Characteristics and prognosis of PCA-1 (anti-Yo) autoimmunity and the utility of the Brief Ataxia Rating Scale in a seropositive cerebellar ataxia cohort.

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive neurometabolic disorder characterized by multisystem involvement and marked clinical heterogeneity. Pathogenic variants in the CYP27A1 gene, encoding mitochondrial sterol-27-hydroxylase, disrupt bile acid synthesis, leading to pathological accumulation of cholestanol in neural tissues, tendons, and other organs.This study aimed to characterize two novel CTX cases with compound heterozygous variants in the CYP27A1 gene through integrated clinical-genetic analysis, and to systematically synthesize current evidence on CTX through a literature review.Molecular investigations employed a tiered sequencing strategy: whole-exome sequencing (WES) for variant discovery, third-generation sequencing for variant screening of WES-negative samples, and Sanger sequencing for familial segregation validation.We present two Chinese juvenile-onset CTX cases demonstrating characteristic multisystem involvement, including both extraneural manifestations and progressive neurological deterioration. Genetic investigations revealed three CYP27A1 variants: the previously unreported c.845 - 46_881del83, the splicing variant c.1477-2A > C, and a novel nonsense variant c.487C > T in exon 3. Both probands exhibited compound heterozygosity, sharing the c.845 - 46_881del83 variant alongside distinct second alleles (c.1477-2A > C and c.487C > T, respectively). Then, a literature review synthesizes current evidence on clinical manifestations, genotypic patterns, and therapeutic approaches in CTX.This study expands the CYP27A1 mutational spectrum with two novel variants and validates the diagnostic utility of long-read sequencing (LRS) in resolving complex autosomal recessive cerebellar ataxia (ARCA) cases. The synthesis of clinical and literature evidence underscores the need for early recognition of CTX's heterogeneous presentations.

Patients with cerebellar ataxia experience fatigue, impaired executive function, and psychosocial deficits. Personal social networks affect physical and mental well-being but there are no data on their effect on quality of life (QOL) and function in ataxia. We examined social network metrics in patients with cerebellar ataxia to test the hypothesis that supportive relationships enhance quality of life and physical function. We used a cross-sectional, survey-interview design with the Personal Network Survey for Clinical Research, World Health Organization QOL-BREF (WHOQOL), Functional Staging Scale for Ataxia, Friedreich's Ataxia Rating Scale-Activities of Daily Living (FARS-ADL), and Patient-Reported Outcome Measure of Ataxia (PROM-Ataxia). We used univariate and bivariate descriptive statistics and bivariate correlations to explore relationships between social network characteristics and QOL, and multivariable linear regression for associations between them. In 106 ataxia patients (56 ± 15.3years), social network size averaged 7.6 ± 2.8 people, mostly friends (52%) and family (33%). Social networks were dense (0.7 ± 0.3) and constrained (0.5 ± 0.1). Omnibus test showed that positive relationships, camaraderie, weekly communication, and high levels of emotional support correlated with PROM-Ataxia Total (p = 0.03), PROM-Ataxia Mental health (p = 0.05), WHOQOL (p = 0.03), FARS-ADL and Functional Staging. Those with constrained social networks and fewer positive relationships reported low QOL, as did those with frequent therapy/counseling and organizational involvement. Positive relationships within social networks of cerebellar ataxia patients positively influence QOL and functional measures. Counterintuitive negative associations with external sources of support need further study to explore causality. Network interventions to enhance emotional support and camaraderie may improve quality of life.

Coexisting cerebellar ataxia and Lambert-Eaton myasthenic syndrome without malignancy: insights from a case and systematic literature review.

