Objective: To describe a new family with Spinocerebellar Ataxia 48 (SCA48) characterized by ataxia and mild chorea as the most prominent initial symptoms as well as early and progressive cognitive decline.

Background: SCA48 was recently described as an autosomal dominant SCA  causing early and prominent cerebellar cognitive-affective syndrome (CCAS) and late onset SCA, related to a heterozygous pathogenic variant  in STUB1 gene. Whereas the first report said that not parkinsonism, choreoatetosis or other movement disorders were present, further description of 8 Italian families included chorea and dystonia as frequent symptoms mimicking SCA17 phenotype.

Method: Seven of 12 affected patients over three generations of a Spanish familysuggesting an autosomal dominant inheritance pattern were evaluated: 6 clinically symptomatic and 1 asymptomatic but radiologically affected. Clinical examination and brain imaging, CT or MRI, were conducted in all the cases. Cognitive assessment was included in four patients. Genetic testing for SCA1, 2, 3, 6, 7, 10, 12 and 17 and HTT was performed in three of them. Genetic testing for C9orf72 followed by whole genome sequencing (WGS) through the NAGEN project (GENOMA-1,000 NAVARRA PROJECT) was carried out in the proband (second generation).

Results: The median age at the disease onset was 48.5 years). Ataxia, dysarthria and chorea at different degrees were present from the beginning in 4 of the clinically affected patients; isolated mild chorea was the first symptom in 1/6 and ataxia in another one. Progressively cognitive decline appeared in 5/6, involving memory, attention, language and executive functions. Two of seven had severe dysphagia and physical dependence and were confined to bed before death. Cerebellar atrophy was present in 7/7, including 1 patient clinically asymptomatic but radiologically affected. Genetic testing for SCA and HTT was negative in 3/7 patients of the second generation, as well as C9orf72  in the proband. WGS identified a heterozygous pathogenic variant in STUB1 gene (c.791_792delTG p.Val264GlyfsTer4).

Conclusion: – Chorea seems to be a frequent and early symptom in the recently described new SCA48.
– SCA48 should be included in Huntington disease –like differential diagnosis as SCA17 is.
– Further investigations are needed in order to know the real prevalence of SCA48.

References: 1. Genis D, Ortega-Cubero S, San Nicolás H, Corral J, Gardenyes J, de Jorge L et al. Heterozygous STUB1 mutation causes familial ataxia with cognitive affective syndrome (SCA48), Neurology 91 (2018) e1988–e1998. 2. De Michele G, Lieto M, Galatolo D, et al. Spinocerebellar ataxia 48 presenting with ataxia associated with cognitive, psychiatric, and extrapyramidal features: Areport of two Italian families. Parkinsonism Relat Disord. 2019; 65: 91–96. 3. Lieto M, Riso V, Galatolo D, De Michele G, Rossi S, Barghigiani M et al. The complex phenotype of spinocerebellar ataxia type 48 in eight unrelated Italian families. European Journal of Neurology 2020, 27: 498–505.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/sca48-ataxia-plus-chorea-in-a-new-spanish-family/