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Multiple system atrophy is a rare, fatal neurodegenerative disorder with symptoms of autonomic failure plus parkinsonism, cerebellar ataxia, or both. We report results of the first prospective natural history study of multiple system atrophy in the USA, and the effects of phenotype and autonomic failure on prognosis. We recruited participants with probable multiple system atrophy—of either the parkinsonism subtype (MSA-P) or the cerebellar ataxia subtype (MSA-C)—at 12 neurology centres in the USA specialising in movement or autonomic disorders. We followed up patients every 6 months for 5 years and assessed them with the Unified Multiple System Atrophy Rating Scale part I (UMSARS I; a functional score of symptoms and ability to undertake activities of daily living), UMSARS II (neurological motor evaluation), and the Composite Autonomic Symptoms Scale (COMPASS)-select (a measure of autonomic symptoms and autonomic functional status). We assessed potential predictors of outcome. We used Cox proportional hazards models to calculate univariate hazard ratios for shorter survival using age at disease onset as a continuous variable and sex, clinical phenotype, and early development of neurological and autonomic manifestations as categorical variables. We recruited 175 participants. Mean age at study entry was 63·4 years (SD 8·6). Median survival from symptom onset was 9·8 years (95% CI 8·8–10·7) and median survival from enrolment was 1·8 years (0·9–2·7). Participants with severe symptomatic autonomic failure (symptomatic orthostatic hypotension, urinary incontinence, or both) at diagnosis (n=62) had a worse prognosis than those without severe disease (n=113; median survival 8·0 years, 95% CI 6·5–9·5 vs 10·3 years, 9·3–11·4; p=0·021). At baseline, patients with MSA-P (n=126) and MSA-C (n=49) had much the same symptoms and functional status: mean UMSARS I 25·2 (SD 8·08) versus 24·6 (8·34; p=0·835); mean UMSARS II 26·4 (8·8) versus 25·4 (10·5; p=0·764); COMPASS-select 43·5 (18·7) versus 42·8 (19·6; p=0·835). Progression over 5 years, assessed by change in UMSARS I, UMSARS II, and COMPASS-select, was modest. Probable multiple system atrophy is a late-stage disease with short survival. The natural histories of MSA-P and MSA-C are similar and severe symptomatic autonomic failure at diagnosis is associated with worse prognosis. US National Institutes of Health, Mayo Clinic, and Kathy Shih Memorial Foundation.

Background Autosomal-dominant spinocerebellar ataxia (ADCA) due to intronic GAA repeat expansion in FGF14 (SCA27B) is a recent, relatively common form of late-onset ataxia. Objective Here, we aimed to: (1) investigate the relative frequency of SCA27B in different clinically defined disease subgroups with late-onset ataxia collected among 16 tertiary Italian centers; (2) characterize phenotype and diagnostic findings of patients with SCA27B; (3) compare the Italian cohort with other cohorts reported in recent studies. Methods We screened 396 clinically diagnosed late-onset cerebellar ataxias of unknown cause, subdivided in sporadic cerebellar ataxia, ADCA, and multisystem atrophy cerebellar type. We identified 72 new genetically defined subjects with SCA27B. Then, we analyzed the clinical, neurophysiological, and imaging features of 64 symptomatic cases. Results In our cohort, the prevalence of SCA27B was 13.4% (53/396) with as high as 38.5% (22/57) in ADCA. The median age of onset of SCA27B patients was 62 years. All symptomatic individuals showed evidence of impaired balance and gait; cerebellar ocular motor signs were also frequent. Episodic manifestations at onset occurred in 31% of patients. Extrapyramidal features (17%) and cognitive impairment (25%) were also reported. Brain magnetic resonance imaging showed cerebellar atrophy in most cases (78%). Pseudo-longitudinal assessments indicated slow progression of ataxia and minimal functional impairment. Conclusion Patients with SCA27B in Italy present as an adult-onset, slowly progressive cerebellar ataxia with predominant axial involvement and frequent cerebellar ocular motor signs. The high consistency of clinical features in SCA27B cohorts in multiple populations paves the way toward large-scale, multicenter studies.