Deep intronic GAA repeat expansions in intron 1 of the FGF14 gene were identified in 2023 as cause of late-onset cerebellar ataxia. Since then, GAA-FGF14-related ataxia (SCA27B) has emerged as one of the most common genetic causes of late-onset cerebellar ataxia. To describe the clinical, genetic, and imaging features of a large Dutch cohort. The Radboudumc genetic database was queried for GAA-FGF14 expansions ≥200. Repeat length was assessed using locus-spanning polymerase chain reaction (PCR), repeat-primed PCR, and PacBio sequencing. A subset was validated using Oxford Nanopore. Clinical and imaging data were retrospectively reviewed. 127 individuals with GAA-FGF14 expansions ≥200 were identified; clinical data were available from 116, including 109 symptomatic and 7 asymptomatic/presymptomatic individuals. Fifteen individuals carried GAA200-249 expansions; 60% exhibited at least one core SCA27B feature. Episodic symptoms occurred in 72.5%; 24% had prior emergency department or outpatient transient ischemic attack clinic visits. Brain magnetic resonance imaging frequently showed non-specific white matter abnormalities (>90%); Superior cerebellar peduncle sign was present in 67.7%. Among those treated, 54.1% reported symptomatic benefit from 4-aminopyridine. Nanopore and PacBio sequencing results showed high correlations. We observed an inverse relationship between age at onset and disease progression. Core SCA27B features emerge in those carrying GAA200-249 expansions. SCA27B may mimic stroke in patients with episodic symptoms. In our cohort, later onset was associated with faster disease progression. The superior cerebellar peduncle sign may aid diagnosis, while relevance of white matter changes remains unclear. Positive response to 4-aminopyridine was reported in approximately half of patients. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Spinocerebellar ataxias (SCAs) are a group of progressive neurodegenerative disorders caused by pathogenic variants in more than 40 genes with diverse cellular functions. In this study, we identified the c.247C > T p.(Arg83Trp) variant in RAB3A, encoding a small GTPase involved in membrane-associated regulated exocytosis, in two families with cerebellar ataxia. Affected individuals presented with adult-onset, gradually progressive cerebellar symptoms, often accompanied by mild gait spasticity and tremors. Variable features of neurodevelopmental disorders were also observed. Brain MRI consistently revealed cerebellar atrophy, often accentuated in the vermis, and neuropathological examinations demonstrated diffuse cerebellar cortical degeneration. Functionally, the R83W mutation lies within the conserved switch II region of Rab3A, a domain critical for effector interaction. Although the mutant Rab3A R83W retained GTP-binding affinity, it failed to bind the key effector proteins RIM1 and Rabphilin-3A, highlighting the functional importance of R83 in effector complex formation, as supported by structural analysis. In PC12 cells, the R83W mutant exhibited diffuse cytoplasmic localization, in contrast to the vesicle- and neurite-tip localization of the wild-type and GTP-bound Rab3A mutant. The concordant localization pattern of R83W and GDP-bound Rab3A mutants suggests that R83W-induced mislocalization results from a failure to engage downstream effector proteins. In the cerebellum, Rab3A was predominantly localized to parallel fiber terminals and was absent from postsynaptic Purkinje cells. These findings suggest that disruption of the interaction between Rab3A and its effector proteins may underlie disease pathogenesis, possibly involving presynaptic dysfunction at parallel fiber-Purkinje cell synapses mediated by the Rab3A-RIM1 complex.

Spinocerebellar ataxia type 3 (SCA3) is a hereditary neurodegenerative disorder characterized by cerebellar ataxia, whereas amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease. We herein report a 62-year-old man with genetically confirmed SCA3 who subsequently developed rapidly progressive asymmetric muscle weakness, atrophy, and fasciculations. Clinical features, including preserved tendon reflexes and widespread denervation observed on electromyography, support the diagnosis of concomitant sporadic ALS. Our literature review revealed only a few similar cases, suggesting the under-recognition of this rare combination. This case underscores the importance of considering coexisting ALS in patients with SCA3 to enable a timely diagnosis and management.

Immunotherapies in autoimmune movement disorders and cerebellar ataxia.

CACH syndrome (Childhood Ataxia with Central Nervous System Hypomyelination), also known as Vanishing White Matter disease, is a rare genetic leukodystrophy caused by mutations in the EIF2B genes, which lead to impaired control of protein synthesis and the cellular stress response. It most commonly presents in childhood as progressive cerebellar ataxia, often triggered by an infectious episode, trauma, or stress. We report the clinical case of an 8-year-old female patient hospitalized for ataxia in the pediatric neurology and neurometabolic disorders unit of the Pediatrics II Department at the Childrens Hospital of Rabat, in whom the diagnosis of CACH syndrome was established and genetically confirmed. CACH syndrome is a rare genetic pediatric leukodystrophy characterized by cerebellar ataxia, frequently triggered by stress or infection. Diagnosis is based on characteristic brain MRI findings and confirmed by genetic testing. Early recognition of the disease allows avoidance of aggravating factors and optimization of symptomatic management.

