A 7-month-old Belgian Malinois puppy was presented for progressively worsening ataxia and episodes of aggression. General physical examination was unremarkable, and neurological examination revealed ambulatory tetraparesis, spinocerebellar ataxia, thoracic limb pseudo-hypermetria, exaggerated head movements, bilateral vestibular signs and a bilateral divergent strabismus. A magnetic resonance imaging (MRI) of the brain and cervical spinal cord revealed a generalized cerebral atrophy. The dog woke up from anesthesia in a severe episode of disorientation and aggression, wherefore he was euthanized. Histopathology of the brain revealed diffuse and widespread oligodendroglial dysplasia with myelinated fibers disorganization. A disease-associated nonsense variant in NECAP1 (NC_049248.1:g.8636271G>A on chromosome 27), introducing a stop codon at codon 48 (XM_038576681.1:c.142C>T (p.Arg48*)) and truncating the only isoform by 83%, was identified by whole genome sequencing (WGS). The variant segregated in the affected family with a recessive mode of inheritance, but was not present in 158 undiagnosed Belgian Malinois from the Belgian population. The exact same variant, as well as another NECAP1 variant (c.301 + 1G>A), have been associated with early onset epileptic encephalopathy (EOEE) in humans, a disease that is characterized by intractable epileptic seizures and profound global developmental delay in young children. In conclusion, a previously unreported leukoencephalomyelopathy with oligodendroglial dysplasia causes spinocerebellar ataxia and abnormal behavior in Belgian Malinois.

Peripheral lymphocyte subsets in spinocerebellar Ataxia type 2: Insights into disease mechanisms and potential immunomodulation.

Challenges in the diagnosis of spinocerebellar ATAXIA 27B.

Proper localization of the SCA13-linked K+ channel in Purkinje neurons requires a microtubule-stabilizing protein.

Spinocerebellar ataxia type 3 (SCA3), the most common autosomal dominant ataxia, is driven by the accumulation of polyglutamine-expanded (polyQ) ATXN3 proteins. While promising as biomarkers, their longitudinal trajectories across multiple biofluids remain poorly defined. To quantify polyQ ATXN3 levels in cerebrospinal fluid (CSF), plasma, and urine within a comprehensive cohort, utilizing serial measurements to map protein dynamics. We employed a validated immunoassay to quantify polyQ ATXN3 in 97 symptomatic and 13 presymptomatic SCA3 patients, correlating levels with clinical features, ancestry, disease status, and longitudinal progression. Asian participants exhibited lower plasma but elevated urinary polyQ ATXN3 levels relative to other ancestries. While CSF levels were higher in symptomatic patients at baseline, they showed a significant longitudinal decline. PolyQ ATXN3 is a viable multi-biofluid biomarker. Declining CSF levels likely reflect neurodegeneration, supporting its role in tracking progression and emphasizing the need for ancestry-based adjustment in trials. © 2026 International Parkinson and Movement Disorder Society.

Episodic ataxia type 2 (EA2) is an autosomal dominant channelopathy caused by CACNA1A mutations, typically presenting with recurrent episodes of ataxia, vertigo, and hemiplegic migraine, often with a normal brain MRI or cerebellar atrophy. This report describes a 47-year-old man with a 22-year history of recurrent severe headaches, limb weakness, truncal ataxia, sensory disturbances, and profound fatigue, triggered by stress or minor trauma. Interictal recovery was complete, but serial MRI revealed extensive T2/FLAIR white matter hyperintensities, initially raising concern for multiple sclerosis or cerebral vasculitis. Lumbar puncture was unremarkable. Genetic testing identified a pathogenic heterozygous CACNA1A variant (c.7411C > T, p.R2471*), confirming EA2. Symptomatic management with acetazolamide and trigger avoidance improved episode frequency and severity. This case highlights the diagnostic challenges of EA2 when MRI shows atypical white matter lesions and emphasizes the value of genetic testing in atypical presentations. Recognizing these findings can prevent misdiagnosis, guide targeted therapy, and inform family counseling. Pearls: · The variability of CACNA1A- related disorders is broad and continues to expand. The gene-phenotype spectrum includes episodic ataxia type 2 (EA2), familial hemiplegic migraine type 1 (FMH1), sporadic hemiplegic migraine (SHM), spinocerebellar ataxia type 6, epilepsy and developmental epileptic encephalopathy. · Patients with episodic ataxia type 2 have either a normal MRI or cerebellar atrophy, mainly at the vermis. · Episodic ataxia type 2, may be treated with acetazolamide and 4-aminopyridine. Oysters: · EA2 may present in the absence of family history. · It is very common for patients with EA2, to be erroneously diagnosed with another disorder, and the disease is very infrequent. · CACNA1A associated diseases may present with clinical overlap.

