Case Series of Cerebellar Ataxia with Tremor Due to Heterozygous STUB1 Variants (SCA48) without TBP Expansions: Further Evidence for SCA48 as a Monogenic Disease

Clinically-relevant variants in the STUB1 gene have been associated with an autosomal dominant spinocerebellar ataxia 48 (SCA48), a recently described inherited neurodegenerative condition that is characterised by cognitive and psychiatric changes. To describe the clinical phenotype and genetic findings of three new Australian probands with STUB1 to expand the current understanding of the spectrum of clinical presentation and natural history of SCA48. Clinical and genetic review of patients diagnosed with SCA48 ataxia drawn from our centres. The third case was derived from a collaborating centre (Royal Brisbane Hospital). We identified three unrelated SCA48 patients with heterozygous pathogenic STUB1 variants. All presented with slowly progressive cerebellar ataxia with tremor and additional findings of dysarthria, parkinsonism, hypertonia, cognitive and psychiatric symptoms. Age of onset varied from 34 to 65 years of age. Brain MRI showed significant diffuse cerebellar atrophy, affecting the vermis and cerebellar hemispheres. We identified two novel pathogenic variants of STUB1 gene, and one previously reported pathogenic variant. Genetic testing for intermediate expansions of TBP (SCA17) identified TBP repeats within the normal range of 25-40 in all 3 probands. Our case series expands the clinical spectrum of SCA48. We highlight the importance of tremor as part of the clinical phenotype including upper limb rest tremor and Parkinsonian signs. Our cases lacked pathological TBP expansions and provide additional evidence that STUB1 (SCA48) can manifest as a monogenic disease.