CMT 2D and dSMA: The G526R glycyl-tRNA synthetase gene mutation in distal hered

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Neurology. 2006 Jun 13;66(11):1721-6.

The G526R glycyl-tRNA synthetase gene mutation in distal hereditary

motor neuropathy type V.

Dubourg O, Azzedine H, Yaou RB, Pouget J, Barois A, Meininger V,

Bouteiller D, Ruberg M, Brice A, LeGuern E.

INSERM U679, Consultation Pluridisciplinaire des Neuropathies

Hereditaires, Groupe Hospitalier Pitie-Salpetriere, Paris, France.

dubourg@...

BACKGROUND: Distal hereditary motor neuropathy (dHMN) or distal

spinal muscular atrophy (dSMA) is a heterogeneous group of disorders

characterized almost exclusively by degeneration of motor nerve

fibers, predominantly in the distal part of the limbs. One subtype,

dHMN type V (dHMN-V), is transmitted by autosomal dominant

inheritance and predominantly involves the hands.

It is allelic with Charcot-Marie-Tooth disease 2D (CMT2D), in which a

similar phenotype is associated with sensory signs. Missense

mutations in the glycyl-tRNA synthetase (GARS) gene have been

recently reported in families with either dHMN-V, CMT2D, or both.

METHODS:

The authors searched for GARS mutations in eight dHMN-V families.

RESULTS: The authors found the G526R missense mutation in three

families (16 patients) of Algerian Sephardic Jewish origin. All

patients shared a common disease haplotype, suggestive of a founder

effect. The clinical phenotype consists of a slowly progressive,

purely motor distal neuropathy. It starts in the hands in most

patients, but also in both distal upper and lower limbs or in distal

lower limbs alone. The age at onset in symptomatic individuals was

between the second to fourth decades, but four mutation carriers were

still asymptomatic, two of whom were already age 49 years.

Electrophysiology showed that the motor fibers of the median nerve

were the most affected in upper limbs. Sensory nerve action

potentials were normal.

CONCLUSIONS: The age at onset of patients with the G526R mutation in

the GARS gene varied widely, but the clinical and electrophysiologic

presentation was uniform and progressed slowly. Glycyl-tRNA

synthetase mutations are a frequent cause of familial distal

hereditary motor neuropathy type V but, because of the reduced

penetrance of the disease, could also account for isolated cases.