脊髄小脳変性症(多系統萎縮症を除く。)

Many neurological diseases impact specific brain regions despite widespread expression of the disease-related protein. Spinocerebellar ataxia type 1 (SCA1) primarily affects the cerebellum, though Ataxin-1 (ATXN1) is widely expressed. We previously showed that intensified interaction between mutant ATXN1 and Capicua (CIC) drives SCA1 pathogenesis in the cerebellum, whereas ATXN1 loss augments amyloid β production in the hippocampus and cortex. CIC, however, forms a complex with ATXN1 and its paralog, Ataxin-1-like (ATXN1L), yet knockout of either yields completely different phenotypes. To determine whether this could be due to CIC having two isoforms, we generated mice bearing either the long (CIC-L) or short (CIC-S) isoform. Loss of CIC-L led to cognitive deficits, whereas loss of CIC-S caused early postnatal lethality, phenocopying ATXN1 and ATXN1L knockout mice, respectively. Furthermore, CIC-L preferentially interacts with ATXN1, and CIC-S with ATXN1L. Our data underscore the importance of isoform-paralog interplay in studying regional vulnerability in neurodegenerative diseases.

Oculomotor dysfunction is common in ataxias, but its impact on patient-reported visual function remains insufficiently understood. To characterize patient-reported visual function across ataxias and assess the functional significance of specific oculomotor abnormalities in spinocerebellar ataxias. Participants were recruited at Massachusetts General Hospital (n = 117): 56 with genetically-defined ataxias (SCA2, SCA3, SCA6, SCA27B, CANVAS), and 61 controls. Patient-reported visual function was assessed using a 13-item subset of the Visual Activities Questionnaire targeting depth perception, visual acuity/spatial vision, and visual processing speed. Clinical oculomotor assessments focused on four domains: abnormal eye movements at rest, gaze-evoked nystagmus, ocular pursuit abnormalities, and dysmetria of saccades. Clinical severity was assessed with the Brief Ataxia Rating Scale and Modified International Cooperative Ataxia Rating Scale, and subjective symptoms with PROM-Ataxia. Group comparisons, correlations, and regression analyses were performed. All ataxia groups reported significantly worse visual function than controls, with the largest deficits in visual processing speed. Compared with age-matched controls, SCA3 and SCA6 individuals had significantly greater functional impairment across all subcategories. In ataxias, visual function correlated moderately with PROM-Ataxia and weakly with clinical oculomotor scores. Gaze-evoked nystagmus was the only oculomotor sign independently associated with reduced visual function. Ataxias are associated with substantial visual impairment, particularly in visual processing speed. Gaze-evoked nystagmus predicts reduced visual function in ataxias, highlighting the functional relevance of fixation instability. Patient-reported measures of visual function and oculomotor assessments are essential for capturing visual disability in clinical care and trials.

Spinocerebellar ataxia (SCA) is a group of genetic neurodegenerative disorder characterised by progressive cerebellar and associated structural dysfunction. The prevalence of SCA subtypes are considerably variation among different ethnic groups and regions. However, the relative frequencies of these SCA subtypes remain understudied in northern Chinese populations. The study aimed to characterise the geographical heterogeneity of SCA subtypes between northern and southern China. We retrospectively analysed the genotypes and the clinical features of SCA patients primarily from northern China in Beijing Tiantan Hospital over the past five years. We compared the relative frequencies of subtypes found in the northern cohort with those reported in southern China. A total of 105 unrelated Chinese families were genetically verified, comprising 80 families from northern China and 25 families from southern China. Among the 80 families from northern China, SCA3 was identified in 46 families (57.5%), followed by SCA2 in 13 families (16.3%), SCA1 in 11 families (13.8%), SCA6 in 5 families (6.3%), and other SCA subtypes in the remaining 5 families (6.3%). A published cohort study conducted in southern China reported 102 genetically confirmed SCA families, including 74 families with SCA3.The comparative analysis revealed a significant decrease in the relative frequency of SCA3 in 80 families compared to a southern Chinese cohort of 102 families (72.5%, P < 0.05). Our data indicate a potential geographic variation in SCA subtype distribution, characterised by a lower relative frequency of SCA3 in northern China. Nationwide multi-center studies are required to validate the finding.

Polyglutamine diseases are primarily age-dependent neurodegenerative disorders, but patient-based data also point to a broader, multisystem biology. Clinical, imaging, biochemical, and post-mortem studies support peripheral involvement across multiple organ systems in the onset and progression of Huntington's Disease, Spinal and Bulbar Muscular Atrophy, Dentatorubral-Pallidoluysian Atrophy, and six Spinocerebellar Ataxias. Various peripheral abnormalities often emerge before or alongside overt neurological symptoms, contribute to disability and mortality, and are only partly explained by deconditioning or medications. Current data support viewing polyglutamine diseases as systemic protein-misfolding syndromes with organ-selective vulnerability, where peripheral tissues both mirror and modify CNS pathology in humans. Here, we propose that integrated, longitudinal, multisystem phenotyping and targeted organ-directed interventions are essential components of future research investigations, clinical care, and trial design.