GAA-FGF14 ataxia (SCA27B): phenotypic profile, natural history progression and 4-aminopyridine treatment response

Brain, Год журнала: 2023, Номер 146(10), С. 4144 - 4157

Опубликована: Май 11, 2023

Abstract Ataxia due to an autosomal dominant intronic GAA repeat expansion in FGF14 [GAA-FGF14 ataxia, spinocerebellar ataxia 27B (SCA27B)] has recently been identified as one of the most common genetic late-onset ataxias. We here aimed characterize its phenotypic profile, natural history progression, and 4-aminopyridine (4-AP) treatment response. conducted a multi-modal cohort study 50 GAA-FGF14 patients, comprising in-depth phenotyping, cross-sectional longitudinal progression data (up 7 years), MRI findings, serum neurofilament light (sNfL) levels, neuropathology, 4-AP response data, including series n-of-1 studies. consistently presented [60.0 years (53.5–68.5), median (interquartile range)] pancerebellar syndrome, partly combined with afferent sensory deficits (55%) dysautonomia (28%). Dysautonomia increased duration while cognitive impairment remained infrequent, even advanced stages. Cross-sectional assessments indicated mild [0.29 Scale for Assessment Rating (SARA) points/year], not exceeding moderate disease severity stages (maximum SARA score: 18 points). Functional relatively slowly (unilateral mobility aids after 8 50% patients). Corresponding slow low extra-cerebellar involvement, sNfL was relative controls. Concurrent second diseases (including progressive supranuclear palsy neuropathology) represented major individual aggravators severity, constituting important caveats planning future trials. A relevance everyday living reported by 86% treated patients. three prospective experiences on/off design showed marked reduction daily symptomatic time symptom on 4-AP. Our characterizes ataxia. It paves way towards large-scale studies trials this newly discovered, possibly frequent, treatable

Язык: Английский

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Autosomal dominant cerebellar ataxias: new genes and progress towards treatments

The Lancet Neurology, Год журнала: 2023, Номер 22(8), С. 735 - 749

Опубликована: Июль 19, 2023

Язык: Английский

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Spinocerebellar ataxia 27B: A novel, frequent and potentially treatable ataxia

Clinical and Translational Medicine, Год журнала: 2024, Номер 14(1)

Опубликована: Янв. 1, 2024

Abstract Hereditary ataxias, especially when presenting sporadically in adulthood, present a particular diagnostic challenge owing to their great clinical and genetic heterogeneity. Currently, up 75% of such patients remain without diagnosis. In an era emerging disease‐modifying gene‐stratified therapies, the identification causative alleles has become increasingly important. Over past few years, implementation advanced bioinformatics tools long‐read sequencing allowed number novel repeat expansion disorders, as recently described spinocerebellar ataxia 27B (SCA27B) caused by (GAA)•(TTC) intron 1 fibroblast growth factor 14 ( FGF14 ) gene. SCA27B is rapidly gaining recognition one most common forms adult‐onset hereditary ataxia, with several studies showing that it accounts for substantial (9–61%) previously undiagnosed cases from different cohorts. First natural history multiple reports have already outlined progression core phenotype this disease, which consists late‐onset slowly progressive pan‐cerebellar syndrome frequently associated cerebellar oculomotor signs, downbeat nystagmus, episodic symptoms. Furthermore, preliminary shown promising symptomatic benefits 4‐aminopyridine, marketed drug. This review describes current knowledge molecular basis, epidemiology, features prospective treatment strategies SCA27B.

Язык: Английский

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Quantitative Gait and Balance Outcomes for Ataxia Trials: Consensus Recommendations by the Ataxia Global Initiative Working Group on Digital-Motor Biomarkers

The Cerebellum, Год журнала: 2023, Номер 23(4), С. 1566 - 1592

Опубликована: Ноя. 13, 2023

With disease-modifying drugs on the horizon for degenerative ataxias, ecologically valid, finely granulated, digital health measures are highly warranted to augment clinical and patient-reported outcome measures. Gait balance disturbances most often present as first signs of cerebellar ataxia reported disabling features in disease progression. Thus, gait constitute promising relevant performance outcomes trials.This narrative review with embedded consensus will describe evidence sensitivity evaluating severity progression, propose a protocol establishing metrics natural history studies trials, discuss issues their use outcomes.

