Inherited neuropathies with predominant upper limb involvement: genetic heterogeneity and overlapping pathologies

Area of Science:

• Neurology
• Genetics
• Clinical Medicine

Background:

• Inherited peripheral neuropathies can manifest initially with upper limb muscle weakness.
• The underlying mechanisms for this upper limb-predominant phenotype are not fully understood.
• Charcot-Marie-Tooth disease (CMT) is a group of inherited disorders affecting peripheral nerves.

Purpose of the Study:

• To clinically, neurophysiologically, and genetically characterize patients with upper limb-predominant Charcot-Marie-Tooth disease (CMT).

Main Methods:

• Analysis of clinical, electrophysiological, and genetic data from 11 patients with upper limb-predominant neuropathy.
• Patients were selected from a larger cohort of 461 individuals with inherited neuropathy.
• Gene panel sequencing was employed for genetic analysis.

Main Results:

• Two patients exhibited an overlapping neuropathy and myopathy phenotype.
• Autosomal dominant mutations in GARS were identified in four patients.
• A homozygous mutation in SH3TC2 was found in one patient; six patients remained genetically undiagnosed.

Conclusions:

• Upper limb-onset inherited neuropathies are genetically diverse.
• Autosomal dominant GARS mutations are a frequent cause, but other CMT genes can also be implicated.
• A significant portion of patients cannot be diagnosed using current gene panels, indicating the need for further genetic research.