Spinocerebellar ataxia type 3 (SCA3) shows marked phenotypic heterogeneity and clinico-radiological dissociation, wherein macrostructural atrophy often fails to fully account for clinical severity. Although structural and functional connectivity abnormalities are well recognized, their potential interaction and neurobiological mechanisms remain poorly understood. This study aimed to identify potential biomarkers for SCA3 by linking structural connectivity-functional connectivity (SC-FC) coupling to mitochondrial function, neurotransmitter distribution, and gene expression. This dual-center study included discovery (117 SCA3, 165 healthy controls [HC]) and independent validation (24 SCA3, 48 HC) cohorts. Participants underwent multimodal 3 T magnetic resonance imaging (MRI) and clinical assessments (Scale for the Assessment and Rating of Ataxia [SARA]; International Cooperative Ataxia Rating Scale [ICARS]; Montreal Cognitive Assessment [MoCA]; Hamilton Depression Rating Scale [HAMD]). Regional and network-level SC-FC coupling was quantified using multiple regression and compared across disease-duration strata. Coupling alterations were spatially mapped to biological atlases (Allen Human Brain Atlas, MitoBrainMap, and positron emission tomography [PET]-based neurotransmitter receptor atlases) using bootstrapped Spearman's correlations (false discovery rate [FDR]-corrected). Gene enrichment analysis was implemented to characterize enriched biological pathways. SCA3 patients exhibited significant, atrophy-independent SC-FC decoupling in the bilateral dorsolateral putamen (dlPu), which correlated with ICARS scores. This decoupling pattern spatially aligned with mitochondrial complex II, 5-HT2A/5-HT4 receptors densities, and genes enriching for synaptic regulation and cellular homeostasis. By integrating SC-FC coupling with biological atlases, this study reveals the pathological underpinnings of clinico-radiological dissociation in SCA3 and identifies dlPu decoupling as a promising early-stage candidate imaging marker, providing an early and objective target for future neuroprotective trials. Chinese Clinical Trial Registry (ChiCTR): 1800019901, 2000039434. © 2026 International Parkinson and Movement Disorder Society.

Spinocerebellar ataxia type 27B is a recently described autosomal dominant, late-onset cerebellar ataxia caused by an intronic GAA repeat expansion in the fibroblast growth factor 14 (FGF14) gene. Despite being recognized as a frequent adult-onset ataxia, its full clinical spectrum remains incompletely understood.To characterize the neurological, cognitive, and paraclinical phenotype of patients with heterozygous FGF14 repeat expansions (>200) and expand the currently known motor and non-motor features, as well as to assess the co-occurrence of other repeat expansions.In this cross-sectional single-center study, patients with heterozygous FGF14 repeat expansions underwent standardized neurological examination and cognitive screening. Paraclinical data were reviewed when available.18 patients were included in the study (mean age at onset: 64 [37-79], at examination: 76 [61-94]). They all presented with gait ataxia, most commonly a lateral veering gait with corrective sidesteps. In addition to the core known cerebellar phenotype, we identified other movement-disorder manifestations, including myokymia, myoclonus, dystonia, and parkinsonism, with nigrostriatal degeneration confirmed in one patient. Cognitive impairment was common, with two-thirds of patients fulfilling criteria for cerebellar cognitive-affective syndrome (mean MoCA: 25 [21-29], CCAS: 86.9/120 [62-108]). Worse CCAS and MoCA performance was associated with increasing ataxia severity. FGF14 repeat expansions ranged from 210 to 520, and co-occurrence with heterozygous expansions in RFC1 or ATXN8/ATXN8OS were identified in three patients. Earlier diagnostic misclassification as transient ischemic attack was reported in 33%. These findings expand the known phenotype of spinocerebellar ataxia type 27B, emphasizing it as a multisystem movement disorder.

