Documenting manifestations and impacts of autosomal recessive spastic ataxia of Charlevoix–Saguenay to develop patient-reported outcome

Tremblay, Marjolaine; Girard-Côté, Laura; Brais, Bernard; Gagnon, Cynthia

doi:10.1186/s13023-022-02497-1

Cited by 5 publications

(2 citation statements)

References 134 publications

(413 reference statements)

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“…Because of the high prevalence of ARSACS in the area where the project took place, the project was mainly conducted with ARSACS as a "model ataxia" for PRAIS development. Prior to the data collection, a systematic review of the literature was performed to identify all the documented manifestations and impacts of ARSACS [23].…”

Section: Methodsmentioning

confidence: 99%

The Development of a New Patient-Reported Outcome Measure in Recessive Ataxias: The Person-Reported Ataxia Impact Scale

Tremblay

Brais

Asselin³

et al. 2023

Cerebellum

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Introduction. Autosomal recessive cerebellar ataxias (ARCAs) are inherited neurological disorders that can affect both thecentral and peripheral nervous systems. To assess the effects of interventions according to the perception of people affected, patient-reported outcome measures (PROMs) must be available.Objective. This paper presents the development process of the Person-Reported Ataxia Impact Scale (PRAIS), a new PROM in recessive ataxias, and the documentation of its content validity, interpretability, and construct validity (structural and discriminant).Patients and methods.The development followed the PROMIS framework and the Food and Drug Administration guidelines. A mixed-method study design was used to develop the PROM. A systematic review of the literature, semistructured interviews, and discussion groups was conducted to constitute an item pool. Experts' consultation helped formulate items, and the questionnaire was sent online to be completed by people affected. Statistical analyseswere performed to assess the structural and discriminant validity.Results. A total of 125 people affected by recessive ataxia completed the questionnaire. The factoranalysis con rmed the three components: physical functions and activities, mental functions, and social functions. The statistical analysis showed that it can discriminate between stages of mobility and level of autonomy. It showed very good levels of internal consistency (0.79 to 0.89).Conclusion. The Person-Reported Ataxia Impact Scale (PRAIS) is a 38-item questionnaire that assesses the manifestations and impacts of the disease according to the perception of people affected by recessive ataxia. It can be used in clinical and research settings.

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Section: Methodsmentioning

confidence: 99%

The Development of a New Patient-Reported Outcome Measure in Recessive Ataxias: The Person-Reported Ataxia Impact Scale

Tremblay

Brais

Asselin³

et al. 2023

Cerebellum

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“…1 Initially described as a progressive neurologic disorder originating in Québec, Canada, with a prevalence of 1 in 1932 in the Charlevoix and Saguenay-Lac-St-Jean regions, autosomal recessive spastic ataxia of Charlevoix-Saguenay belongs to a group of rare inherited disorders, autosomal recessive cerebellar ataxias, with the most common being Friedrich ataxia. 2 A mutation of the SACS gene, which encodes the protein sacsin on chromosome 13q12, results in the disorder and can be identified with genetic testing. 3 Two mutations in the SACS gene were originally linked to autosomal recessive spastic ataxia of Charlevoix-Saguenay in Québec; today, more than 200 mutations are linked to the disorder around the globe.…”

Section: Introductionmentioning

confidence: 99%

Thickened Retinal Nerve Fiber Layer Without Hypermyelination in Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

Suarez,

Martin,

Ong

2024

Journal of VitreoRetinal Diseases

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Purpose: To report the retinal findings in a patient with autosomal recessive spastic ataxia of Charlevoix-Saguenay. Methods: A case was evaluated. Results: A 16-year-old male patient with a known diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay was referred for evaluation of retinal hypermyelination given its frequent association with the condition. The patient was asymptomatic with a best-corrected visual acuity of 20/20. Optical coherence tomography of the peripapillary retinal nerve fiber layer (RNFL) showed bilateral thickening in each eye (average thicknesses: 180 µm, right eye; 177 µm, left eye). An examination showed no myelinization of the RNFL. Conclusions: Most studies to date describe RNFL thickening secondary to hypermyelination as a characteristic finding in autosomal recessive spastic ataxia of Charlevoix-Saguenay. This case provides evidence that this thickening may be a result of hypertrophy rather than hypermyelination. Further investigation is needed to define the pathophysiologic cause of RNFL thickening in autosomal recessive spastic ataxia of Charlevoix-Saguenay.

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Driving Mitochondrial Fission Improves Cognitive, but not Motor Deficits in a Mouse Model of Ataxia of Charlevoix-Saguenay

Chen,

Merrill,

Jong

et al. 2024

Cerebellum

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Autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by loss-of-function mutation in the SACS gene, which encodes sacsin, a putative HSP70-HSP90 co-chaperone. Previous studies with Sacs knock-out (KO) mice and patient-derived broblasts suggested that SACSIN mutations inhibit the function of the mitochondrial ssion enzyme dynamin-related protein 1 (Drp1). This in turn resulted in mitochondrial hyperfusion and dysfunction. We experimentally tested this hypothesis by genetically manipulating the mitochondrial ssion/fusion equilibrium, creating double KO (DKO) mice that also lack positive (PP2A/Bβ2) and negative (PKA/AKAP1) regulators of Drp1. Neither promoting mitochondrial fusion (Bβ2 KO) nor ssion (Akap1 KO) in uenced progression of motor symptoms in Sacs KO mice. However, our studies identi ed profound learning and memory de cits in aged Sacs KO mice. Moreover, this cognitive impairment was rescued in a gene dose-dependent manner by deletion of the Drp1 inhibitor PKA/Akap1. Our results are inconsistent with mitochondrial dysfunction as a primary pathogenic mechanism in ARSACS. Instead, they imply that promoting mitochondrial ssion may be bene cial at later stages of the disease when pathology extends to brain regions subserving learning and memory.

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Documenting manifestations and impacts of autosomal recessive spastic ataxia of Charlevoix–Saguenay to develop patient-reported outcome

Cited by 5 publications

References 134 publications

The Development of a New Patient-Reported Outcome Measure in Recessive Ataxias: The Person-Reported Ataxia Impact Scale

The Development of a New Patient-Reported Outcome Measure in Recessive Ataxias: The Person-Reported Ataxia Impact Scale

Thickened Retinal Nerve Fiber Layer Without Hypermyelination in Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

Driving Mitochondrial Fission Improves Cognitive, but not Motor Deficits in a Mouse Model of Ataxia of Charlevoix-Saguenay

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