Spinocerebellar ataxia type 36 (SCA36)-caused by a GGCCTG hexanucleotide repeat expansion in the NOP56 gene-has traditionally been considered to originate from a founder effect in the Ashida River basin of southern Japan. However, its genetic background remains incompletely understood. In this study, we analyzed five Japanese patients with SCA36 from four unrelated families using long-read sequencing to determine repeat length and reconstruct detailed haplotypes around the NOP56 locus. We successfully resolved extended haplotypes ranging from approximately 90 kb to 1.3 Mb. All five individuals shared a 5.3-kb haplotype adjacent to the repeat expansion, while four patients from northern Japan shared a larger haplotype block of at least 95.2 kb. Comparison with seven previously reported Korean SCA36 cases revealed a shared 4.2-kb haplotype, and available data from other populations were concordant within a ~ 2.1-kb core region. Notably, the shared 5.3-kb haplotype is relatively common in the general population, suggesting that the underlying core haplotype may represent a permissive haplotypic background rather than a unique founder haplotype. These findings indicate that SCA36 is unlikely to be explained solely by a regional founder in southern Japan. Instead, a shared permissive haplotypic background may underlie repeat expansion, with large pathogenic expansion arising independently in different populations. This pattern may be consistent with a stepwise process of repeat expansion.

Autosomal recessive spinocerebellar ataxia type 4 (SCAR4), caused by biallelic vacuolar protein-sorting 13D (VPS13D) variants, is a rare, clinically heterogeneous disorder. To describe an adult-onset SCAR4 case with a 30-year course and compare its features to those of published cases. We analyzed the clinical and imaging findings of a 58‑year‑old man and performed a literature review with pooled analysis of reported VPS13D/SCAR4 cases. The patient developed gait disturbance in his twenties, followed by progressive cerebellar and sensory ataxia, pyramidal signs, and peripheral neuropathy. MRI showed mild cerebellar atrophy. Fluorodeoxyglucose positron emission tomography and brain perfusion single-photon emission computed tomography revealed slightly reduced signals in the anterior cerebellum. Whole-exome sequencing revealed compound heterozygous VPS13D variants, including a pathogenic frameshift and a likely pathogenic missense variant. A literature review identified 47 cases. SCAR4 should be considered in sporadic adults with cerebellar ataxia, pyramidal signs, and peripheral neuropathy.

The CAG expansion in the ataxin-3 (ATXN3) protein is the underlying cause of Spinocerebellar Ataxia Type 3 (SCA3), a polyglutamine disease. The aggregation of mutant ATXN3 protein is hypothesized to contribute to neuronal dysfunction, neurodegeneration, or neuroinflammation. Mesenchymal stem cells have pleiotropic therapeutic properties, and adipose-derived mesenchymal stem cells (ADMSC) have been shown to be safe and well-tolerated in SCA3 patients. In this study, we evaluated the therapeutic effects of ADMSC in SCA3 mice. In a mouse model of SCA3, the Purkinje-cell-specific L7 promoter drives the expression of a truncated form of human ataxin-3 with 69 glutamine repeats. SCA3 mice exhibited cerebellar Purkinje cell degeneration, reduced myelination, and increased gliosis; pathological features also observed in SCA3 patients. SCA3 mice received repeated intravenous administrations of ADMSC, and efficacy was assessed by rotarod performance, molecular and pathological changes, and serum neurofilament light chain (NfL) levels. ADMSC-treated SCA3 mice showed significant improvements in rotarod performance, a reduction in accumulated toxic mutant ATXN3-69Q protein in Purkinje cells, decreased demyelination, and alleviation of neuroinflammatory and systemic inflammatory responses during disease progression. Furthermore, NfL levels, a potential biomarker for SCA3 disease progression, were inversely correlated with the rotarod performance. Based on these findings, we conclude that ADMSC enhance motor function in SCA3 mice by reducing neuroinflammation, demyelination and aggregated mutant ataxin-3 protein levels in Purkinje cells. ADMSC have the potential to serve as a disease-modifying therapy for SCA3 patients.

Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine neurodegenerative disorder in which metabolic involvement may extend beyond proteotoxicity alone. We integrated cerebellar RNA sequencing with transcriptome-constrained genome-scale metabolic modeling to characterize metabolic dysregulation in transgenic SCA3 (84Q) versus control (15Q) mice and to relate cerebellar changes to circulating insulin-related measures. Differential expression and preranked gene set enrichment analyses revealed coordinated suppression of insulin/glucose-homeostasis modules and lipid/sterol programs in the SCA3 cerebellum. Context-specific metabolic models derived from iMM1865 and analyzed using parsimonious flux balance analysis, flux variability analysis, and flux sampling indicated reduced oxidative metabolism together with increased nucleotide salvage, one-carbon metabolism, and proteostasis-associated remodeling. Distribution-level comparisons of sampled fluxes detected widespread network reorganization despite modest median shifts. Plasma insulin was elevated in 84Q mice, whereas cerebellar Ins2 and Igf1 transcripts were reduced, consistent with an insulin-related dysregulation signature. Together, these data support broad metabolic reprogramming in the SCA3 cerebellum, including insulin/IGF-related alterations, and nominate pathway-level candidates for future mechanistic validation.

