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

Abstract

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

Polyglutamine-expanded ataxin-3: a target engagement marker for Spinocerebellar ataxia type 3 in peripheral blood

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A longitudinal quantitative analysis of gait in patients with SCA-12

“…As compared to other SCAs, SCA12 is considered to progress slowly. A follow-up study in SCA3 reported an average of 56% increase in the ICARS (International Cooperative Ataxia Rating Scale) score over five years [7] but similar studies have not been conducted for SCA12. We aimed to study the evolution of symptoms in three patients of SCA12 by analyzing clinical features and objective gait assessment, over a period of 5–6 years.…”

Neurofilament Light Chain and Intermediate HTT Alleles as Combined Biomarkers in Italian ALS Patients

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