[FA2H gene-associated spastic paraplegia (SPG35) - familial case with late onset]

Area of Science:

• Genetics
• Neurology
• Rare Diseases

Background:

• Autosomal recessive spastic paraplegia type 35 (SPG35) is typically a childhood-onset disorder.
• It is associated with mutations in the FA2H gene and presents with spastic paraparesis and specific MRI abnormalities.
• Late-onset SPG35 is exceptionally rare, with limited documented cases.

Observation:

• A rare case of late-onset SPG35 was observed in two sisters from a Russian family, with symptom onset in their late 20s and 40s.
• Clinical manifestations included progressive spastic paraparesis, cognitive-personal decline, and dysarthria.
• MRI revealed periventricular leukopathy, cerebral and cerebellar atrophy, globus pallidus hypointensity, and corpus callosum thinning.

Findings:

• Whole genome sequencing and Sanger sequencing identified compound-heterozygous missense variants (c.232G>A, p.Glu78Lys and c.137G>A, p.Gly46Asp) in the FA2H gene.
• The identified variants were previously described, but their presence in a compound-heterozygous state led to a late-onset phenotype.
• The mother carried one of the identified variants (p.Glu78Lys) in a heterozygous state.

Implications:

• This case expands the clinical spectrum of SPG35, highlighting the possibility of late-onset presentations.
• Understanding the genetic basis and phenotypic variability of SPG35 is crucial for diagnosis and potential therapeutic strategies.
• Further research into FA2H gene function and its role in neurodegeneration is warranted.