A new variant in the UCHL1 gene supporting its implication in late-onset ataxia with optic atrophy

UCHL1 encodes the neuronal protein UCH-L1, which plays a critical role in protein turnover Day (Prog Neurobiol 90(3):327-362, 2010). Variants in UCHL1 have been implicated in neurodegenerative disorders and hereditary spastic paraplegia (HSP) Mi (Ageing Res Rev 6:101856, 2023); Choi et al. (J Biol Chem 279(13):13256-64, 2004); Li et al. (Ann Clin Transl Neurol 7(8):1420-8, 2020). Monoallelic loss-of-function variants have recently been linked to adult-onset hereditary spastic paraparesis with ataxia and optic atrophy (SPG79A), as well as to adult-onset ataxia with optic atrophy in the absence of pyramidal signs, highlighting the phenotypic variability associated with UCHL1 variants Marelli et al. (J Neurol 271(9):6038-44, 2024).

We report two Italian brothers presenting with progressive cerebellar ataxia, who underwent comprehensive neurological examination, ophtalmological examination, brain MRI, neurophysiological testing, and genetic analysis using targeted next-generation sequencing of ataxia- and spasticity-related genes.

A novel monoallelic nonsense variant in UCHL1 (c.418 C > T; p.(Gln140*)) was identified in both siblings. Clinically, patients showed predominantly ataxic symptoms, optic neuropathy and no pyramidal signs, CONCLUSION: Our study supports UCHL1 analysis in cases of autosomal dominant adult-onset cerebellar ataxia with optic atrophy, further expanding the clinical and genetic continuum between ataxic and spastic presentations.