Insights into phenotypic variability caused by GARS1 pathogenic variants

Area of Science:

• Neurology
• Genetics
• Molecular Biology

Background:

• Pathogenic variants in the glycyl-tRNA synthetase 1 (GARS1) gene are linked to several neuromuscular disorders.
• These include Charcot-Marie-Tooth disease type 2D, distal hereditary motor neuropathy (dHMN) type V, and infantile spinal muscular atrophy.

Purpose of the Study:

• To investigate the clinical spectrum of GARS1 variants, specifically the c.794C>T (p.Ser265Phe) missense variant.
• To characterize the phenotype associated with this GARS1 variant, including neurological, electrophysiological, and histological findings.

Main Methods:

• A cross-sectional, retrospective study of 12 patients with the GARS1 c.794C>T variant.
• Review of clinical data, nerve conduction studies, MRI, and intraepidermal nerve fiber density in skin biopsies.

Main Results:

• Onset at a mean age of 9.5 years, with intrinsic hand muscles affected early.
• Predominant distal muscle weakness, particularly in the thenar complex and first dorsal interosseous.
• Electrophysiology confirmed exclusively motor axonal neuropathy; MRI showed leg muscle atrophy and fatty infiltration.
• Six patients had a "split hand" index, and nine showed reduced intraepidermal nerve fiber density.

Conclusions:

• GARS1 variants can manifest as dHMN with "split hand" and sensory disturbances.
• Sensory symptoms may occur despite normal sensory nerve conduction studies.
• This suggests dorsal root ganglion sensory neuron dysfunction impacting dermal nerve endings.