Establishment and characterization of two human pluripotent stem cell lines from patients with ATX-FGF14/spinocerebellar ataxia 27A (SCA27A).

Rare diseases, affecting approximately 8% of the global population, remain among the most underserved areas in modern medicine due to their low prevalence, complex genetic origins, and limited commercial incentives for drug development. Rare neurological disorders, in particular, pose formidable challenges owing to their progressive nature and the difficulty of delivering thera-peutics across the blood-brain barrier. This review explores the emerging role of nanomedicine in transforming rare disease management through precision-targeted drug delivery, enhanced bioavail-ability, and the ability to bypass biological barriers. Nanoparticles (NPs)-including PEGylated NPs, lipid-based NPs, polymeric NPs, and hybrid formulations-are being engineered to deliver therapeu-tic agents for gene therapy, enzyme replacement, and RNA interference. These platforms have shown promise in treating conditions such as Krabbe disease, Niemann-Pick type C1, spinocerebel-lar ataxia type 1, and prion diseases. Additionally, nanotherapeutics are being investigated for pulmonary and congenital lung disorders, including cystic fibrosis and idiopathic pulmonary fibro-sis, with improved tissue penetration and reduced systemic toxicity. The review also highlights the potential of AI-integrated diagnostics and personalized nanomedicine to address disease heterogene-ity and improve patient outcomes. Despite these advances, significant barriers remain, including regulatory complexity, high development costs, and limited clinical models. The manuscript calls for collaborative innovation across academia, industry, and regulatory bodies to accelerate clinical translation and ensure equitable access. By bridging molecular innovation with patient-centric care, nanotherapeutics offer a paradigm shift in the diagnosis and treatment of rare diseases, potentially redefining therapeutic landscapes and improving the quality of life for affected individuals.

Spinocerebellar ataxia type 3 (SCA3) is caused by CAG repeat expansion in ATXN3, which inversely correlates with age at onset but does not fully account for interindividual variability. A recent study in a mixed European/South and NorthAmerican cohort suggested that the PRKN V380L variant (rs1801582), particularly in C/C homozygotes, was associated with earlier disease onset. We therefore performed a replication analysis to evaluate the frequency and potential clinical relevance of rs1801582 in a Japanese SCA3 cohort. rs1801582 genotypes were determined by Sanger sequencing in 228 genetically confirmed SCA3 patients and 260 SCA6 patients as convenience disease controls. Genotype frequencies were additionally compared with East Asian reference populations from the 1000 Genomes Project Phase 3 dataset. Associations with age at onset were evaluated using multivariable linear regression adjusted for expanded ATXN3 CAG repeat length, normal ATXN3 CAG repeat length, and sex. Genotype frequencies in SCA3 (G/G: 86.0%, G/C: 13.2%, C/C: 0.9%) were similar to those in controls (G/G: 85.8%, G/C: 13.5%, C/C: 0.8%) and closely resembled those reported in East Asian reference populations. Because of the extremely small number of C/C carriers (n = 2), subsequent analyses focused on G/G and G/C carriers. In SCA3, median age at onset was comparable between genotypes (42 vs. 41years), and median expanded ATXN3 CAG repeat lengths did not differ between groups (71 vs. 71 repeats). Multivariable regression analysis adjusting for expanded ATXN3 CAG repeat length, normal ATXN3 CAG repeat length, and sex demonstrated that rs1801582 was not independently associated with age at onset (β = - 0.42years, p = 0.84), whereas expanded CAG repeat length remained a strong predictor (β = - 1.68years per repeat, p < 0.0001). The rs1801582 C/C genotype is extremely rare in Japan; therefore, the present cohort had limited statistical power to directly evaluate the previously proposed recessive modifier effect. No detectable association between rs1801582 genotype and age at onset was identified among G/G and G/C carriers in this Japanese cohort. These findings highlight the importance of population-specific validation and adequately powered replication studies when evaluating candidate genetic modifiers in SCA3.

