Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Jan;89(1):66-73.
doi: 10.1002/ana.25919. Epub 2020 Oct 7.

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

Vanessa B Leotti  1   2 , Jeroen J de Vries  3 , Camila M Oliveira  4 , Eduardo P de Mattos  5 , Gerard J Te Meerman  6 , Ewout R Brunt  3 , Harm H Kampinga  5 , Laura B Jardim  4   7   8 , Dineke S Verbeek  6
Affiliations

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

Vanessa B Leotti et al. Ann Neurol. 2021 Jan.

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.

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Paulson H. Repeat expansion diseases. Handb Clin Neurol 2018;147:105-123.
    1. Ruano L, Melo C, Silva MC, Coutinho P. The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies. Neuroepidemiology 2014;42:174-183.
    1. van de Warrenburg BPC, Sinke RJ, Verschuuren-Bemelmans CC, et al. Spinocerebellar ataxias in The Netherlands: prevalence and age at onset variance analysis. Neurology 2002;58:702-708.
    1. Sequeiros J, Martins S, Silveira I. Epidemiology and population genetics of degenerative ataxias. Handb Clin Neurol 2012;103:227-251.
    1. Saute JAM, Jardim LB. Machado Joseph disease: clinical and genetic aspects, and current treatment. Expert Opin Orphan Drugs 2015;3:517-535.

Publication types

LinkOut - more resources