Язык: Английский

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FARS‐ADL across Ataxias: Construct Validity, Sensitivity to Change, and Minimal Important Change

Movement Disorders, Год журнала: 2024, Номер 39(6), С. 965 - 974

Опубликована: Март 20, 2024

Abstract Background Patient‐focused outcomes present a central need for trial‐readiness across all ataxias. The Activities of Daily Living part the Friedreich Ataxia Rating Scale (FARS‐ADL) captures functional impairment and longitudinal change but is only validated in Ataxia. Objective Validation FARS‐ADL regarding disease severity patient‐meaningful impairment, its sensitivity to genetic Methods Real‐world registry data 298 ataxia patients genotypes were analyzed, including (1) cross‐correlation with FARS‐stage, Assessment (SARA), Patient‐Reported Outcome Measure (PROM)‐ataxia, European Quality Life 5 Dimensions visual analogue scale (EQ5D‐VAS); (2) within trial‐relevant 1‐year median follow‐up, anchored Patient Global Impression Change (PGI‐C); (3) general linear modeling factors age, sex, depression (nine‐item Health Questionnaire [PHQ‐9]). Results correlated overall disability (rho FARS‐stage = 0.79), clinical SARA 0.80), patient‐reported PROM‐ataxia 0.69, rho EQ5D‐VAS –0.37), indicating comprehensive construct validity. Also at item level, genotype (SCA3, RFC1), corresponding effector domains; items quality life. was sensitive interval, progressing worsening PGI‐C. Minimal important 1.1. points based on intraindividual variability stable Depression captured using (+0.3 points/PHQ‐9 count) EQ5D‐VAS, not or SARA. Conclusion reflects both ataxias, timescales perceiving change. It thus presents promising patient‐focused outcome upcoming trials. © 2024 Authors. Movement Disorders published by Wiley Periodicals LLC behalf International Parkinson Disorder Society.

Язык: Английский

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Longitudinal Changes in Patient‐ and Clinical‐Reported Outcomes in Early Spinocerebellar Ataxia Types 1, 2, 3, and 6 from the IDEA Study

Movement Disorders Clinical Practice, Год журнала: 2025, Номер unknown

Опубликована: Янв. 28, 2025

Abstract Background Clinical outcomes assessments (COAs) in spinocerebellar ataxia (SCA) need to be standardized, ataxia‐specific, sensitive change, clinically relevant, and meaningful patients. Objectives To evaluate the longitudinal 1‐ 2‐year performances of different patient reported outcomes, including Patient Reported Outcome Measure Ataxia (PROM‐Ataxia), clinician FARS SARA, those with early manifest symptoms SCA 1, 2, 3, 6. Methods We studied 53 patients stage SCA1‐3 SCA6 from The Instrumented Data Exchange for Study 24 age‐matched healthy controls. Participants were seen every 6 months 2 years. Mixed models used estimate change over 12‐ 24‐months follow‐up. Changes on FARS‐FS PGI‐C as anchors changes. Results Among persons SCA, mean age was 48.7 years SARA score 9.3. Few measures showed statistically significant changes at 12 months. At 24‐months, FARS‐ADL, PROM‐Ataxia total, physical, ADL scores strongest associations change. Conclusions or derived outcome measures, such FARS‐ADL sub domain PROM‐Ataxia, can capture patients’ symptom experience a period its impact daily activities, even disease. More work is needed identify that reliably earlier.

Язык: Английский

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Spinocerebellar Ataxia Progression Measured with the Patient‐Reported Outcome Measure of Ataxia

Movement Disorders, Год журнала: 2025, Номер unknown

Опубликована: Март 4, 2025

ABSTRACT Background The Patient‐Reported Outcome Measure of Ataxia (PROM‐Ataxia) has been validated cross‐sectionally but not longitudinally. Objective We aimed to validate PROM‐Ataxia as a measure patient experience disease over time, examine overall and domain‐specific progression, test convergent validity with other clinical outcome assessments (COAs). Methods derived data from 176 patients spinocerebellar ataxia types 1, 2, 3, 6, 7, 8, or 10 in the Clinical Research Consortium for Study Cerebellar at baseline 1 year. classified patients' severity stage (“severity”) according Friedreich's Rating Scale Functional Staging into mild , moderate severe subgroups. Analyses entire cohort by subgroup included internal consistency, sensitivity severity, predictive modeling score changes, correlations COAs: Brief Scale, Assessment Ataxia, Fatigue Severity Cognitive Affective Syndrome scale, EuroQol 5‐Dimension, responsiveness progression. Results exhibited high consistency correlated COAs. Scores demonstrated evolving experience. Progression was sigmoidal, greatest change patients. Compared COAs, captured most change. Mental features worsened fastest patients, physical activities daily living Conclusion is more sensitive than captures evolution year, reveals Studies larger cohorts different diagnoses longer periods may provide insights further enhance care research. © 2025 International Parkinson Movement Disorder Society.