Biomarker-based technologies for predicting age of onset are currently being developed for carriers and individuals at 50% risk of autosomal dominant neurodegenerative diseases such as Huntington’s disease, frontotemporal dementia and spinocerebellar ataxias. Qualitative interview studies indicate that carriers and individuals at 50% risk expect that onset predictions would be valuable for life planning but would also impact mental health. Ethically responsible implementation of biomarker-based onset prediction in research and clinical settings requires maximizing the utility and minimizing negative psychosocial effects. We present a framework specifying features that influence the value and impact of onset predictions, grouped into four domains: features of the disease, the onset-predictive test, the individual, and the context. The framework is intended to support ethicists, researchers, developers, and healthcare professionals in anticipating and addressing the ethical implications of current and emerging onset prediction technologies for individuals at risk of genetic neurodegenerative disease.

Spinocerebellar ataxia type 10 in a Guatemalan family: Characterization and preliminary evaluation of neurofilament light chain as a biomarker.

Spinocerebellar ataxia 1 (SCA1) is a fatal hereditary neurodegenerative disorder with no approved therapies, and gene-targeting strategies have thus far failed in clinical trials. Exercise remains the only intervention shown to provide clinical benefit in patients with spinocerebellar ataxias (SCAs), yet the underlying mechanisms remain poorly understood. Using the Atxn1154Q/2Q knock-in mouse model, we implemented a prolonged voluntary wheel-running paradigm from 4 to 16 weeks of age. Mice were then phenotyped using motor and cognitive behavioral assays. Following euthanasia, cerebellar tissue was harvested for histological analysis and unbiased transcriptomics. Unrestricted exercise rescued motor ataxia but not degeneration in this SCA1 mouse model at the ages in this study. Transcriptional profiling of cerebellar tissue separated wild-type (WT) sedentary and exercise mice by differential gene expression, but in SCA1 mice the most pronounced changes occurred at the level of RNA splicing, particularly in ion channel modules. Exercise led to a significant rescue of splicing events in SCA1 mice, with minimal impact on gene expression changes. Further, both exercised SCA1 and WT mice exhibited splicing patterns more similar to each other than their sedentary counterparts. Together with emerging evidence in other SCAs, our findings confirm aberrant splicing as a central driver of SCA pathophysiology and identify splicing-regulated networks as actionable therapeutic targets. The observed benefits in SCA1 mice suggest that correcting mis-spliced ion channels may be a viable strategy for disease modification across SCAs and related neurodegenerative disorders. ANN NEUROL 2026.

This review describes the clinically and genetically heterogenous group of 52 Spinocerebellar ataxias (SCAs). After a brief description of the epidemiology and clinical spectrum, this review highlights the functional neuroanatomy, the need for sufficient sampling based on this knowledge, and showcases examples of neuropathology. In addition, a comprehensive overview of the pathogenesis of the different forms of spinocerebellar ataxias (SCAs) is given.

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease marked by progressive motor deficits and Purkinje cell (PC) degeneration, driven by polyglutamine expansion in ataxin-1. While oligodendroglial dysfunction precedes PC loss, its direct contribution toward SCA1 pathogenesis remains unclear. Here, using an oligodendroglia-specific SCA1 conditional knockin mouse model, we demonstrate that mutant ataxin-1 in oligodendrocytes is sufficient to drive aspects of SCA1-related pathology, including dysregulated myelination, PC axonal shrinkage, and torpedo formation, ultimately impairing motor coordination. Transcriptomic analysis uncovers cerebellar oligodendrocyte subtypes with distinct gene expression signatures and aberrant abundance that contribute to demyelination. This, compounded by a progressive decline in the neuroprotective functions of a cerebellum-specific oligodendrocyte subtype, establishes a critical link between demyelination, axo-myelinic dysfunction, and axonal pathology in SCA1. Upstream transcriptional regulator analysis in oligodendroglia identifies transcription factor 7-like 2 (TCF7L2) and huntingtin (HTT) as key mediators of oligodendroglial dysfunction in SCA1, suggesting shared pathogenic mechanisms with other polyglutamine diseases. Collectively, these findings establish oligodendroglia as key mediators of SCA1 pathogenesis and underscore their critical role in preserving PC axonal integrity.

