脊髄小脳変性症(多系統萎縮症を除く。)

BACKGROUND: Preclinical studies have suggested that DL-3-n-butylphthalide (NBP) may exhibit neuroprotective effects in neurodegenerative diseases; however, no human trial has evaluated NBP in spinocerebellar ataxia type 3 (SCA3). OBJECTIVES: The aim of the study was to evaluate the efficacy and safety of oral NBP in patients with SCA3 over 12 months. METHODS: Patients were randomly assigned (1:1) to oral NBP (200 mg thrice daily) or placebo for 12 months. The primary outcomes were 12-month changes in the Scale for Assessment and Rating of Ataxia (SARA) and Spinocerebellar Ataxia Functional Index (SCAFI). Safety outcomes included adverse events (AEs) and serious adverse events (SAEs). RESULTS: The modified intention-to-treat (mITT) population included 116 patients (NBP, n = 56; placebo, n = 60). The primary endpoints, change in SARA and SCAFI, were significantly different between NBP and placebo groups (SARA, estimated marginal mean difference: -0.86, 95% confidence interval [CI]: -1.56 to -0.16, P = 0.02; SCAFI, estimated marginal mean difference: 0.16, 95% CI: 0.01-0.31, P = 0.03) in mITT population using a mixed-effect model, with improved clinical outcome in the NBP group. Overall, AE rates were not significantly different between groups (13 AEs [23.2%] in NBP vs. 9 AEs [15%] in placebo, P = 0.26), although drug-related AEs were numerically more frequent with NBP (12 [21.4%] vs. 6 [10.0%], P = 0.09); no SAE occurred in either group. CONCLUSIONS: Oral administration of NBP was safe and generally well tolerated. Significant differences in clinical outcomes were observed in the treatment group compared to the placebo. NBP administration showed preliminary evidence of clinical benefit in SCA3. © 2026 International Parkinson and Movement Disorder Society.

A pathogenic GGC repeat expansion in zinc finger homeobox 3 (ZFHX3), encoding a pure polyglycine (polyG) tract, causes spinocerebellar ataxia type 4 (SCA4). Intermediate expansions of other SCA loci have been implicated in amyotrophic lateral sclerosis (ALS), while repeat motif composition is recognised to influence pathogenicity in neurodegenerative diseases. Given the genetic pleiotropy between ALS and SCA, we evaluated whether ZFHX3 GGC expansions are associated with ALS and characterised repeat motif composition. ZFHX3 GGC repeat sizes were genotyped using ExpansionHunter in short-read whole-genome sequencing data from ALS cases and healthy controls of European ancestry. Repeat sizes were visually inspected using REViewer, and motif configurations were manually derived from a subset. Receiver operating characteristic analysis and Youden's J statistic identified a candidate repeat size threshold. Logistic regression tested associations of repeat length and motif composition with ALS, while regression models assessed clinical phenotypes. Across 5785 ALS cases and 7982 controls, no association was observed between ZFHX3 expansions and ALS risk. Longer alleles showed a nominal association with later disease onset, however this did not remain significant after Bonferroni correction. Among 802 ALS cases and 800 controls, 50 distinct motif compositions were identified, including 11 encoding pure polyG tracts characteristic of pathogenic SCA4 expansions; none were associated with ALS. Although no association with ALS was observed, this study established the dynamic nature of ZFHX3 repeat motif composition and configuration. Variation within and between repeat sizes, including pure polyG repeats, supports consideration of motif composition alongside allele length when evaluating neurodegenerative disease risk.

The clinical assessment of spinocerebellar ataxia type 3 (SCA3) is hindered by subjective factors and inter-rater variability. This study utilizes a previously validated wearable plantar pressure insole system established in our prior work to build a multiscenario digital balance detection framework, and assesses its efficacy in differentiating SCA3 patients from healthy individuals and in evaluating disease severity. The study involved 74 SCA3 patients and 45 healthy controls, who were equipped with custom-developed plantar force sensors to perform standing tasks with eyes open (EO) and eyes closed (EC). Center of pressure (COP) variables were analyzed to determine their correlation with clinical characteristics and their discriminative capability. An XGBoost model was employed to classify disease severity, with SHAP analysis providing enhanced interpretability. COP variables derived from EC tasks demonstrated superior performance in terms of area under the curve, accuracy, sensitivity, and specificity compared to those from EO tasks. Significant correlations were identified between COP variables, such as the eyes closed, left side sway velocity (EC-L velocity) SD, and clinical scores (r > 0.4). The model achieved an accuracy of 87% in classifying disease severity, with SHAP analysis highlighting key variables and interactions. COP variables offer a robust, multidimensional measure of motor dysfunction.

In response to a case report on a patient with spinocerebellar ataxia type 8, presenting with early-onset parkinsonism and treated with deep brain stimulation, we report an analogous case, who responded optimally to continuous subcutaneous foscarbidopa/foslevodopa infusion.