Brain Advance Access originally published online on July 13, 2005
Brain 2005 128(10):2304-2314; doi:10.1093/brain/awh590
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Phenotypic spectrum of disorders associated with glycyl-tRNA synthetase mutations
1 Barrow Neurological Institute, Phoenix, AZ, USA, 2 The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus, 3 National Institute of Neurological Disorders and Stroke and 4 Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA, 5 University of Sydney, ANZAC Research Institute at Concord Hospital, Concord, Australia, 6 INSERM U.573, Centre Paul Broca, Hôpital Sainte-Anne, Paris, France and 7 Department of Pediatrics, Division of Medical Genetics, University of Iowa, Iowa City, IA, USA
Corresponding author: Lev G. Goldfarb, MD, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 5625 Fishers Lane, Room 4S06, Bethesda, MD 20892-9404, USA E-mail: goldfarbl{at}ninds.nih.gov
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.
Key Words: Charcot-Marie-Tooth disease; distal spinal muscular atrophy; genotype–phenotype relationships; glycyl-tRNA synthetase; hand-predominant muscle atrophy
Abbreviations: CAP = cytoskeleton-associated protein; CMAP = compound motor action potential; CMT = Charcot-Marie-Tooth disease; dHMN = distal hereditary motor neuronopathy; dSMA = distal spinal muscular atrophy; EM = electron microscopy; EMG = electromyography; MNF = myelinated nerve fibre; SNAP = sensory nerve action potential; UMNF = unmyelinated nerve fibre
Received February 25, 2005. Revised May 3, 2005. Accepted June 9, 2005.
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