The natural history of spinocerebellar ataxia type 1, 2, 3, and 6

Abstract

Objective: To obtain quantitative data on the progression of the most common spinocerebellar ataxias (SCAs) and identify factors that influence their progression, we initiated the EUROSCA natural history study, a multicentric longitudinal cohort study of 526 patients with SCA1, SCA2, SCA3, or SCA6. We report the results of the 1-and 2-year follow-up visits. Methods:As the primary outcome measure we used the Scale for the Assessment and Rating of Ataxia (SARA, 0-40), and as a secondary measure the Inventory of Non-Ataxia Symptoms (INAS, 0-16) count. Results:The annual increase of the SARA score was greatest in SCA1 (2.18 Ϯ 0.17, mean Ϯ SE) followed by SCA3 (1.61 Ϯ 0.12) and SCA2 (1.40 Ϯ 0.11). SARA progression in SCA6 was slowest and nonlinear (first year: 0.35 Ϯ 0.34, second year: 1.44 Ϯ 0.34). Analysis of the INAS count yielded similar results. Larger expanded repeats and earlier age at onset were associated with faster SARA progression in SCA1 and SCA2. In SCA1, repeat length of the expanded allele had a similar effect on INAS progression. In SCA3, SARA progression was influenced by the disease duration at inclusion, and INAS progression was faster in females.

Targeting potassium channels to treat cerebellar ataxia

“…Retrospective review of patient records and unblinded assessments in patients are, however, susceptible to bias. Given the duration of follow‐up, and the sustained improvements in patients where the natural history of disease is progressive,63, 64 our findings in patients are encouraging for the utility of potassium channel activators in the treatment of symptoms in patients with SCA. It is possible that changes in Purkinje neuron membrane excitability are present in many etiologies of SCA, and that the ion channel targets of chlorzoxazone and baclofen are relevant targets in these SCAs as well.…”

Mutant ataxin1 disrupts cerebellar development in spinocerebellar ataxia type 1

“…The extent of the increase in arborization was proportional to CAG repeat length (which governs the SCA1 phenotype, with more repeats producing more severe disease and earlier onset) (33)(34)(35)36). In other words, the patients who showed earlier disease onset had more BC collaterals than those patients with milder, later-onset disease in the fifth or sixth decade of life ( Figure 3, B and C).…”

MR Imaging in Spinocerebellar Ataxias: A Systematic Review

“…Five studies evaluated MR spectroscopy of infratentorial regions in SCA3/MJD [10][11][12][13][14][15][16][17][18][19][20][21][22] ; all of them evaluated cerebellar structures, and only 1 evaluated the brain stem (see On-line Table 1 for the main findings). 19 The N-acetylaspartate/creatine ratio was evaluated in 4 studies with ROIs in the cerebellar hemispheres/cortex, [20][21][22] all with reduced NAA/Cr ratios; 2 of them had inverse correlations with SARA scores.…”

“…1,3 Sleep, cognitive, and psychiatric symptoms are also frequent in PolyQ-SCA, possibly due to a more widespread CNS degeneration. 4,5 Natural history studies with well-validated SCA scales, such as the Scale for the Assessment and Rating of Ataxia (SARA) 6 and the Neurologic Examination Score for Spinocerebellar Ataxia 7 were concordant with both the very slow disease progression [8][9][10] and the necessity for large sample sizes to test disease-modifying therapies in future randomized clinical trials. [8][9][10][11][12][13] Surrogate biomarkers could hasten randomized clinical trials and drug discoveries for SCA.…”