Autosomal Recessive Cerebellar Ataxias in Europe: Frequency, Onset, and Severity in 677 Patients

Traschütz, Andreas; Adarmes‐Gómez, Astrid; Anheim, Mathieu; Baets, Jonathan; Falkenburger, Björn H.; Gburek‐Augustat, Janina; Doss, Sarah; Kamm, Christoph; Klivényi, Péter; Grobe‐Einsler, Marcus; Klopstock, Thomas; Minnerop, Martina; Münchau, Alexander; Pane, Chiara; Renaud, Mathilde; Santorelli, Filippo M.; Schöls, Ludger; Timmann, Dagmar; Vielhaber, Stefan; Haack, Tobias B.; Warrenburg, Bart P. van de; Zanni, Ginevra; Synofzik, Matthis

doi:10.1002/mds.29397

Cited by 12 publications

(6 citation statements)

References 7 publications

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“…Albeit preliminary, given the limited number of observations and heterogeneous time courses, such data are urgently required for trial planning, as treatments are on the horizon for several of these ARCAs, either for the whole ataxia disease type 37 or for individual patients thereof susceptible to individualized genetic treatments 38 . Our longitudinal data partly confirm, partly revise earlier results on ARCA progression estimates from a smaller, European, and cross‐sectional only cohort 39 . The progression rates of 1.56 SARA points/yr in POLG ‐ataxia and 0.57 SARA points/yr in SPG7 corroborate and extend earlier findings in these ataxias 40,41 .…”

Section: Discussionsupporting

confidence: 78%

“…38 Our longitudinal data partly confirm, partly revise earlier results on ARCA progression estimates from a smaller, European, and cross-sectional only cohort. 39 The progression rates of 1.56 SARA points/yr in POLG-ataxia and 0.57 SARA points/yr in SPG7 corroborate and extend earlier findings in these ataxias. 40,41 In ARSACS, where responsiveness of the SARA in annual intervals is controversial, 14,42 our data suggest that even without ceiling effects, the SARA may not be sensitive to change over 1 year.…”

Section: Longitudinal Natural History Datasupporting

confidence: 85%

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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

Traschütz

Adarmes‐Gómez

Anheim

et al. 2023

Annals of Neurology

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

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Section: Discussionsupporting

confidence: 78%

Section: Longitudinal Natural History Datasupporting

confidence: 85%

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

Traschütz

Adarmes‐Gómez

Anheim

et al. 2023

Annals of Neurology

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“…The study cohort was part of the PROSPAX study, a prospective international longitudinal multi-center natural progression study in spastic ataxias (ClinicalTrials.gov, No: NCT04297891). Twenty-four patients with genetically confirmed ARSACS with available gait recordings and 50 healthy controls (HC) were recruited from four centers in four countries (Istanbul, Turkey; Pisa, Italy; Saguenay, Canada; Tübingen, Germany) based on the following inclusion criteria: (1) genetically confirmed and clinically manifest ARSACS; (2) ability to walk at least 10m freely without any walking aid; (3) absence of severe comorbidities (due to ARSACS or unrelated) which present a major confounder for evaluation of gait and stance such as: amputation, blindness, severe dementia, severe joint deformities or contractures, or fixed orthoses. HC had no history of any neurologic or psychiatric disease, no family history of neurodegenerative disease, and did not show any neurological signs upon clinical examination.…”

Section: Methodsmentioning

confidence: 99%

“…Treatment trials are on the horizon for many spastic ataxias(1), including Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) as one of the most frequent spastic ataxias worldwide (2, 3). ARSACS is a multisystemic neurodegenerative disease characterized by progressive cerebellar ataxia, spasticity, and peripheral neuropathy, with disease onset usually from early childhood to early adult years(4).…”

Section: Introductionmentioning

confidence: 99%

Digital gait outcomes for ARSACS: discriminative, convergent and ecological validity in a multi-center study (PROSPAX)

