Objective: Genetic and phenotypic characterization of six patients from two families, with pathogenic variants on the STUB1 gene.

Background: Biallelic pathogenic variants on the STUB1 gene were initially described in association with SCAR16, of childhood onset. In 2018, a new form of autosomal dominant spinocerebellar ataxia (SCA48) was described in a Spanish family, associated with heterozygous variants on the STUB1 gene, presenting with a complex phenotype, including late-onset ataxia, neuropsychiatric symptoms and extrapyramidal syndromes (chorea, dystonia and parkinsonism).

Method: Analysis of clinical, imagiological and genetic data.

Results: On the first family (A), the index case was a man presenting with gait instability at age 40, associated with a pancerebellar syndrome on neurological examination. His brother, currently 54 years old, had cerebellar and pyramidal syndromes, of late-onset, frontal cognitive impairment and craniocervical choreodystonic movements. Brain MRI showed cerebellar atrophy in both cases. The genetic study of the index case identified a novel heterozygous nonsense variant, NM_005861.4:c.829C>T (p.(Gln277*)), on the STUB1 gene, also found in his sibling. Their parents were asymptomatic but they had two paternal aunts and one first degree cousin with a similar phenotype. Both their aunts, 65 and 69 years old, also presented with a late onset cerebellar syndrome (beginning in the 5^th-6^th decades), pronounced frontal cognitive impairment and craniocervical and upper limb chorea. Genetic testing is still in progress. The cousin, a female currently 42 years old, began with behavioral changes and ataxia at 27 years old, and later developed generalized chorea and dystonia. Her genetic testing revealed the same variant on the STUB1 gene.
On the second family (B), the index case is a 78-year-old female, with symptoms beginning in the 6^th decade, presenting with apathy, midline cerebellar syndrome and generalized chorea with blepharospasm. Genetic testing revealed one heterozygous disease-causing variant c.146A>G (p.(Tyr49Cys)) on the STUB1 gene, previously reported in the literature. On brain MRI, cerebellar atrophy was also evident. No additional affected relatives are known.

Conclusion: SCA48 may present as a wide multisystemic neurological syndrome, including significant cognitive disfunction and extrapyramidal symptoms, congruent with a Huntington-like phenotype.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/clinical-and-genetic-characterization-of-two-portuguese-families-with-spinocerebellar-ataxia-48/