Ataxia-Telangiectasia (AT) is a rare neurodegenerative disorder characterized by progressive neuronal loss and chronic neuroinflammation. Emerging evidence indicates that aberrant overexpression of the adaptor protein TYROBP promotes sustained recruitment and activation of spleen tyrosine kinase (SYK), contributing to pathogenic inflammatory signaling in AT. In this study, we applied a drug repositioning strategy to identify clinically approved compounds that inhibit SYK activity. An integrated in silico workflow was employed, combining convolutional neural network (CNN)-based molecular docking with network medicine analysis using the SAveRUNNER platform to screen a library of 2342 FDA-approved drugs. The top-ranked candidates were further evaluated using long-timescale molecular dynamics simulations and post-simulation redocking to assess their binding stability and conformational persistence within the SYK catalytic pocket under explicit solvent conditions. This multilevel computational analysis identified vemurafenib and palbociclib as the most promising SYK inhibitors, both exhibiting sustained binding affinity and stable intermolecular interactions following protein relaxation. These findings support the feasibility of repurposing FDA-approved drugs to modulate SYK-driven neuroinflammatory pathways and provide a mechanistic framework for developing novel neuroprotective interventions for AT.

We describe a patient admitted with altered mental status and nutritional deficiency who was misdiagnosed with Wernicke Encephalopathy. Subsequently, as an outpatient, she was diagnosed with Celiac disease (CeD) following extensive neurologic workup. While CeD and other gluten-associated disorders are typically associated with gastrointestinal symptoms, patients may also present with neurologic symptoms, such as altered mental status, ataxia, and encephalopathy. Once a gluten-free diet was initiated along with nutritional supplements, the patient's mental status gradually improved. Given CeD's diverse symptom profile, it can often be a challenging to clinically suspect and diagnose accurately.

Friedreich's ataxia (FRDA) is an inherited neurodegenerative disorder caused by a GAA repeat expansion within the FXN gene, leading to reduced frataxin levels. This deficiency results in mitochondrial dysregulation, oxidative stress, and progressive cell death. Currently, only one approved treatment exists for FRDA in the United States, Canada, and the European Union, which improves neurological outcomes but has not been fully evaluated for broader disease symptoms. Therefore, identifying new therapeutic targets remains essential. Sphingolipids are increasingly recognized for their roles in neurodegeneration with emerging evidence indicating their dysregulation in FRDA. Here, we investigate whether sphingolipid-metabolizing enzymes are similarly affected and assess the therapeutic potential of targeting them. Our findings demonstrate that these enzymes are dysregulated across multiple FRDA models. Importantly, their modulation in vitro and in vivo significantly reduces mitochondrial dysfunction, enhances frataxin expression, and improves key pathological features of the disease, highlighting sphingolipid metabolism as a promising therapeutic target for FRDA.

Bilateral symmetrical calcification of striatum and pallidum with or without involvement of other brain structures is a rare radiological finding. Genetic causes predominates once hypoparathyroidism is ruled out. Clinical features include a variable combination of neuropsychiatric and motor symptoms, including dystonia, Parkinsonism, ataxia, psychosis, dementia, chorea, and frontal-subcortical cognitive dysfunction. One third of primary familial brain calcification is asymptomatic. Solute carrier 20 A2 gene mutation accounts for the majority of primary familial brain calcification. Here we describe a case of primary brain calcification due to a novel mutation in Solute carrier 20A gene in a 55-year-old woman.

Multiple system atrophy (MSA) is a rare, rapidly progressive neurodegenerative disorder characterized by varying combinations of Parkinsonian features, cerebellar ataxia, and autonomic dysfunction. The disease is classified into two major subtypes based on predominant symptoms: The Parkinsonian variant (MSA-P) and the cerebellar variant (MSA-C). MSA-C, in particular, presents significant diagnostic challenges due to its overlapping clinical features with other neurodegenerative disorders, such as cerebellar ataxias and atypical Parkinsonian syndromes. Early stages of the disease may not show conclusive findings on conventional imaging, further complicating diagnosis. We report a case of a middle-aged woman who presented with progressive ataxia, dysarthria, orthostatic symptoms, and urinary disturbances. Initial clinical assessment and structural imaging were inconclusive. The patient showed poor response to standard pharmacological therapy, including levodopa. This prompted further evaluation with functional imaging, which demonstrated regional hypometabolism in the brainstem and cerebellum - findings supportive of a diagnosis of MSA-C. Comprehensive autoimmune and metabolic workups were negative, reinforcing the clinical suspicion. This case highlights the importance of a thorough diagnostic approach in patients with progressive cerebellar and autonomic symptoms. While definitive biomarkers for MSA are lacking, advanced imaging techniques such as fluorodeoxyglucose positron emission tomography can provide supportive evidence in challenging cases. Early identification of MSA, even when classic signs like the "hot cross bun" sign are absent on magnetic resonance imaging, is essential to initiate symptomatic treatment, plan supportive care, and guide patient and family counseling.

Hypertrophic olivary degeneration (HOD) is a delayed trans-synaptic consequence of injury to the dentato-rubro-olivary pathway - the Guillain-Mollaret triangle (GMT) - and represents one of the few conditions in which the inferior olivary nucleus (ION), a pivotal node of the olivopontocerebellar system, paradoxically enlarges rather than atrophies following disconnection. Its peak magnetic resonance imaging (MRI) appearance closely mimics a primary brainstem neoplasm, and failure to recognize it has led to unnecessary biopsy in documented cases. We report a case of a 79-year-old man with uncontrolled hypertension who developed palatal tremor and contralateral cerebellar ataxia 7 months after a spontaneous left cerebellar hemorrhage. Brain MRI demonstrated T2/fluid attenuation inversion recovery hyperintensity with hypertrophy of the right ION, blooming at the left dentate nucleus, and no restricted diffusion - the full diagnostic triad of HOD, established on a single examination. Neoplasm was confidently excluded without biopsy. This case illustrates that systematic, anatomy-guided interpretation of multi-sequence MRI - anchored by knowledge of GMT connectivity - is sufficient for definitive HOD diagnosis from a single study, with particular relevance for elderly patients and resource-limited clinical settings in which olivary degeneration may otherwise be misattributed to recurrent cerebrovascular disease or primary malignancy.