Thais Lampert Monte1, Fernanda Santos Pereira2, Estela da Rosa Reckziegel3, Marina Coutinho Augustin3, Lucas Dorídio Locks-Coelho3, Amanda Senna P Santos3, José Luiz Pedroso4, Orlando Barsottini4, Fernando Regla Vargas5, Maria-Luiza Saraiva-Pereira6, Laura Bannach Jardim7. 1. Programa de Pós-Graduação em Ciências Médicas, Universidade Federal do Rio Grande do Sul, Brazil; Serviço de Neurologia, Hospital de Clínicas de Porto Alegre, Rio Grande do Sul, Brazil. 2. Laboratório de Identificação Genética, Hospital de Clínicas de Porto Alegre, Rio Grande do Sul, Brazil. 3. Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Brazil. 4. Setor de Neurologia Geral e Ataxias, Disciplina de Neurologia Clínica da UNIFESP - Escola Paulista de Medicina, Universidade Federal de São Paulo, Brazil. 5. Departamento de Genética e Biologia Molecular, Universidade Federal do Estado do Rio de Janeiro, Brazil. 6. Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul, Brazil; Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Brazil; Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Rio Grande do Sul, Brazil; Laboratório de Identificação Genética, Hospital de Clínicas de Porto Alegre, Rio Grande do Sul, Brazil; Rede Neurogenética, Hospital de Clínicas de Porto Alegre, Rio Grande do Sul, Brazil. 7. Programa de Pós-Graduação em Ciências Médicas, Universidade Federal do Rio Grande do Sul, Brazil; Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul, Brazil; Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Brazil; Departamento de Medicina Interna, Universidade Federal do Rio Grande do Sul, Brazil; Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Rio Grande do Sul, Brazil; Laboratório de Identificação Genética, Hospital de Clínicas de Porto Alegre, Rio Grande do Sul, Brazil; Rede Neurogenética, Hospital de Clínicas de Porto Alegre, Rio Grande do Sul, Brazil; Instituto Nacional de Genética Médica Populacional, Brazil. Electronic address: ljardim@hcpa.edu.br.
Abstract
BACKGROUND: Spinocerebellar ataxia type 2 (SCA2) is due to a CAG expansion (CAGexp) at ATXN2. SCA2 presents great clinical variability, alongside characteristic ataxia with saccadic slowness. AIMS: To study parkinsonism, dementia, dystonia, and amyotrophy as subphenotypes of SCA2, and to explore the effect of CAG repeats at different loci and of mitochondrial polymorphism A10398G as modifiers of phenotype. METHODS: Symptomatic subjects were classified by presence/absence of neurological signs mentioned above; SARA and NESSCA scores were obtained. CAG repeats at ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7 and RAI1, and polymorphism A10398G at mtDNA were established. Group characteristics were compared, with a p < 0.05. RESULTS: Forty-eight SCA2 individuals were included. Age at onset, CAGexp, and disease duration explained 53% and 43% of SARA and NESSCA variations, respectively. CAGexp of subjects with and without parkinsonism were different (medians of 42 and 39 repeats) as well as of subjects with and without dystonia (44 and 40 repeats). Amyotrophy was not significantly related to any variable under study. Concerning polymorphism A10398G, 83% of subjects with and 34% of those without cognitive decline carried 10398G at (p = 0.003). DISCUSSION: Treating the four phenotypic subgroups as outcomes was a valid strategy to identify modifiers of disease. Among correlations found, some confirmed previous reports, such as that between dystonia and CAGexp. Of note was the association between cognitive decline and the variant G at mitochondrial polymorphism A10398G, a variant formerly related to earlier ages at onset in SCA2.
BACKGROUND:Spinocerebellar ataxia type 2 (SCA2) is due to a CAG expansion (CAGexp) at ATXN2. SCA2 presents great clinical variability, alongside characteristic ataxia with saccadic slowness. AIMS: To study parkinsonism, dementia, dystonia, and amyotrophy as subphenotypes of SCA2, and to explore the effect of CAG repeats at different loci and of mitochondrial polymorphism A10398G as modifiers of phenotype. METHODS: Symptomatic subjects were classified by presence/absence of neurological signs mentioned above; SARA and NESSCA scores were obtained. CAG repeats at ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7 and RAI1, and polymorphism A10398G at mtDNA were established. Group characteristics were compared, with a p < 0.05. RESULTS: Forty-eight SCA2 individuals were included. Age at onset, CAGexp, and disease duration explained 53% and 43% of SARA and NESSCA variations, respectively. CAGexp of subjects with and without parkinsonism were different (medians of 42 and 39 repeats) as well as of subjects with and without dystonia (44 and 40 repeats). Amyotrophy was not significantly related to any variable under study. Concerning polymorphism A10398G, 83% of subjects with and 34% of those without cognitive decline carried 10398G at (p = 0.003). DISCUSSION: Treating the four phenotypic subgroups as outcomes was a valid strategy to identify modifiers of disease. Among correlations found, some confirmed previous reports, such as that between dystonia and CAGexp. Of note was the association between cognitive decline and the variant G at mitochondrial polymorphism A10398G, a variant formerly related to earlier ages at onset in SCA2.
Authors: Pei-Hsin Kuo; Shi-Rui Gan; Jie Wang; Raymond Y Lo; Karla P Figueroa; Darya Tomishon; Stefan M Pulst; Susan Perlman; George Wilmot; Christopher M Gomez; Jeremy D Schmahmann; Henry Paulson; Vikram G Shakkottai; Sarah H Ying; Theresa Zesiewicz; Khalaf Bushara; Michael D Geschwind; Guangbin Xia; S H Subramony; Tetsuo Ashizawa; Sheng-Han Kuo Journal: Parkinsonism Relat Disord Date: 2017-10-23 Impact factor: 4.891