Beichert,

Ilg,

Kessler

et al. 2024

Preprint

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BackgroundWith treatment trials on the horizon, this study aimed to identify candidate digital-motor gait outcomes for Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS), capturable by wearable sensors with multi-center validity, and ideally also ecological validity during free walking outside laboratory settings.MethodsCross-sectional multi-center study (4 centers), with gait assessments in 36 subjects (18 ARSACS patients; 18 controls) using three body-worn sensors (Opal, APDM) in laboratory settings and free walking in public space. Sensor gait measures were analyzed for discriminative validity from controls, and for convergent (i.e. clinical and patient-relevance) validity by correlations with SPRSmobility(primary outcome) and SARA, SPRS and FARS-ADL (exploratory outcomes).ResultsOf 30 hypothesis-based digital gait measures, 14 measures discriminated ARSACS patients from controls with large effect sizes (|Cliff’s δ| > 0.8) in laboratory settings, with strongest discrimination by measures of spatiotemporal variability Lateral Step Deviation (δ=0.98), SPcmp (δ=0.94) and Swing CV (δ=0.93). Large correlations with the SPRSmobilitywere observed for Swing CV (Spearman’s ρ = 0.84), Speed (ρ=-0.63) and Harmonic Ratio V (ρ=-0.62). During supervised free walking in public space, 11/30 gait measures discriminated ARSACS from controls with large effect sizes. Large correlations with SPRSmobilitywere here observed for Swing CV (ρ=0.78) and Speed (ρ=-0.69), without reductions in effect sizes compared to lab settings.ConclusionWe identified a promising set of digital-motor candidate gait outcomes for ARSACS, applicable in multi-center settings, correlating with patient-relevant health aspects, and with high validity also outside lab settings, thus simulating real-life walking with higher ecological validity.

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“…Extended author information available on the last page of the article behind the development of brain damage in genetically determined SPAX [2,4].…”

Section: Introductionmentioning

confidence: 99%

An MRI evaluation of white matter involvement in paradigmatic forms of spastic ataxia: results from the multi-center PROSPAX study

Scaravilli,

Gabusi,

Mari

et al. 2024

J Neurol

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Background Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Spastic Paraplegia Type 7 (SPG7) are paradigmatic spastic ataxias (SPAX) with suggested white matter (WM) involvement. Aim of this work was to thoroughly disentangle the degree of WM involvement in these conditions, evaluating both macrostructure and microstructure via the analysis of diffusion MRI (dMRI) data. Material and methods In this multi-center prospective study, ARSACS and SPG7 patients and Healthy Controls (HC) were enrolled, all undergoing a standardized dMRI protocol and a clinimetrics evaluation including the Scale for the Assessment and Rating of Ataxia (SARA). Differences in terms of WM volume or global microstructural WM metrics were probed, as well as the possible occurrence of a spatially defined microstructural WM involvement via voxel-wise analyses, and its correlation with patients’ clinical status. Results Data of 37 ARSACS (M/F = 21/16; 33.4 ± 12.4 years), 37 SPG7 (M/F = 24/13; 55.7 ± 10.7 years), and 29 HC (M/F = 13/16; 42.1 ± 17.2 years) were analyzed. While in SPG7, only a mild mean microstructural damage was found compared to HC, ARSACS patients present a severe WM involvement, with a reduced global volume (p < 0.001), an alteration of all microstructural metrics (all with p < 0.001), without a spatially defined pattern of damage but with a prominent involvement of commissural fibers. Finally, in ARSACS, a correlation between microstructural damage and SARA scores was found (p = 0.004). Conclusion In ARSACS, but not SPG7 patients, we observed a complex and multi-faced involvement of brain WM, with a clinically meaningful widespread loss of axonal and dendritic integrity, secondary demyelination and, overall, a reduction in cellularity and volume.

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Autosomal Recessive Cerebellar Ataxias in Europe: Frequency, Onset, and Severity in 677 Patients

Cited by 12 publications

References 7 publications

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

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

Digital gait outcomes for ARSACS: discriminative, convergent and ecological validity in a multi-center study (PROSPAX)

An MRI evaluation of white matter involvement in paradigmatic forms of spastic ataxia: results from the multi-center PROSPAX study

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