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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 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.

Objective The diagnosis of childhood‐onset cerebellar ataxia (CA) is often challenging due to variations in symptoms and etiologies. Despite the known regional differences in the prevalence of etiologies underlying CA, the frequency and characteristics of CA in Japan remain unclear. We conducted a questionnaire‐based survey to identify the clinical characteristics of childhood‐onset CA in the Japanese population. Materials and Methods Questionnaires were sent to 1,103 board‐certified pediatric neurologists in Japan from 2016 to 2017. The primary survey requested the number of patients with CA under care, and the follow‐up secondary questionnaire requested additional clinical characteristics of the patients. Results The primary survey obtained 578 responses (response rate, 52.4%) on 385 patients with CA, including 171 diagnosed and 214 undiagnosed cases (diagnostic rate, 44.4%). The most frequent etiology was dentatorubropallidoluysian atrophy (DRPLA), followed by mitochondrial disorders and encephalitis. The secondary survey obtained the clinical characteristics of 252 cases (119 diagnosed and 133 undiagnosed cases). Multiple logistic regression analysis revealed that a younger age at onset, hearing issues, and short stature were associated with a higher risk of remaining undiagnosed with CA in Japan. Conclusions The diagnostic rate of childhood‐onset CA in the current study was comparable to those reported in other countries. The high prevalence of autosomal dominant ataxia, especially DRPLA, was a signature of CA in Japan. These data offer insights into the characteristics of childhood‐onset CA in the Japanese population. We conducted a questionnaire‐based survey to identify the clinical characteristics of childhood‐onset cerebellar ataxia (CA) in Japan Questionnaires were sent to 1,103 board‐certified pediatric neurologists. The most frequent etiology of childhood‐onset CA was dentatorubropallidoluysian atrophy (DRPLA), followed by mitochondrial disorders and encephalitis. Fifty‐six percent of the collected cases remained undiagnosed. Multiple logistic regression analysis revealed that a younger age at onset, hearing issues, and short stature were associated with a higher risk of remaining undiagnosed with CA in Japan.

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: 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.

Friedreich's ataxia is a rare autosomal recessive neurodegenerative disorder. Here we report cross-sectional baseline data to establish the biological and clinical characteristics for a prospective, international, European Friedreich's ataxia database registry. Within the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS) framework, we assessed a cohort of patients with genetically confirmed Friedreich's ataxia. The primary outcome measure was the Scale for the Assessment and Rating of Ataxia (SARA) and secondary outcome measures were the Inventory of Non-Ataxia Signs (INAS), the performance-based coordination test Spinocerebellar Ataxia Functional Index (SCAFI), the neurocognitive phonemic verbal fluency test, and two quality-of-life measures: the activities of daily living (ADL) part of the Friedreich's Ataxia Rating Scale and EQ-5D. The Friedreich's ataxia cohort was subdivided into three groups: early disease onset (≤14 years), intermediate onset (15–24 years), and late onset (≥25 years), which were compared for clinical characteristics and outcome measures. We used linear regression analysis to estimate the annual decline of clinical outcome measures based on disease duration. This study is registered with ClinicalTrials.gov, number NCT02069509. We enrolled 592 patients with genetically confirmed Friedreich's ataxia between Sept 15, 2010, and April 30, 2013, at 11 sites in seven European countries. Age of disease onset was inversely correlated with the number of GAA repeats in the frataxin (FXN) gene: every 100 GAA repeats on the smaller repeat allele was associated with a 2·3 year (SE 0·2) earlier onset. Regression analyses showed significant estimated annual worsening of SARA (regression coefficient 0·86 points [SE 0·05], INAS (0·14 points [0·01]), SCAFI Z scores (−0·09 [0·01]), verbal fluency (−0·34 words [0·07]), and ADL (0·64 points [0·04]) during the first 25 years of disease; the regression slope for health-related quality-of-life state from EQ-5D was not significant (−0·33 points [0·18]). For SARA, the predicted annual rate of worsening was significantly higher in early-onset patients (n=354; 1·04 points [0·13]) and intermediate-onset patients (n=137; 1·17 points [0·22]) than in late-onset patients (n=100; 0·56 points [0·10]). The results of this cross-sectional baseline analysis of the EFACTS cohort suggest that earlier disease onset is associated with larger numbers of GAA repeats and more rapid disease progression. The differential estimated progression of ataxia symptoms related to age of onset have implications for the design of clinical trials in Friedreich's ataxia, for which SARA might be the most suitable measure to monitor disease progression. European Commission.