Язык: Английский

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Digital Gait Biomarkers Allow to Capture 1‐Year Longitudinal Change in Spinocerebellar Ataxia Type 3

Movement Disorders, Год журнала: 2022, Номер 37(11), С. 2295 - 2301

Опубликована: Авг. 31, 2022

ABSTRACT Measures of step variability and body sway during gait have shown to correlate with clinical ataxia severity in several cross‐sectional studies. However, serve as a valid progression biomarker, these measures prove their sensitivity robustly capture longitudinal change, ideally within short time frames (eg, 1 year). We present the first multicenter analysis study spinocerebellar ataxias. performed combined (n = 28) (1‐year interval, n 17) Spinocerebellar Ataxia type 3 subjects (including seven preataxic mutation carriers). Longitudinal showed significant change between baseline 1‐year follow‐up, high effect sizes (stride length variability: P 0.01, size r prb 0.66; lateral sway: 0.007, 0.73). Sample estimation for indicates required cohort 43 detecting 50% reduction natural progression, compared 240 score Scale Assessment Rating (SARA). These thus promising motor biomarkers upcoming interventional © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf International Parkinson Disorder Society

Язык: Английский

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Responsiveness of the Scale for the Assessment and Rating of Ataxia and Natural History in 884 Recessive and Early Onset Ataxia Patients

Annals of Neurology, Год журнала: 2023, Номер 94(3), С. 470 - 485

Опубликована: Май 27, 2023

The Scale for the Assessment and Rating of Ataxia (SARA) is most widely applied clinical outcome assessment (COA) genetic ataxias, but presents metrological regulatory challenges. To facilitate trial planning, we characterize its responsiveness (including subitem-level relations to ataxia severity patient-focused outcomes) across a large number provide first natural history data several them.Subitem-level correlation distribution-based analysis 1,637 SARA assessments in 884 patients with autosomal recessive/early onset (370 2-8 longitudinal assessments) were complemented by linear mixed effects modeling estimate progression sample sizes.Although subitem varied between severities, gait/stance showed robust granular scaling broadest range (SARA < 25). Responsiveness was diminished incomplete subscale use at intermediate or upper levels, nontransitions ("static periods"), fluctuating decreases/increases. All subitems except nose-finger moderate-to-strong correlations activities daily living, indicating that metric properties-not content validity-limit responsiveness. captured mild-to-moderate many genotypes (eg, SYNE1-ataxia: 0.55 points/yr, oculomotor apraxia type 2: 1.14 POLG-ataxia: 1.56 points/yr), no change others (autosomal recessive spastic Charlevoix-Saguenay, COQ8A-ataxia). Whereas sensitivity optimal mild 10), it substantially deteriorated advanced > 25; 2.7-fold size). Use novel rank-optimized without finger-chase reduces sizes 20 25%.This study comprehensively characterizes COA properties annualized changes within ataxias. It suggests specific approaches optimizing might qualification design. ANN NEUROL 2023;94:470-485.

Язык: Английский

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Digital Gait Measures Capture 1‐Year Progression in Early‐Stage Spinocerebellar Ataxia Type 2

Movement Disorders, Год журнала: 2024, Номер 39(5), С. 788 - 797

Опубликована: Фев. 28, 2024

Abstract Background With disease‐modifying drugs in reach for cerebellar ataxias, fine‐grained digital health measures are highly warranted to complement clinical and patient‐reported outcome upcoming treatment trials monitoring. These need demonstrate sensitivity capture change, particular the early stages of disease. Objective Our aim is unravel gait sensitive longitudinal change the—particularly trial‐relevant—early stage spinocerebellar ataxia type 2 (SCA2). Methods We performed a multicenter study with combined cross‐sectional 1‐year interval analysis early‐stage SCA2 participants (n = 23, including nine pre‐ataxic expansion carriers; median, ATXN2 CAG repeat 38 ± 2; Scale Assessment Rating Ataxia [SARA] score 4.8 4.3). Gait was assessed using three wearable motion sensors during 2‐minute walk, analyses focused on spatio‐temporal variability that have shown severity (eg, lateral step deviation). Results found significant changes between baseline follow‐up large effect sizes (lateral deviation P 0.0001, size r prb 0.78), whereas SARA showed no ( 0.67). Sample estimation indicates required cohort n 43 detect 50% reduction natural progression. Test–retest reliability minimal detectable confirm accuracy detecting identified change. Conclusions by can progression within just 1 year—in contrast outcome. Lateral represents promising measure interventional trials, particularly ataxia. © 2024 The Authors. Movement Disorders published Wiley Periodicals LLC behalf International Parkinson Disorder Society.

Язык: Английский

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