The inherited cerebellar ataxias: an update

Coarelli, Giulia; Wirth, Thomas; Tranchant, Christine; Kœnig, M.; Dürr, Alexandra; Anheim, Mathieu

doi:10.1007/s00415-022-11383-6

Cited by 39 publications

(41 citation statements)

References 65 publications

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“…With disease-modifying drugs on the horizon for degenerative ataxias, [1][2][3][4] sensitive performance measures are highly warranted. Gait disturbance often presents as a first sign of cerebellar ataxia [5][6][7] and is one of the most patient-reported disabling features throughout the disease course; [8][9][10] therefore, suggesting a high potential for gait performance measures as both progression and response markers in upcoming treatment trials.…”

Section: Introductionmentioning

confidence: 99%

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

Seemann,

Daghsen,

Cazier

et al. 2024

Movement Disorders

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

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Section: Introductionmentioning

confidence: 99%

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

Seemann,

Daghsen,

Cazier

et al. 2024

Movement Disorders

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“…Although dysfunction, disconnection and eventual loss of Purkinje cells are central to many degenerative forms of cerebellar ataxia, extracerebellar damage can be substantial in patients and knock in mouse models (Hekman and Gomez, 2015; Huang and Verbeek, 2019; Klockgether et al, 2019; Sen et al, 2019; Coarelli et al, 2023). Thus, it is generally not straightforward to link Purkinje cell pathology to the development of ataxic gait in patients.…”

Section: Discussionmentioning

confidence: 99%

“…Gait ataxia, which is characterized by balance problems and walking abnormalities, is one of the more common consequences of cerebellar dysfunction, and is a key hallmark of a large number of acquired and inherited diseases (Earhart and Bastian, 2001; Stolze et al, 2002; Schmitz-Hübsch et al, 2006; Ilg et al, 2007; Morton and Bastian, 2007; Klockgether, 2010; Vinueza Veloz et al, 2015; Synofzik and Schule, 2017; Buckley et al, 2019; Buijsen et al, 2019; Klockgether et al, 2019; Lieto et al, 2019; Machado et al, 2020; Shah et al, 2021; Beaudin et al, 2022; Joyce et al, 2022; Castiglia et al, 2023; Coarelli et al, 2023). Clinical characteristics, severity and disease course vary between patients, and depend among others on the nature of the pathological mutation and the possible involvement of extracerebellar damage (van de Warrenburg et al, 2002; Klockgether et al, 2019; Diallo et al, 2020; Manto et al, 2020; Shah et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Different Purkinje cell pathologies cause specific patterns of progressive ataxia in mice

Jaarsma,

Birkisdóttir,

van Vossen

et al. 2023

Preprint

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Background Gait ataxia is one of the most common and impactful consequences of cerebellar dysfunction. Purkinje cells, the sole output neurons of the cerebellar cortex, are often involved in the underlying pathology, but their specific functions during locomotor control in health and disease remain obfuscated. Objectives We aimed to describe the effect of gradual adult-onset Purkinje cell degeneration on gaiting patterns in mice and whether two different mechanisms that both lead to Purkinje cell degeneration caused different patterns in the development of gait ataxia. Methods Using the ErasmusLadder together with a newly developed limb detection algorithm and machine learning-based classification, we subjected mice to a physically challenging locomotor task with detailed analysis of single limb parameters, intralimb coordination and whole-body movement. We tested two Purkinje cell-specific mouse models, one involving stochastic cell death due to impaired DNA repair mechanisms (Pcp2-Ercc1-/-), the other carrying the mutation that causes spinocerebellar ataxia type 1 (Pcp2-ATXN1[82Q]). Results Both mouse models showed increasingly stronger gaiting deficits, but the sequence with which gaiting parameters deteriorated depended on the specific mutation. Conclusions Our longitudinal approach revealed that gradual loss of Purkinje cell function can lead to a complex pattern of loss of function over time, and this pattern depends on the specifics of the pathological mechanisms involved. We hypothesize that this variability will also be present in disease progression in patients, and our findings will facilitate the study of therapeutic interventions in mice, as very subtle changes in locomotor abilities can be quantified by our methods.

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“…We will include studies involving patients with DCA and exclude studies involving individuals with ataxia other than DCA. DCA encompasses a large number of diagnoses,1 which typically are ADSCA,3 SCA,4–6 FA,7 MSA-C,8 SAOA9 and ARSACS 10. SCA is most typically of the SCA1, 2, 3, 6 and 31 subtypes, among others 54.…”

Section: Methods and Analysismentioning

confidence: 99%

Effects of non-invasive brain stimulation for degenerative cerebellar ataxia: a protocol for a systematic review and meta-analysis

et al. 2023

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IntroductionTo date, the medical and rehabilitation needs of people with degenerative cerebellar ataxia (DCA) are not fully met because no curative treatment has yet been established. Movement disorders such as cerebellar ataxia and balance and gait disturbance are common symptoms of DCA. Recently, non-invasive brain stimulation (NIBS) techniques, including repetitive transcranial magnetic stimulation and transcranial electrical stimulation, have been reported as possible intervention methods to improve cerebellar ataxia. However, evidence of the effects of NIBS on cerebellar ataxia, gait ability, and activity of daily living is insufficient. This study will aim to systematically evaluate the clinical effects of NIBS on patients with DCA.Methods and analysisWe will conduct a preregistered systematic review and meta-analysis based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. We will include randomised controlled trials to assess the effects of NIBS on patients with DCA. The primary clinical outcome will be cerebellar ataxia, as measured by the Scale for Assessment and Rating of Ataxia and the International Cooperative Ataxia Rating Scale. The secondary outcomes will include gait speed, functional ambulatory capacity and functional independence measure, as well as any other reported outcomes that the reviewer considers important. The following databases will be searched: PubMed, Cochrane Central Register of Controlled Trials, CINAHL and PEDro. We will assess the strength of the evidence included in the studies and estimate the effects of NIBS.Ethics and disseminationBecause of the nature of systematic reviews, no ethical issues are anticipated. This systematic review will provide evidence on the effects of NIBS in patients with DCA. The findings of this review are expected to contribute to clinical decision-making towards selecting NIBS techniques for treatment and generating new clinical questions to be addressed.PROSPERO registration numberCRD42023379192.

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The inherited cerebellar ataxias: an update

Cited by 39 publications

References 65 publications

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

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

Different Purkinje cell pathologies cause specific patterns of progressive ataxia in mice

Effects of non-invasive brain stimulation for degenerative cerebellar ataxia: a protocol for a systematic review and meta-analysis

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