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.

Few data sources are available to assess the global and regional risk of sequelae from bacterial meningitis. We aimed to estimate the risks of major and minor sequelae caused by bacterial meningitis, estimate the distribution of the different types of sequelae, and compare risk by region and income. We systematically reviewed published papers from 1980 to 2008. Standard global burden of disease categories (cognitive deficit, bilateral hearing loss, motor deficit, seizures, visual impairment, hydrocephalus) were labelled as major sequelae. Less severe, minor sequelae (behavioural problems, learning difficulties, unilateral hearing loss, hypotonia, diplopia), and multiple impairments were also included. 132 papers were selected for inclusion. The median (IQR) risk of at least one major or minor sequela after hospital discharge was 19·9% (12·3–35·3%). The risk of at least one major sequela was 12·8% (7·2–21·1%) and of at least one minor sequela was 8·6% (4·4–15·3%). The median (IQR) risk of at least one major sequela was 24·7% (16·2–35·3%) in pneumococcal meningitis; 9·5% (7·1–15·3%) in Haemophilus influenzae type b (Hib), and 7·2% (4·3–11·2%) in meningococcal meningitis. The most common major sequela was hearing loss (33·9%), and 19·7% had multiple impairments. In the random-effects meta-analysis, all-cause risk of a major sequela was twice as high in the African (pooled risk estimate 25·1% [95% CI 18·9–32·0%]) and southeast Asian regions (21·6% [95% CI 13·1–31·5%]) as in the European region (9·4% [95% CI 7·0–12·3%]; overall I 2=89·5%, p<0·0001). Risks of long-term disabling sequelae were highest in low-income countries, where the burden of bacterial meningitis is greatest. Most reported sequelae could have been averted by vaccination with Hib, pneumococcal, and meningococcal vaccines.

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.

BackgroundSpinocerebellar ataxias (SCAs) are rare dominantly inherited neurodegenerative disorders that lead to severe disability and premature death.ObjectiveTo better characterize the natural history of the most common SCAs, SCA1, SCA2, SCA3 and SCA6, we performed a meta-analysis of literature to determine disease progression, provide data for sample-sizes calculations for interventional trials and study the impact of geographical locations and study follow-up on disease progression.MethodsA systematic literature search from MEDLINE and EMBASE databases for longitudinal natural history studies of SCA patients was conducted. Studies using the Scale for the Assessment and Rating Ataxia (SARA) as outcome measure were considered. Random-effect (RE) meta-analysis was applied to estimate pooled disease progression.ResultsSix studies with 1215 SCA patients enrolled between 2005 and 2016 were finally selected. Annual pooled SARA score increase was 1.83 (1.46–2.20) in patients with SCA1, 1.40 (1.19–1.61) in patients with SCA2, 1.41 (0.97–1.84) in patients with SCA3, and 0.81 (0.66–0.97) in patients with SCA6. For patients with SCA3, disease progression was faster in studies located in Asia and Europe than in the US. Two-arm interventional trials of 1-year duration to achieve 80% power and α level of 5% would require 92 patients per group with SCA1, 97 with SCA2, 115 with SCA3, and 430 with SCA6 to detect a 50% reduction in disease progression.ConclusionThis meta-analysis provides quantitative data on the progression of the most common spinocerebellar ataxias based on patient numbers that exceed those of previous studies and confirms that disease progression is faster in SCA1, intermediate in SCA2 and SCA3 and slower in SCA6, with similar rates of disease progression in SCA2 and SCA3 between different populations, suggesting a possibility of international collaborative studies. Nevertheless, individual-patient data meta-analysis is needed to better understand the risk factors that influence disease progression and improve patient stratification in interventional trials.