Background To describe the epidemiology, clinical features, degree of disability and genetic characteristics of a cohort of patients with a vestibulo-cerebellar ataxia of very late onset (LOVCA). Methods We analysed the clinical, radiological, and genetic characteristics of a cohort of 50 patients with LOVCA. Where possible, patients were followed over the full course of the disease, including clinical, and molecular genetic analysis of genes known to cause episodic ataxia. Results Ten patients are familial and 40 sporadic. Forty-three patients had an episodic onset, with episodes of gait ataxia characterized especially by sudden instability with downbeat nystagmus, visual symptoms, dizziness, and falls. Progression began on average 1.5 years after the onset of episodes. Of the patients followed over the full course of the disease, 87% became disabled. Women seem more prone to disability than men. An FGF14 intronic GAA repeat expansion was found in 61% of patients with available DNA. The prevalence of LOVCA is 5.03/10 5 inhabitants. Treatment with 4-aminopyridine reduced the number and severity of episodes. Conclusion LOVCA appears after the age of 50 and commonly leads to an inability to stand up and walk. The disease caused mild atrophy only in half of the patients and few changes were observed by MRI. The most common genetic cause was a heterozygous GAA expansion in FGF14 (SCA27B). One third of our patients have no aetiological diagnosis. Disability seems to be a result of the complete loss of the vestibulocerebellar function, which is presumably a result of degeneration of this system.

Cerebellar ataxias with autosomal dominant transmission are rare, but identification of the associated genes has provided insight into the mechanisms that could underlie other forms of genetic or non-genetic ataxias. In many instances, the phenotype is not restricted to cerebellar dysfunction but includes complex multisystemic neurological deficits. The designation of the loci, SCA for spinocerebellar ataxia, indicates the involvement of at least two systems: the spinal cord and the cerebellum. 11 of 18 known genes are caused by repeat expansions in the corresponding proteins, sharing the same mutational mechanism. All other SCAs are caused by either conventional mutations or large rearrangements in genes with different functions, including glutamate signalling (SCA5/ SPTBN2) and calcium signalling (SCA15/16/ ITPR1), channel function (SCA13/ KCNC3, SCA14/ PRKCG, SCA27/ FGF14), tau regulation (SCA11/ TTBK2), and mitochondrial activity (SCA28/ AFG3L2) or RNA alteration (SCA31/ BEAN-TK2). The diversity of underlying mechanisms that give rise to the dominant cerebellar ataxias need to be taken into account to identify therapeutic targets.

Background: Hereditary cerebellar ataxias (HCA) and hereditary spastic paraplegias (HSP) are two groups of neurodegenerative disorders that usually present with progressive gait impairment, often leading to permanent disability. Advances in genetic research in the last decades have improved their diagnosis and brought new possibilities for prevention and future treatments. Still, there is great uncertainty regarding their global epidemiology. Summary: Our objective was to assess the global distribution and prevalence of HCA and HSP by a systematic review and meta-analysis of prevalence studies. The MEDLINE, ISI Web of Science and Scopus databases were searched (1983-2013) for studies performed in well-defined populations and geographical regions. Two independent reviewers assessed the studies and extracted data and predefined methodological parameters. Overall, 22 studies were included, reporting on 14,539 patients from 16 countries. Multisource population-based studies yielded higher prevalence values than studies based primarily on hospitals or genetic centres. The prevalence range of dominant HCA was 0.0-5.6/10 5 , with an average of 2.7/10 5 (1.5-4.0/10 5 ). Spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease was the most common dominant ataxia, followed by SCA2 and SCA6. The autosomal recessive (AR) HCA (AR-HCA) prevalence range was 0.0-7.2/10 5 , the average being 3.3/10 5 (1.8-4.9/10 5 ). Friedreich ataxia was the most frequent AR-HCA, followed by ataxia with oculomotor apraxia or ataxia-telangiectasia. The prevalence of autosomal dominant (AD) HSP (AD-HSP) ranged from 0.5 to 5.5/10 5 and that of AR-HSP from 0.0 to 5.3/10 5 , with pooled averages of 1.8/10 5 (95% CI: 1.0-2.7/10 5 ) and 1.8/10 5 (95% CI: 1.0-2.6/10 5 ), respectively. The most common AD-HSP form in every population was spastic paraplegia, autosomal dominant, type 4 (SPG4), followed by SPG3A, while SPG11 was the most frequent AR-HSP, followed by SPG15. In population-based studies, the number of families without genetic diagnosis after systematic testing ranged from 33 to 92% in the AD-HCA group, and was 40-46% in the AR-HCA, 45-67% in the AD-HSP and 71-82% in the AR-HSP groups. Key Messages: Highly variable prevalence values for HCA and HSP are reported across the world. This variation reflects the different genetic make-up of the populations, but also methodological heterogeneity. Large areas of the world remain without prevalence studies. From the available data, we estimated that around 1:10,000 people are affected by HCA or HSP. In spite of advances in genetic research, most families in population-based series remain without identified genetic mutation after extensive testing.