Introduction: Neurodegenerative diseases such as multiple system atrophy (MSA), spinocerebellar ataxia (SCA), and Friedreich’s ataxia (FRDA) progressively impair the nervous system, affecting approximately 15% of the global population. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive method, may promote neuroplasticity. The cerebellum, central to motor control and neural connectivity, is a promising rTMS target. Therefore, this research aims to evaluate the efficacy of rTMS in treating neurodegenerative cerebellar ataxia. Methods: A systematic review and meta-analysis was conducted per PRISMA guidelines, searching ten databases (to August 9, 2025). Eligible studies were RCTs comparing rTMS with sham in cerebellar ataxia. The review was registered on PROSPERO (CRD420251127471). Study quality was assessed with Cochrane RoB 2.0; meta-analysis used Review Manager 5.4.1, and meta-regression was performed in JASP 0.19.3. Results: Seven RCTs involving a total of 256 patients were included. rTMS significantly improved SARA (SMD = -0.84, p = 0.004, I² = 73%). ICARS showed no significant difference (SMD = -0.82, p = 0.43, I² = 96%). Meta-regression and sensitivity analysis were done to find key heterogeneity sources. Most studies had low bias. Conclusions: rTMS significantly improves SARA scores in neurodegenerative cerebellar ataxia if compared to sham, while ICARS shows insignificant differences. Further research is needed.Keywords: Neurodegenerative ataxia, Repetitive Transcranial Magnetic Stimulation, Sham-controlled

We present a school-aged girl with ataxia-telangiectasia (AT), a rare autosomal recessive neurodegenerative disorder. She presented with progressive cerebellar ataxia beginning at 12 months, ocular telangiectasias developing at 4 years and unusually extensive cutaneous telangiectasias on the dorsum of hands, feet and limbs emerging at 5 years. Laboratory investigations revealed elevated alpha-fetoprotein levels, decreased immunoglobulin A and G and cerebellar atrophy on MRI. The patient experienced recurrent sinopulmonary infections requiring monthly intravenous immunoglobulin therapy. This patient demonstrates the classical neurological manifestations of AT alongside an atypical distribution of prominent cutaneous telangiectasias, emphasising the importance of early recognition for appropriate management and genetic counselling.

Spinocerebellar ataxia, autosomal recessive type 23 (SCAR23) is an ultra-rare inherited disorder caused by biallelic Loss-of-Function (LoF) variants in TDP2, a nuclear enzyme involved in DNA double-strand breaks repair. To date, only 12 cases with homozygous variants and complex neurological phenotypes have been reported. We describe a 20-year-old male presenting with cerebellar ataxia, drug-resistant epilepsy, mild intellectual disability, and recurring craniofacial traits observed in SCAR23. Additional findings included polycythemia and a pituitary hamartoma. Clinical exome sequencing (CES) identified two novel TDP2 nonsense variants. In silico and structural analyses indicated that both variants affect highly conserved residues in the catalytic domain. Longitudinal video-oculography confirmed downbeat nystagmus (DBN), while static stabilometry captured subtle postural changes over 12 months not detected by routine clinical examination, highlighting the utility of quantitative digital assessments. This case expands the genotypic spectrum of SCAR23 and highlights recurring facial traits that may aid recognition. The coexisting SHOX deletion (i.e., Leri-Weill syndrome) was considered unrelated to the neurological phenotype. Digital assessments provided objective measures of motor function over time. Our findings broaden the clinical and molecular characterization of SCAR23 and illustrate the potential of digital biomarkers for longitudinal monitoring. Despite the lack of functional validation and the inherent limitations of a single-case report, these observations provide valuable insights for future research in this ultra-rare disorder.

The diagnosis of hereditary ataxias caused by repeat expansions continue to present unique methodological challenges, especially for developing countries where genomic medicine services are not well established. The purpose of this work is to present a cohort of patients who presented with adult-onset ataxia of suspected genetic etiology, but had remained undiagnosed until now. They were analyzed for a set of repeat expansions including the genes causing the more recently identified types, SCA27BandRFC1-related CANVAS. Patients with a possible diagnosis of hereditary cerebellar ataxia with adult onset underwent genetic testing to detect a set of repeat expansions known to cause autosomal dominant ataxia. In selected cases, a complete vestibular function evaluation and brain magnetic resonance imaging was acquired. In 17 of the 56 studied cases (including 11 of 43 index cases) we established a genetic diagnosis, which demonstrates that this is a promising approach to adult-onset ataxias in a population that remains underrepresented in worldwide genomic studies. We identified 9 individuals with SCA27B and 7 with CANVAS, highlighting the epidemiological relevance of these newly recognized etiologies, an information useful for planning the allocation of resources towards improving the access to genomic medicine in in our region.

