The impact of interrupted ATXN10 expansions on clinical findings of spinocerebellar ataxia type 10

BACKGROUND: Spinocerebellar ataxia type 10 (SCA10), due to an ATTCT repeat expansion in ATXN10, has variable expressivity and the role of presence (ATTCTint +) and absence (ATTCTint-) of interruptions in the repeat is not clear. We aimed to describe the relations between ATTCTint + and age at onset, seizures, and neurologic severity in ataxic and non-ataxic carriers from Brazil.

METHODS: Family, age at onset (AO), and seizures data plus DNA were obtained from symptomatic carriers already diagnosed in Porto Alegre, Curitiba, and São Paulo, Brazil. Patients and their relatives were invited to be evaluated through Scale of Assessment and Rating of Ataxia (SARA) and other clinical scales; a SARA > 2.5 classified subjects as ataxic carriers. Repeat-primed PCR (RP-PCR) defined the expansions with (ATTCTint +) or without (ATTCTint-) interruptions. Comparisons were performed for a p level of 0.05.

RESULTS: Among 78 ataxic carriers, earlier AO (p = 0.039) and higher occurrences of epilepsy (p < 0.0001) were seen in subjects with ATTCTint + than in those with ATTCTint-. Clinical scales were worse in 34 ataxics than in 7 non-ataxics and 10 related controls (p = 0.006) and did not discriminate non-ataxics from controls. The 11 ataxic ATTCTint + carriers had higher SARA scores per year of disease duration than the 23 ATTCTint- carriers (r = 0.879, beta = 0.45, p = 0.0001).

DISCUSSION: ATTCTint + carriers had worse clinical findings than ATTCTint- carriers: earlier AO, more seizures, and worse ataxia scores. Interruptions in the expanded repeat have a real impact in SCA10 phenotype.