Background This study aimed to investigate the prevalence, characteristics, and determinants of peripheral neuropathy in a large cohort of patients affected by spinocerebellar ataxia type 27B (SCA27B), a late‐onset cerebellar ataxia caused by heterozygous GAA repeat expansions in the first intron of the FGF14 gene. Methods A retrospective, multicenter study in which medical records of SCA27B patients diagnosed between January 2023 and July 2024 in 21 French ataxia/neurogenetic centers were reviewed. Those who had undergone electrodiagnostic study were included. Results Among 332 SCA27B patients, 170 had undergone an electrodiagnostic study and were included. Forty‐two (25%) were diagnosed with neuropathy: 16 with length‐dependent axonal sensorimotor neuropathy, 24 with length‐dependent axonal sensory neuropathy, one with sensory, and one with motor neuronopathy. Neuropathy was associated with male sex, older age at electrodiagnostic study, and risk factors for neuropathy but not with GAA expansion sizes. Patients with neuropathy had more severe disability at the last visit (median SARA score 12 vs. 8, p = 0.0024). Conclusions The prevalence of neuropathy in SCA27B patients was similar to that reported in the elderly general population. Neuropathies were predominantly non‐specific length‐dependent axonal neuropathies, primarily driven by aging and known risk factors rather than the underlying genetic abnormality.

Background Idiopathic Late-Onset Cerebellar Ataxia (ILOCA) is a challenging and heterogeneous disorder characterized by progressive cerebellar ataxia beginning after the age of 40 without a family history of cerebellar ataxia. Despite extensive investigations, many cases remain undiagnosed. The advent Next Generation Sequencing (NGS) has significantly advanced the identification of genetic causes associated with ILOCA. Objective This study aims to review the concept of ILOCA, its historical perspective, epidemiology, diagnostic criteria, and the impact of the new era of genetic diagnosis facilitated by NGS technologies. Methods A comprehensive literature review was conducted, focusing on the genetic advancements in diagnosing ILOCA. Results ILOCA accounts for a significant proportion of late-onset cerebellar ataxias. The prevalence of late-onset cerebellar ataxias ranges from 2.2 to 12.4 per 100,000 individuals, with genetic causes identified in up to 30–50% of cases using NGS. Key genetic findings include repeat expansion disorders such as Spinocerebellar Ataxia type 27 B, Cerebellar Ataxia, Neuropathy and Vestibular Areflexia Syndrome and Friedreich Ataxia. SCAs and Autosomal Recessive Cerebellar Ataxia caused by point mutations are also frequently observed in large cohorts. Advances in NGS have increased the diagnostic yield for ILOCA. Conclusion ILOCA represents a significant diagnostic challenge due to its heterogeneous nature and the overlap with other neurodegenerative and genetic conditions. The use of NGS technologies has revolutionized the diagnostic approach, uncovering genetic causes in a substantial number of previously undiagnosed cases. Routine investigation of specific genes associated with ILOCA is recommended to improve diagnostic accuracy and patient management.

