Tooth disease is a genetically heterogeneous group of

hereditary motor and sensory neuropathies. Three loci for the axonal

autosomal recessive subgroup (ARCMT2) have been reported in 1q21

(CMT2B1, LMNA), 8q21 (CMT4A and CMT2K, GDAP1) and 19q13 (CMT2B2). We

report here a clinical, electrophysiological, pathological and

genetic study in 13 Moroccan families with ARCMT2 phenotypes.

Clinical and electrophysiological examinations were performed in all

index cases and 64 'at-risk' relatives. Thirty-one patients were

clinically affected. A peroneal nerve biopsy was obtained from three

patients.

Four families were linked to the 1q21 locus, all had the LMNA R298C

mutation. Six families were linked to the 8q21 locus, all had the

GDAP1 S194X mutation. Founder effects for both mutations were

suggested by the analysis of microsatellite markers close to the

genes. The three remaining families were excluded from the three

known loci.

The electrophysiological findings were consistent with an axonal

neuropathy.

The clinical data show that in CMT2B1 the disease began most often

in the second decade and progressed gradually from distal to

proximal muscles.

Three of our patients with the longest disease durations (>24 years)

had also severe impairment in the scapular muscles. Reported here

for the first time, this might be a hallmark of CMT2B1.

Patients with CMT4A/2K had onset most often before the age of 2

years. Most had severe clubfoot from the beginning, one of the

hallmarks of CMT4A/2K.

None of our patients with CMT4A/2K had vocal cord paralysis.

The clinical phenotype of the three families that are not linked to

the three known loci presented some particularities that were not

seen in those with known genetic defects.

One family was characterized by late onset of the disease (>20

years) or a mild neuropathy that was diagnosed only when the family

was examined.

In a second family, dorsal scoliosis was the most prominent symptom.

In the third family, symptoms began in the second decade with a

moderate neuropathy associated with a pronounced scoliosis.

These families illustrate the extent of clinical and genetic

heterogeneity in ARCMT2.