The progression rate of spinocerebellar ataxia type 2 changes with stage of disease.

BACKGROUND: Spinocerebellar ataxia type 2 (SCA2) affects several neurological structures, giving rise to multiple symptoms. However, only the natural history of ataxia is well known, as measured during the study duration. We aimed to describe the progression rate of ataxia, by the Scale for the Assessment and Rating of Ataxia (SARA), as well as the progression rate of the overall neurological picture, by the Neurological Examination Score for Spinocerebellar Ataxias (NESSCA), and not only during the study duration but also in a disease duration model. Comparisons between these models might allow us to explore whether progression is linear during the disease duration in SCA2; and to look for potential modifiers. RESULTS: Eighty-eight evaluations were prospectively done on 49 symptomatic subjects; on average (SD), study duration and disease duration models covered 13 (2.16) months and 14 (6.66) years of individuals' life, respectively. SARA progressed 1.75 (CI 95%: 0.92-2.57) versus 0.79 (95% CI 0.45 to 1.14) points/year in the study duration and disease duration models. NESSCA progressed 1.45 (CI 95%: 0.74-2.16) versus 0.41 (95% CI 0.24 to 0.59) points/year in the same models. In order to explain these discrepancies, the progression rates of the study duration model were plotted against disease duration. Then an acceleration was detected after 10 years of disease duration: SARA scores progressed 0.35 before and 2.45 points/year after this deadline (p = 0.013). Age at onset, mutation severity, and presence of amyotrophy, parkinsonism, dystonic manifestations and cognitive decline at baseline did not influence the rate of disease progression. CONCLUSIONS: NESSCA and SARA progression rates were not constant during disease duration in SCA2: early phases of disease were associated with slower progressions. Modelling of future clinical trials on SCA2 should take this phenomenon into account, since disease duration might impact on inclusion criteria, sample size, and study duration. Our database is available online and accessible to future studies aimed to compare the present data with other cohorts.

Neurological phenotypes in spinocerebellar ataxia type 2: Role of mitochondrial polymorphism A10398G and other risk factors.

BACKGROUND: Spinocerebellar ataxia type 2 (SCA2) is due to a CAG expansion (CAGexp) at ATXN2. SCA2 presents great clinical variability, alongside characteristic ataxia with saccadic slowness. AIMS: To study parkinsonism, dementia, dystonia, and amyotrophy as subphenotypes of SCA2, and to explore the effect of CAG repeats at different loci and of mitochondrial polymorphism A10398G as modifiers of phenotype. METHODS: Symptomatic subjects were classified by presence/absence of neurological signs mentioned above; SARA and NESSCA scores were obtained. CAG repeats at ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7 and RAI1, and polymorphism A10398G at mtDNA were established. Group characteristics were compared, with a p < 0.05. RESULTS: Forty-eight SCA2 individuals were included. Age at onset, CAGexp, and disease duration explained 53% and 43% of SARA and NESSCA variations, respectively. CAGexp of subjects with and without parkinsonism were different (medians of 42 and 39 repeats) as well as of subjects with and without dystonia (44 and 40 repeats). Amyotrophy was not significantly related to any variable under study. Concerning polymorphism A10398G, 83% of subjects with and 34% of those without cognitive decline carried 10398G at (p = 0.003). DISCUSSION: Treating the four phenotypic subgroups as outcomes was a valid strategy to identify modifiers of disease. Among correlations found, some confirmed previous reports, such as that between dystonia and CAGexp. Of note was the association between cognitive decline and the variant G at mitochondrial polymorphism A10398G, a variant formerly related to earlier ages at onset in SCA2.

NESSCA Validation and Responsiveness of Several Rating Scales in Spinocerebellar Ataxia Type 2.

Spinocerebellar ataxia type 2 (SCA2), caused by a CAG expansion (CAGexp) at ATXN2, has a complex clinical picture. While validated ataxia scales are available, comprehensive instruments to measure all SCA2 neurological manifestations are required. This study aims to validate the Neurological Examination Score for the assessment of Spinocerebellar Ataxias (NESSCA) to be used in SCA2 and to compare its responsiveness to those obtained with other instruments. NESSCA, SARA, SCAFI, and CCFS scales were applied in symptomatic SCA2 patients. Correlations were done with age at onset, disease duration, CAGexp, and between scales. Responsiveness was estimated by comparing deltas of stable to worse patients after 12 months, according to Patient Global Impression of change, and the area under the curve (AUC) of the Receiver Operating Characteristics curve of scores range. Eighty-eight evaluations (49 patients) were obtained. NESSCA had an even distribution and correlated with disease duration (r = 0.55), SARA (r = 0.63), and CAGexp (rho = 0.32): both explained 44% of NESSCA variance. Deltas (95% CI) after 1 year in stable and worse patients were only significantly different for SARA. NESSCA, SARA, SCAFI, and CCFS AUC were 0.63, 0.81, 0.49, and 0.48, respectively. NESSCA is valid to be used in SCA2. However, the only instrument that presented good responsiveness to change in 1 year was SARA. We suggest that NESSCA can be used as a secondary outcome in future trials in SCA2 due to the burden of neurological disabilities related to disease progression.

Clinical Scales Predict Significant Videofluoroscopic Dysphagia in Machado Joseph Disease Patients.

BACKGROUND: Although aspiration is one of the main causes of death in SCA, such as SCA3/Machado Joseph disease (SCA3/MJD), clinical studies on dysphagia are lacking for these diseases. The aims of this study were to characterize dysphagia in SCA3/MJD through videofluoroscopy (VF) of swallowing, correlate VF with disease severity criteria and weight loss, and determine the clinical criteria cutoffs for performing VF in the clinical routine, in order to detect aspiration. METHODS: A cross-sectional study on 34 SCA3/MJD patients was performed. Clinical and molecular data, as well as body mass index (BMI), were obtained. Neurological scales, such as the Scale for the Assessment and Rating of Ataxia (SARA), and the Swallowing Quality of Life (SWAL-QOL) questionnaire were applied. The VF scores, Dysphagia Outcome and Severity Scale (DOSS) and penetration/aspiration scale (PAS), were obtained: Moderate-to-severe scores were grouped as "significant dysphagia." RESULTS: Overall, 31 of 34 individuals showed abnormal scores at VF. SARA, BMI, and the domain "eating duration" of SWAL-QOL correlated with VF: Their relation to significant dysphagia (DOSS <4 points or PAS >3) was evaluated through receiver operating characteristic curves. A sensitivity of 100% was equivalent to a cutoff of 15 points on SARA score, 23.72 kg/m2 on BMI, and 60% on eating duration-SWAL-QOL (P < 0.05). CONCLUSION: Significant dysphagia was not related to age at onset, disease duration, or CAG repeat expansion, but with SARA scores, lower BMI, and the domain eating duration of SWAL-QOL. As a guideline for preventing aspiration, we suggest that SARA scores greater than 15 or eating duration-SWAL-QOL lower than 60% should urge VF studies in SCA3/MJD.