Proliferation of specific nucleotide sequences within the coding and non-coding regions of numerous genes has been implicated in approximately 40 neurodegenerative disorders. Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS), a neurodegenerative disorder, is distinguished by a pathological triad of sensory neuropathy, bilateral vestibular areflexia and cerebellar impairments. It manifests in adults gradually and is autosomal recessive and multi-system ataxia. Predominantly, CANVAS is associated with biallelic AAGGG repeat expansions in intron 2 of the RFC1 gene. Although various motifs have been identified, only a subset induces pathological consequences, by forming stable secondary structures that disrupt gene functions both in vitro and in vivo. The pathogenesis of CANVAS remains a subject of intensive research, yet its precise mechanisms remain elusive. Herein, we aim to comprehensively review the epidemiology, clinical ramifications, molecular mechanisms, genetics, and potential therapeutics in light of the current findings, extending an overview of the most significant research on CANVAS.

Background: Cerebellar ataxia is one of the most common movement disorders in mitochondrial disease, with POLG mutations being a frequent cause. This scoping review aimed to summarize current knowledge regarding cerebellar ataxia due to POLG mutations, focusing on epidemiological, clinical, radiological features and genotype-phenotype correlations. Methods: We searched PubMed and Web of Science databases for all articles published in English till September 2025 describing cases of POLG-related cerebellar ataxia. Results: In homozygous or compound heterozygous POLG mutation carriers, cerebellar ataxia seems to be progressive, and can initiate from either the bulbar muscles, trunk, or limbs. Age at onset varies greatly, ranging from birth to the early 70s. The most common variants in POLG-related cerebellar ataxia are W748S and A476T, localized in the linker region of POLG gene. Cerebellar ataxia due to POLG mutations can present in combination with progressive external ophthalmoplegia, sensory neuropathy, epilepsy (including status epilepticus), headache, other hyperkinetic movement disorders such as myoclonus and tremor, cognitive or affective disorders. Brain imaging commonly reveals atrophy of the vermis or cerebellar hemispheres, cortical atrophy, and/or bilateral T2/FLAIR lesions in both white matter and deep brain nuclei, including inferior olivary nuclei. Conclusion: POLG-related ataxia should be included in the differential diagnosis of slowly progressive cerebellar ataxias. POLG-related disease comprises a continuum of clinical features; the combination with progressive external ophthalmoplegia, sensory neuropathy, epilepsy, hyperkinetic movement disorders, as well as characteristic imaging findings, can aid the diagnosis of this underdiagnosed entity. These findings contribute to a better characterization of the phenotype-genotype relationship in the extended pool of POLG-related mitochondrial diseases. Highlights This review summarizes current knowledge regarding cerebellar ataxia due to POLG mutations. A slowly progressive cerebellar ataxia in combination with sensory neuropathy, progressive external ophthalmoplegia, epilepsy, myoclonus, and characteristic imaging findings, including cerebellar atrophy, bilateral lesions in deep brain nuclei (thalami, olivary nuclei) should raise suspicion for POLG-related disease.

Ataxias are one of the most frequent complaints in Neurogenetics units worldwide. Currently, more than 50 subtypes of spinocerebellar ataxias and more than 60 recessive ataxias are recognized. We conducted an 11-year prospective, observational, analytical study in order to estimate the frequency of pediatric and adult genetic ataxias in Argentina, to describe the phenotypes of this cohort and evaluate the diagnostic yield of the algorithm used in our unit. We included 334 ataxic patients. Our diagnostic approach was successful in one-third of the cohort. A final molecular diagnosis was reached in 113 subjects. This rate is significantly higher in the subgroup of patients with a positive family history, where the diagnostic yield increased to 55%. The most prevalent dominant and recessive ataxias in Argentina were SCA-2 (36% of dominant ataxias) and FA (62% of recessive ataxias), respectively. Next generation sequencing-based assays were diagnostic in the 65% of the patients requiring these tests. These results provide relevant epidemiological information, bringing a comprehensive knowledge of the most prevalent subtypes of genetic ataxias and their phenotypes in our territory and laying the groundwork for rationally implementing genetic diagnostic programs for these disorders in our country.