Objective: We present a case of SCA48 found on multi-gene sequencing panel [MGSP] after negative dementia workup.

Background: Spinocerebellar ataxia [SCA] is a genotypically & phenotypically diverse disorder marked by progressive ataxia, pyramidal/extrapyramidal symptoms, peripheral neuropathy & cognitive deficits. Variants are often due to autosomal dominant CAG repeat expansions on certain genes. SCA48 is an adult-onset autosomal dominant variant with cognitive & cerebellar manifestations & abnormal movements. It is caused by STIP1 homology & U-box containing1 [STUB1] gene mutation which also causes autosomal recessive SCA16.

Method: In 2016, a 63-year-old female of European descent developed fluctuating, progressive mild cognitive difficulties with inability to perform activities of daily living & acute confusional episodes. She had word finding & expression difficulties with perseveration. Her spouse noted abnormal leg movements with progressive walking problems requiring use of walker over subsequent years. There was associated intermittent agitation & apathy. She denied family history of neurological disorders.

Neurological exam revealed uncoordinated, dysarthric speech with inappropriate intonation, dysmetria, L>R, truncal ataxia & wide based gait without arm swing. Suppressible, distractible tapping movements of both legs were observed. MoCA scores were in mild cognitive impairment range [21-23] with deficits in attention, visuospatial, verbal fluency & executive skills.

Results: MRI brain +/- contrast showed diffuse cerebral & bilateral cerebellar atrophy along with L cerebellar cavernoma. Workup including DaTscan, EEG monitoring, CSF basic studies, Alzheimer’s disease biomarkers & autoimmune dementia panel were negative except slightly elevated serum GAD65 [0.26]. Neuropsychological testing revealed cognitive deficits in multiple domains suggestive of underlying neurodegenerative process. GeneDx SCA Repeat Expansion panel [ATXN1,2,3,7,8OS, CACNA1A] was negative. Ataxia Xpanded panel showed STUB1 likely pathogenic variant. Patient’s clinical presentation was consistent with SCA48.

Conclusion: Through this case, we highlight the diagnostic challenges associated with novel SCA variants, presenting with cognitive deficits, with negative family histories & SCA repeat expansion panel. In such cases, phenotypic presentation guides diagnostic workup, including MGSP. We also propose addition of STUB1 to genetic panels for inherited ataxias.

References: 1. Clinical and pathologic phenotype of a large family with heterozygous STUB1 mutation [doi:10.1212/NXG.0000000000000417]
2. Clinical and functional characterization of a novel STUB1 frameshift mutation in autosomal dominant spinocerebellar ataxia type 48 (SCA48) [doi:10.1186/s12929-021-00763-1]
3. Heterozygous STUB1 missense variants cause ataxia, cognitive decline, and STUB1 mislocalization [doi:10.1212/NXG.0000000000000397]
4. Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment [doi:10.1038/s41436-
020-0899-x]
5. The molecular basis of spinocerebellar ataxia type 48 caused by a de novo mutation in the ubiquitin ligase CHIP [doi:10.1016/j.jbc.2022.101899]

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MDS Abstracts - https://www.mdsabstracts.org/abstract/diagnostic-challenges-with-novel-sca-variants-a-case-of-stub1-mutation/