Background. Damage to the central (CNS), peripheral and autonomic nervous systems are the leading complications of electrical trauma (ET). Evidence collection. A retrospective informative search was performed using a spatial-vector descriptive model, which was supplemented by a manual search of relevant articles. Forty-two modern literature sources were selected over the past 10 years, of which 76.2 % — over the past 5 years. Evidence synthesis. The leading mechanisms of neurological ET are electroporation, vascular injury, demyelination and the release of thermal energy, which causes the destruction of macromolecules. In this regard, theories of causality, alternative and neurohumoral hypotheses have been proposed. There are several types of nerve damage in ET, including circulatory disorders, ischemic encephalopathy, hypoxic encephalopathy, various dystrophic changes in brain cellular structures and intracranial hemorrhages. The greatest neuronal damage is observed in cases with minimal skin damage (the most significant amount of current falls on internal structures). Direct or indirect effects of ET on the brain are possible, when craniocerebral trauma is caused by the passage of current or direct damage to the brain due to blunt mechanical trauma (or a combination of both). Electric shock can lead to ischemic stroke due to circulatory disturbances or to hemorrhagic stroke due to direct structural damage with necrosis and axonal degeneration. Acute CNS complications include changes in mental status, coma, amnesia, quadriplegia and localized paresis. Motor impairment occurs more often than sensory deficits. Delayed neurological syndromes, such as cerebellar ataxia or autonomic dysfunction, may occur weeks or months after the initial injury due to the development of subsequent ischemia, a decrease in the number of Purkinje cells or the presence of hemorrhages. In situations where the path of the electric current crosses the spinal cord, which usually occurs at the level of C4-C8 (i.e. from one limb to the other), the patient is at risk of spinal cord injury. This type of trauma leads to direct damage to the spinal cord, which causes significant neurological disorders. Conclusions. The leading mechanisms of neurological electrical trauma are electroporation, vascular injury, demyelination and the release of thermal energy. Brain damage in electrical trauma is possible even when the head is not in a direct electrical circuit. The mechanisms of the development of delayed neurological complications are currently not fully understood.

Tau tubulin kinase 2 (TTBK2) is a ubiquitous serine-threonine protein kinase implicated in diverse cellular processes, including microtubule regulation, ciliogenesis, synaptic signaling, and the phosphorylation of key proteins like TDP-43. Despite its relevance, many aspects of TTBK2 function in both physiological and pathological conditions remain poorly understood. Truncating variants in TTBK2 gene cause spinocerebellar ataxia type 11 (SCA11), a rare form of autosomal dominant cerebellar ataxia. However, the functional consequences and pathogenic potential of missense variants have yet to be elucidated. In this study, we developed a CRISPR/Cas9 knock-in cell model harboring a missense variant in TTBK2 kinase domain (NM_173500.4:c.625C > T; p.Leu209Phe) to evaluate its impact on TTBK2 expression, associated protein levels, and phosphoproteomic profiles. TTBK2 missense variant (TTBK2-L209F) was associated with reduced TTBK2 protein levels, altered levels of cytoskeleton-related proteins, and impaired kinase activity, namely toward TDP-43. Phosphoproteomic analyses identified dysregulation in pathways linked to gene regulation, protein degradation, cytoskeletal organization, and TGF-β signaling. These findings provide valuable insights into the biological roles of TTBK2 in cellular signaling. Moreover, this study underscores the importance of functional studies to better understand the consequences of TTBK2 missense variants, particularly those affecting the kinase domain, and their potential contribution to disease.

UCHL1 encodes the neuronal protein UCH-L1, which plays a critical role in protein turnover Day (Prog Neurobiol 90(3):327-362, 2010). Variants in UCHL1 have been implicated in neurodegenerative disorders and hereditary spastic paraplegia (HSP) Mi (Ageing Res Rev 6:101856, 2023); Choi et al. (J Biol Chem 279(13):13256-64, 2004); Li et al. (Ann Clin Transl Neurol 7(8):1420-8, 2020). Monoallelic loss-of-function variants have recently been linked to adult-onset hereditary spastic paraparesis with ataxia and optic atrophy (SPG79A), as well as to adult-onset ataxia with optic atrophy in the absence of pyramidal signs, highlighting the phenotypic variability associated with UCHL1 variants Marelli et al. (J Neurol 271(9):6038-44, 2024). We report two Italian brothers presenting with progressive cerebellar ataxia, who underwent comprehensive neurological examination, ophtalmological examination, brain MRI, neurophysiological testing, and genetic analysis using targeted next-generation sequencing of ataxia- and spasticity-related genes. A novel monoallelic nonsense variant in UCHL1 (c.418C > T; p.(Gln140*)) was identified in both siblings. Clinically, patients showed predominantly ataxic symptoms, optic neuropathy and no pyramidal signs, CONCLUSION: Our study supports UCHL1 analysis in cases of autosomal dominant adult-onset cerebellar ataxia with optic atrophy, further expanding the clinical and genetic continuum between ataxic and spastic presentations.

