Intrafamilial clinical variability in individuals carrying the CHCHD10 mutation Gly66Val

Area of Science:

• Genetics
• Neurology
• Mitochondrial Biology

Background:

• Mutations in the CHCHD10 gene are linked to motor neuron disease and frontotemporal lobar degeneration.
• CHCHD10 encodes a mitochondrially targeted protein, crucial for cellular function.
• Previous studies identified the p.Gly66Val mutation causing late-onset spinal muscular atrophy (SMAJ) or sensorimotor axonal Charcot-Marie-Tooth neuropathy (CMT2) in Finland.

Purpose of the Study:

• To investigate the clinical variability of the CHCHD10 p.Gly66Val mutation in a large Finnish family.
• To assess the range of phenotypes associated with this specific CHCHD10 gene variant.

Main Methods:

• Clinical and neurophysiological examinations of nine affected family members.
• Sanger sequencing to confirm the presence of the CHCHD10 p.Gly66Val mutation.

Main Results:

• The heterozygous p.Gly66Val mutation was found in all affected individuals.
• Phenotypes ranged from proximal sensorimotor neuropathy to spinal muscular atrophy.
• One case presented with early-stage amyotrophic lateral sclerosis (ALS)-like symptoms.
• Age of onset varied significantly, from 30 to 73 years.

Conclusions:

• The CHCHD10 p.Gly66Val variant can manifest as diverse phenotypes, including CMT2, spinal muscular atrophy, and ALS-like disease, within a single family.
• The spectrum of CHCHD10-related neuromuscular diseases is expanding.
• Genetic testing for CHCHD10 mutations should be considered with a low threshold, especially in cases of dominant inheritance or suspected mitochondrial pathology.