Natural history of most common spinocerebellar ataxia: a systematic review and meta-analysis

Diallo, Alhassane; Jacobi, Heike; Montcel, Sophie Tezenas du; Klockgether, Thomas

doi:10.1007/s00415-020-09815-2

Cited by 53 publications

(42 citation statements)

References 18 publications

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“…These figures are in agreement with previous observational studies showing a yearly increase of 1.0-1.75 point of the SARA scores in patients. The progression rates were shown to be different in the early and in the late stages of the disease (33,34). In preclinical subjects, we confirmed a non-linear progression of SARA, with increasing scores around the time of disease onset (18,(35)(36)(37)(38)(39) (Figure 3).…”

Section: Discussionsupporting

confidence: 64%

Progression of Cerebellar Atrophy in Spinocerebellar Ataxia Type 2 Gene Carriers: A Longitudinal MRI Study in Preclinical and Early Disease Stages

et al. 2020

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Spinocerebellar ataxias type 2 (SCA2) is an autosomal dominant inherited disease caused by expanded trinucleotide repeats (≥32 CAG) within the coding region of ATXN2 gene. Age of disease onset primarily depends on the length of the expanded region. The majority of subjects carrying the mutation remain free of clinical signs for few decades (“pre-symptomatic” stage), but in proximity of disease onset subtle neurophysiological, cognitive, and structural brain imaging changes may occur. Aims of the present study are to determine the time-window in which early clinical and neurodegenerative MRI changes may be identified, and to evaluate the rate of the disease progression in both preclinical and early disease phases. We performed a 1-year longitudinal study in 42 subjects: 14 SCA2 patients (mean age 39 years, disease duration 7 years, SARA score 9 points), 13 presymptomatic SCA2 subjects (preSCA2, mean age 39 years, expected time to disease onset 16 years), and 15 gene-negative healthy controls (mean age 33 years). All participants underwent genetic test, neurological examination, cognitive tests, and brain MRI. Evaluations were repeated at 1-year interval. Baseline MRI evaluations in SCA2 patients showed significant atrophy in cerebellum, brainstem, basal ganglia and cortex compared to controls, while preSCA2 subjects had isolated volume loss in the pons, and cortical thinning in specific frontal and parietal areas, namely rostral-middle-frontal and precuneus. One-year longitudinal follow-up demonstrated, in SCA2 patients, volume reduction in cerebellum, pons, superior cerebellar peduncles, and midbrain, and only in the cerebellum in preSCA2 subjects. No progression in clinical or cognitive measures was observed in preSCA2 subjects. The rate of volume loss in the cerebellum and subcortical regions greatly differed between patients and preSCA2. In conclusion, our pilot study demonstrated that MRI measures are highly sensitive to identify longitudinal structural changes in SCA2 patients, and in preSCA2 up to a decade before expected disease onset. These findings may contribute in the understanding of early neurodegenerative processes and may be useful in future therapeutical trials.

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Section: Discussionsupporting

confidence: 64%

Progression of Cerebellar Atrophy in Spinocerebellar Ataxia Type 2 Gene Carriers: A Longitudinal MRI Study in Preclinical and Early Disease Stages

et al. 2020

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“…In addition, for other SCAs, there are conflicting reports regarding the impact of the expanded CAG repeat length on disease progression as measured by SARA: negative results have mainly correlated with small cohorts of specific SCA types (Supplementary Material SS1). A systematic review about SARA progression was recently published, but factors influencing disease progression were not meta‐analyzed 32 …”

Section: Discussionmentioning

confidence: 99%

CAG Repeat Size Influences the Progression Rate of Spinocerebellar Ataxia Type 3

Leotti

Vries

Oliveira

et al. 2020

Annals of Neurology

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Objective In spinocerebellar ataxia type 3/Machado‐Joseph disease (SCA3/MJD), the expanded cytosine adenine guanine (CAG) repeat in ATXN3 is the causal mutation, and its length is the main factor in determining the age at onset (AO) of clinical symptoms. However, the contribution of the expanded CAG repeat length to the rate of disease progression after onset has remained a matter of debate, even though an understanding of this factor is crucial for experimental data on disease modifiers and their translation to clinical trials and their design. Methods Eighty‐two Dutch patients with SCA3/MJD were evaluated annually for 15 years using the International Cooperative Ataxia Rating Scale (ICARS). Using linear growth curve models, ICARS progression rates were calculated and tested for their relation to the length of the CAG repeat expansion and to the residual age at onset (RAO): The difference between the observed AO and the AO predicted on the basis of the CAG repeat length. Results On average, ICARS scores increased 2.57 points/year of disease. The length of the CAG repeat was positively correlated with a more rapid ICARS progression, explaining 30% of the differences between patients. Combining both the length of the CAG repeat and RAO as comodifiers explained up to 47% of the interpatient variation in ICARS progression. Interpretation Our data imply that the length of the expanded CAG repeat in ATXN3 is a major determinant of clinical decline, which suggests that CAG‐dependent molecular mechanisms similar to those responsible for disease onset also contribute to the rate of disease progression in SCA3/MJD. ANN NEUROL 2021;89:66–73

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“…Other statistical techniques include Bayesian methods where information from natural history studies could be borrowed to make prior distributions about expected endpoints and clinical outcomes. 142 Another challenge in clinical trial development that needs to be addressed is financial. Clinical research to be sure is expensive, and funds are especially hard to come by for rare disorders.…”

Section: Innovations In Clinical Trial Designmentioning

confidence: 99%

Section: Efforts Toward Clinical Trial Readinessmentioning

confidence: 99%

Spinocerebellar ataxia clinical trials: opportunities and challenges

Brooker

Edamakanti

Akasha

et al. 2021

Ann Clin Transl Neurol

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The spinocerebellar ataxias (SCAs) are a group of dominantly inherited diseases that share the defining feature of progressive cerebellar ataxia. The disease process, however, is not confined to the cerebellum; other areas of the brain, in particular, the brainstem, are also affected, resulting in a high burden of morbidity and mortality. Currently, there are no disease-modifying treatments for the SCAs, but preclinical research has led to the development of therapeutic agents ripe for testing in patients. Unfortunately, due to the rarity of these diseases and their slow and variable progression, there are substantial hurdles to overcome in conducting clinical trials. While the epidemiological features of the SCAs are immutable, the feasibility of conducting clinical trials is being addressed through a combination of strategies. These include improvements in clinical outcome measures, the identification of imaging and fluid biomarkers, and innovations in clinical trial design. In this review, we highlight current challenges in initiating clinical trials for the SCAs and also discuss pathways for researchers and clinicians to mitigate these challenges and harness opportunities for clinical trial development.

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Natural history of most common spinocerebellar ataxia: a systematic review and meta-analysis

Cited by 53 publications

References 18 publications

Progression of Cerebellar Atrophy in Spinocerebellar Ataxia Type 2 Gene Carriers: A Longitudinal MRI Study in Preclinical and Early Disease Stages

Progression of Cerebellar Atrophy in Spinocerebellar Ataxia Type 2 Gene Carriers: A Longitudinal MRI Study in Preclinical and Early Disease Stages

CAG Repeat Size Influences the Progression Rate of Spinocerebellar Ataxia Type 3

Spinocerebellar ataxia clinical trials: opportunities and challenges

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