title: Phenotypic spectrum of disorders associated with glycyl-tRNA synthetase mutations.
abstract: 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.
authors: Barrow Neurological Institute, Phoenix, AZ, USA.
authors: Kumaraswamy
authors: K
authors: Sivakumar
authors: Theodoros
authors: T
authors: Kyriakides
authors: Imke
authors: I
authors: Puls
authors: Garth A
authors: GA
authors: Nicholson
authors: Benoît
authors: B
authors: Funalot
authors: Anthony
authors: A
authors: Antonellis
authors: Nyamkhishig
authors: N
authors: Sambuughin
authors: Kyproula
authors: K
authors: Christodoulou
authors: John L
authors: JL
authors: Beggs
authors: Eleni
authors: E
authors: Zamba-Papanicolaou
authors: Victor
authors: V
authors: Ionasescu
authors: Marinos C
authors: MC
authors: Dalakas
authors: Eric D
authors: ED
authors: Green
authors: Kenneth H
authors: KH
authors: Fischbeck
authors: Lev G
authors: LG
authors: Goldfarb
mesh_terms: D000293:Adolescent; D000328:Adult; D001132:Arm; D001706:Biopsy / Q000379:methods; D002607:Charcot-Marie-Tooth Disease / Q000208:ethnology / Q000235:genetics / Q000503:physiopathology; D002648:Child; D004576:Electromyography / Q000379:methods; D005192:Family Health; D005260:Female; D006032:Glycine-tRNA Ligase / Q000235:genetics*; D006801:Humans; D007866:Leg; D008297:Male; D008875:Middle Aged; D018908:Muscle Weakness / Q000208:ethnology / Q000235:genetics / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000503:physiopathology; D009134:Muscular Atrophy, Spinal / Q000208:ethnology / Q000235:genetics / Q000503:physiopathology; D009135:Muscular Diseases / Q000208:ethnology / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation; D009431:Neural Conduction / Q000502:physiology; D010641:Phenotype; D013497:Sural Nerve / Q000473:pathology
chemical_list: D006032:Glycine-tRNA Ligase