Neuroophthalmology. 2025 Aug 20;50(4):381-386. doi: 10.1080/01658107.2025.2548315. eCollection 2026.
ABSTRACT
Previously, biallelic variants in ubiquitin carboxy-terminal hydrolase L1 (UCHL1) have been associated with spastic paraplegia type 79, an autosomal recessive early-onset neurodegenerative disorder. Recently, heterozygous variants in UCHL1 have been associated with a neurological syndrome with various combinations of optic atrophy, spasticity, ataxia and neuropathy. We present two independent families presenting with multigenerational optic atrophy. The proband of family A presented in her 60s with worsening gait imbalance and optic atrophy. The proband of family B presented in his 40s with worsening vision and difficulty with tandem gait. Initial genomic testing in both probands did not reveal a diagnosis. Later reanalysis of the existing genomic data, after heterozygous UCHL1 variants were described as causing disease, showed both probands harboured pathogenic variants in UCHL1 which accounted for their phenotype. Heterozygous variants in UCHL1 cause an autosomal dominant neurological syndrome with variable optic atrophy, spastic ataxia and neuropathy. Clinicians should carefully assess the optic nerves in individuals presenting with ataxia and spasticity, as optic atrophy can be asymptomatic and under-reported, yet important in formulating a differential diagnosis and directing genomic testing. In individuals remaining without a molecular diagnosis, it is important to regularly revisit genomic data as a genetic diagnosis may be identified on reanalysis.
PMID:42375238 | PMC:PMC13313211 | DOI:10.1080/01658107.2025.2548315