Vanessa B Leotti1,2, Jeroen J de Vries3, Camila M Oliveira4, Eduardo P de Mattos5, Gerard J Te Meerman6, Ewout R Brunt3, Harm H Kampinga5, Laura B Jardim4,7,8, Dineke S Verbeek6. 1. Departamento de Estatística, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. 2. Programa de Pós-Graduação em Epidemiologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. 3. Expertise Center Movement Disorders Groningen, Department of Neurology, University of Groningen, University Medical Center Groningen (UMCG), Groningen, The Netherlands. 4. Programa de Pós-Graduação em Ciências Médicas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. 5. Department of Biomedical Science of Cell & Systems, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 6. Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 7. Departamento de Medicina Interna, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. 8. Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
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.
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.
Authors: Louisa P Selvadurai; Susan L Perlman; George R Wilmot; Sub H Subramony; Christopher M Gomez; Tetsuo Ashizawa; Henry L Paulson; Chiadi U Onyike; Liana S Rosenthal; Haris I Sair; Sheng-Han Kuo; Eva-Maria Ratai; Theresa A Zesiewicz; Khalaf O Bushara; Gülin Öz; Cameron Dietiker; Michael D Geschwind; Alexandra B Nelson; Puneet Opal; Talene A Yacoubian; Peggy C Nopoulos; Vikram G Shakkottai; Karla P Figueroa; Stefan M Pulst; Peter E Morrison; Jeremy D Schmahmann Journal: Cerebellum Date: 2022-08-12 Impact factor: 3.648