Expanding the spectrum of autosomal dominant UCHL1-associated neurodegeneration: comprehensive characterization of two affected siblings

Autosomal dominant inherited pathogenic variants in UCHL1 are an emerging cause of adult-onset neurodegeneration, most commonly characterized by spasticity, cerebellar ataxia, sensory impairment, and optic nerve atrophy. However, the full phenotypic spectrum remains incompletely defined. We report a Danish family with a heterozygous loss-of-function splice variant in UCHL1 (c.325 + 5G > A, p.(?)) and describe two affected siblings with slowly progressive neurological disease. Results: Both presented in adulthood with gait disturbance due to spastic paraparesis and cerebellar ataxia. One sibling additionally developed parkinsonism and a marked dysexecutive cognitive syndrome, while the other exhibited milder cognitive changes and no evidence of parkinsonism. Structural MRI revealed mild cerebellar atrophy, and [ 18 F]FDG-PET demonstrated cerebellar hypometabolism in both cases, with additional asymmetric cortical hypometabolism in the cognitively affected sibling. A third family member presented with isolated early-onset optic nerve atrophy in adolescence. While the overall phenotype is broadly consistent with previously reported cases, our study adds detailed clinical characterization and describes cognitive impairment and parkinsonian findings that warrant further investigation. Conclusion: Our findings add to the clinical characterization of autosomal dominant pathogenic UCHL1 variants. The potential relevance of cognitive and parkinsonian findings to UCHL1 -associated neurodegeneration remains uncertain and requires further investigation.