ABSTRACT Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a late‐onset multisystem disorder caused by biallelic repeat RFC1 gene expansion. While the core triad comprises cerebellar ataxia, bilateral vestibulopathy, and sensory neuropathy, the phenotypic diversity includes chronic cough, Parkinsonism, and autonomic dysfunction. Cardiac sympathetic denervation on 123 I‐metaiodobenzylguanidine (MIBG) scintigraphy in CANVAS has rarely been reported. We report a 76‐year‐old man with genetically confirmed CANVAS presenting with chronic cough, progressive cerebellar ataxia, induced rigidity, and sensory neuropathy. Brain magnetic resonance imaging revealed cerebellar atrophy; nerve conduction studies showed no sensory nerve action potentials; and cardiac MIBG scintigraphy demonstrated severely reduced uptake. Genetic testing confirmed the presence of compound heterozygous AAGGG/ACAGG expansions in RFC1 . One year later, he developed frequent lightheadedness and orthostatic hypotension. MIBG scintigraphy may provide complementary information for the diagnostic evaluation of CANVAS and may indicate a potential risk of subsequent autonomic involvement.

IntroductionSpinocerebellar ataxias (SCA) form a group of dominantly inherited neurodegenerative diseases represented by progressive cerebellar ataxia and various other neurological deficits. SCA3 is the most prevalent type globally and represents 28% of the autosomal dominant cerebellar ataxias in The Netherlands. The associated oculomotor disorders, with distance esotropia as its hallmark, cause diplopia and often present early. To gain further insight into this, we examined eye movements made during a continuous visual stimulus tracking task (SONDA; Standardized Oculomotor and Neuro-Ophthalmic Disorder Assessment).MethodsThirteen genetically confirmed SCA3 cases underwent SONDA, both monocularly and binocularly. As a reference, we used previously collected data from 36 monocularly and 13 binocularly measured healthy subjects.ResultsSCA3 cases were well capable of tracking the moving stimulus, but they performed the task differently. More specifically, their eyes were not synchronized in their movements, and they made multiple small saccades in response to a large stimulus jump instead of a larger saccade followed by a small corrective saccade. The saccadic amplitude distribution shape was related to the severity of the oculomotor disorder, suggesting that the saccadic amplitude distribution could be used as a biomarker of disease severity.ConclusionOverall, this study highlights that eye-tracking during a standardized task can give valuable insights into how eye movements are affected in SCA3 and provides suggestions for potential biomarkers for severity and the associated treatment options. Longitudinal research is needed to elaborate on these findings and validate the proposed biomarkers.

The RAR-related orphan receptor alpha (RORA) gene encodes a nuclear receptor involved in transcriptional regulation, circadian rhythm, and neurodevelopment. Dominant RORA variants are associated with intellectual developmental disorder with or without epilepsy or cerebellar ataxia, yet the phenotypic spectrum remains poorly defined. We performed comprehensive genetic and clinical analyses in four individuals with RORA variants from three unrelated families, using whole exome sequencing and chromosomal microarray analysis. Identified variants were confirmed by Sanger sequencing. Genetic analyses revealed three distinct RORA variants: a 15q21.2-q22.2 deletion encompassing RORA, a de novo nonsense variant c.499C>T (p.Gln167*), and a novel heterozygous frameshift variant c.683_686del (p.Glu228Valfs*78) segregating within a family. Clinical findings ranged from severe neurodevelopmental delay and epilepsy to mild intellectual disability and behavioral abnormalities, demonstrating marked intrafamilial variability. Notably, the same frameshift variant presented with differing phenotypes in the family, indicating variable expressivity-the first such observation reported in RORA-related disorders. Our findings broaden the genotypic and phenotypic spectrum of RORA-related neurodevelopmental disorders. The observed intrafamilial variability highlights the complexity of RORA-associated pathogenesis and underscores the importance of considering variable expressivity in future genotype-phenotype studies.

'Subthreshold' Expansions in Individuals with Otherwise Typical Clinico-Radiological Features of GAA-FGF14-Related Cerebellar Ataxia (SCA27B).