Objective:

To present this unique case, demonstrating both SCAR16 and SCA48 phenotypes coexisting within a single multigenerational family, adding to the growing evidence of “continuum” between these STUB1 related ataxias.

Background:

Spinocerebellar ataxias (SCAs) are genetically diverse and rare (1–5 per 100,000 individuals). While over 40 subtypes have been described, mutations in the STUB1 gene are rare and notable for their ability to cause both autosomal recessive (SCAR16) and autosomal dominant (SCA48) ataxias with generally distinct clinical phenotypes (early/late onset). Emerging literature shows phenotypic overlap between SCAR16 and SCA48. However, co-occurrence of both forms within a single pedigree remains rare. 

Design/Methods:

A 42-year-old man presented with worsening co-ordination and cognitive issues since early age. O/E Hypometric saccades, scanning speech, dysmetria on finger-to-nose and a wide-based gait requiring a walker. Brain MRI showed cerebellar atrophy. Neuropsychological testing identified slowed processing speed, impaired executive function, and visuospatial deficits. Genome sequencing was performed in the patient and family members.

Results:

The proband and his brother harbored compound heterozygous STUB1 variants (N65S and D302N), consistent with SCAR16. Their paternal grandfather carried only the heterozygous N65S variant, with later-onset ataxia, supporting dominant inheritance consistent with SCA48. Their mother, a heterozygous D302N carrier, remained asymptomatic (non-penetrant in the heterozygous state). This segregation pattern reflects both dominant and recessive disease mechanisms within the same family. The phenotypic differences in the age of onset and severity suggests a strong influence of different alleles of a gene. His cognitive impairments aligned with Cerebellar Cognitive Affective Syndrome (CCAS).

Conclusions:

The coexisting SCAR16 and SCA48 phenotypes within a single family, highlights the complex inheritance patterns of STUB1-related ataxia.

The presence of CCAS, reinforces the importance of recognizing cognitive involvement in cerebellar syndromes.

Due to possible dual inheritance and neurobehavioral involvement, this case supports the evolving understanding of a spectrum model of STUB1-associated cerebellar ataxias.