The prodromal phase of spinocerebellar ataxias (SCAs) has not been systematically studied. Main findings come from a homogeneous SCA type 2 (SCA2) population living in Cuba. The aim of this study was to characterize extensively the prodromal phase of SCA2 by several approaches. Thirty-seven non-ataxic SCA2 mutation carriers and its age- and sex-matched controls underwent clinical assessments, including standardized neurological exam, structured interviews and clinical scales, and looking for somatic and autonomic features, as well as a neuropsychological battery, antisaccadic recordings, and MRI scans. Main clinical somatic features of non-ataxic mutation carriers were cramps, sensory symptoms, sleep disorders, and hyperreflexia, whereas predominating autonomic symptoms were pollakiuria/nocturia, constipation, and frequent throat clearing. Cognitive impairments included early deficits of executive functions and visual memory, suggesting the involvement of cerebro-cerebellar-cerebral loops and/or reduced cholinergic basal forebrain input to the cortex. Antisaccadic task revealed impaired oculomotor inhibitory control but preserved ability for error correction. Cognitive and antisaccadic deficits were higher as carriers were closer to the estimated onset of ataxia, whereas higher Scale for the Assessment and Rating of Ataxia (SARA) scores were associated most notably to vermis atrophy. The recognition of early features of SCA2 offers novel insights into the prodromal phase and physiopathological base of the disease, allowing the assessment of its progression and the efficacy of treatments, in particular at early phases when therapeutical options should be most effective.

Electrooculographical measures of saccade changes are useful for the objective quantification of disease course in spinocerebellar ataxia type 2. The progression rate of saccade slowing is influenced by the expansion size, providing novel insight into the cumulative polyglutamine neurotoxicity, and supporting the usefulness of saccade peak velocity as a sensitive biomarker during the natural history of the disease, and as suitable outcome measure for therapeutic trials.

Having reported the world's highest prevalence of spinocerebellar ataxia type 2 (SCA2), health professionals in Cuba developed a program for the predictive testing of this condition. Between February 2001 and December 2011, a total of 1050 individuals requested their inclusion in the presymptomatic testing (PST) program. Their medical records were retrospectively analyzed in the present descriptive study. A total of 768 participants completed the protocol, 204 withdrew and 78 were excluded. The PST uptake was 24.91%. Females predominated and 70.96% had negative test results. Their main motivations were risk assessment in their descendants, physical and psychological preparation to cope with the disease and planning for the future. The profile of Cuban participants in the predictive testing program is similar to the one reported for other programs all over the world, nevertheless the genetic counseling practice at the community level is a distinctive aspect, which is valuable in providing at-risk individuals with wide and proper knowledge before their testing inclusion request. The SCA2 predictive testing program has high uptake rates and is renowned in our population. Future research is needed to assess the long-term psychological impact in the participants, their partners and relatives.

Pathogenic CAG (cytosine-adenine-guanine) expansions beyond certain thresholds in the ataxin-2 (ATXN2) gene cause spinocerebellar ataxia type 2 (SCA2) and were shown to contribute to Parkinson disease, amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Regulation of ATXN2 gene expression and the function of the protein product are not known. SCA2 exhibits an inverse correlation between the size of the CAG repeat and the age at disease onset. However, a wide range of age at onset are typically observed, with CAG repeat number alone explaining only partly this variability. In this study, we explored the hypothesis that ATXN2 levels could be controlled by DNA methylation and that the derangement of this control may lead to escalation of disease severity and influencing the age at onset. We found that CpG methylation in human ATXN2 gene promoter is associated with pathogenic CAG expansions in SCA2 patients. Different levels of methylation in a SCA2 pedigree without an intergenerational CAG repeat instability caused the disease anticipation in a SCA2 family. DNA methylation also influenced the disease onset in SCA2 homozygotes and SCA3 patients. In conclusion, our study points to a novel regulatory mechanism of ATXN2 expression involving an epigenetic event resulting in differential disease course in SCA2 patients.

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