Upper limb postural tremor is common in both Spinocerebellar Ataxia type 12 (SCA12) and Essential Tremor (ET). In the early stages, their clinical presentation can be similar, leading to potential misdiagnosis. This study aimed to develop and evaluate a low-cost device and methods to quantify 2D reaching kinematics objectively, with the goal of improving differentiation between ET and SCA12 using machine learning (ML) models. We recruited 48 participants, including 16 SCA12 patients, 16 ET patients, and 16 healthy controls (HC). Clinical severity was scored using TETRAS and SARA scales. A Raspberry Pi-based device was used to record upper limb reaching during a button-press task. The videos were processed with DeepLabCut and six 2D kinematic parameters were extracted via MATLAB scripts. We expanded the dataset using Generative Adversarial Networks (GAN). Classification was performed using multiple ML algorithms, with and without GAN-based data augmentation. Both patient cohorts showed significant alterations in kinematic features compared to HC, with SCA12 demonstrating more pronounced abnormality. Kinematic parameters including maximum reaching speed, endpoint precision, and time fraction to peak speed emerged as potential markers for differentiating ET and SCA12. The ML models demonstrated high classification performance in distinguishing HC from patients (CA 88.9%) and SCA12 from ET (CA 83.3%) using original data. The device-guided reaching kinematics provide objective markers of motor impairment. Combined with ML, this approach could enhance diagnostic accuracy; it also has potential for remote monitoring and as an outcome measure in clinical trials.

Depression is a common comorbidity in spinocerebellar ataxia type 2 (SCA2). Despite P300 endogenous evoked potentials reliably indexing early cognitive deficits, their utility as depression biomarkers remains untested. This study aimed to characterize auditory P300 potentials as biomarkers of comorbid depression in SCA2 patients. Twenty SCA2 patients and age/sex-matched controls were stratified by Beck Depression Inventory-II (BDI-II) into depressed (≥ 14) and non-depressed (< 14) subgroups. Auditory P300 oddball paradigms were recorded, and P300 latency and amplitude analyzed in all participants. Two-way ANOVAs examined main effects and disease×depression interactions on P300 variables. SARA quantified ataxia severity. Two-way ANOVAs revealed significant main effects of disease group and depression status on P300 latency (rank-transformed data) and amplitude (parametric data), without significant interactions. Post-hoc Sidák tests confirmed prolonged latency and reduced amplitude in SCA2 patients vs. controls within both depression strata, and in depressed vs. non-depressed subgroups within each cohort. Spearman correlations demonstrated consistent P300-BDI-II relationships, but not associations between P300 parameters and SARA scores. ANCOVA confirmed independent depression effects on P300 parameters after covariate adjustment in SCA2. Auditory P300 latency and amplitude serve as state-dependent biomarkers for depression in SCA2, independent of motor progression. This supports P300 use as a secondary endpoint in clinical trials, enabling earlier diagnosis and precision medicine for affective symptoms.

Suspected autoimmune cerebellar ataxia: Predictors of immunotherapy response and diagnosis reclassification to neurodegenerative disease.

Gerstmann-Sträussler-Scheinker syndrome (GSS) is an extremely rare genetic prion disease caused by pathogenic mutations in the prion protein gene (PRNP). Further reports and thorough evaluation are needed to identify and manage this disease. We report a rare case of GSS in a 56-year-old woman who presented with progressive gait instability, dizziness, and speech difficulties. Initial genetic screening for 12 common spinocerebellar ataxia (SCA) subtypes via PCR-based fragment analysis was negative. However, detailed video-oculography (VOG) revealed key ocular motor abnormalities, including spontaneous upbeat nystagmus with a decreasing slow phase velocity, macro-square wave jerks, horizontal gaze-evoked nystagmus, saccadic hypermetria, and decreased optokinetic nystagmus. Given the family history of gait instability and these specific findings, whole-exome sequencing (WES) was performed, which identified a heterozygous p.Pro102Leu (P102L) mutation in the PRNP gene. Neuroimaging was unremarkable, highlighting the clinical-radiological dissociation. This case demonstrates that a distinctive oculomotor signature can serve as a critical phenotypic lead for GSS, particularly justifying expanded genetic evaluation when conventional SCA panels and neuroimaging are non-diagnostic.