Phenotypic spectrum of disorders associated with glycyl-tRNA synthetase mutation

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Brain. 2005 Jul 13

Phenotypic spectrum of disorders associated with glycyl-tRNA

synthetase mutations.

Sivakumar K, Kyriakides T, Puls I, Nicholson GA, Funalot B,

Antonellis A, Sambuughin N, Christodoulou K, Beggs JL, Zamba-

Papanicolaou E, Ionasescu V, Dalakas MC, Green ED, Fischbeck KH,

Goldfarb LG.

Barrow Neurological Institute, Phoenix, AZ, USA.

We describe clinical, electrophysiological, histopathological and

molecular features of a unique disease caused by mutations in the

glycyl-tRNA synthetase (GARS) gene. Sixty patients from five

multigenerational families have been evaluated.

The disease is characterized by adolescent onset of weakness, and

atrophy of thenar and first dorsal interosseus muscles progressing to

involve foot and peroneal muscles in most but not all cases. Mild to

moderate sensory deficits develop in a minority of patients.

Neurophysiologically confirmed chronic denervation in distal muscles

with reduced compound motor action potentials were features

consistent with both motor neuronal and axonal pathology.

Sural nerve biopsy showed mild to moderate selective loss of small-

and medium-sized myelinated and small unmyelinated axons, although

sensory nerve action potentials were not significantly decreased.

Based on the presence or absence of sensory changes, the disease

phenotype was initially defined as distal spinal muscular atrophy

type V (dSMA-V) in three families, Charcot-Marie-Tooth disease type

2D (CMT2D) in a single family, and as either dSMA-V or CMT2D in

patients of another large family.

Linkage to chromosome 7p15 and the presence of disease-associated

heterozygous GARS mutations have been identified in patients from

each of the five studied families.

We conclude that patients with GARS mutations present a clinical

continuum of predominantly motor distal neuronopathy/axonopathy with

mild to moderate sensory involvement that varies between the families

and between members of the same family. Awareness of these

overlapping clinical phenotypes associated with mutations in GARS

will facilitate identification of this disorder in additional

families and direct future research toward better understanding of

its pathogenesis.