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.