Xian-Jin Shang1, Hao-Ling Xu2, Jin-Shan Yang2, Ping-Ping Chen2, Min-Ting Lin2, Mei-Zhen Qian3, Hui-Xia Lin2, Xiao-Ping Chen4, Yu-Chao Chen2, Bin Jiang5, Yi-Jun Chen2, Wan-Jin Chen2, Ning Wang2, Zhi-Ming Zhou6, Shi-Rui Gan7. 1. Department of Neurology, Yijishan Hospital of Wannan Medical College, Wuhu, China. 2. Department of Neurology and Institute of Neurology, First Affiliated Hospital of Fujian Medical University, Fujian Key Laboratory of Molecular Neurology, Fuzhou, China. 3. Department of Neurology and Institute of Neurology, First Affiliated Hospital of Fujian Medical University, Fujian Key Laboratory of Molecular Neurology, Fuzhou, China; Interdisciplinary Institute of Neuroscience and Technology, Zhejiang University, Hangzhou, China. 4. School of Mathematics and Computer Science & FJKLMAA, Fujian Normal University, Fuzhou, China. 5. Department of Neurology and Institute of Neurology, First Affiliated Hospital of Fujian Medical University, Fujian Key Laboratory of Molecular Neurology, Fuzhou, China; Department of Neurology, The First Affiliated Hospital of Xiamen University, Xiamen, China. 6. Department of Neurology, Yijishan Hospital of Wannan Medical College, Wuhu, China. Electronic address: neuro_depar@hotmail.com. 7. Department of Neurology and Institute of Neurology, First Affiliated Hospital of Fujian Medical University, Fujian Key Laboratory of Molecular Neurology, Fuzhou, China. Electronic address: ganshirui@fjmu.edu.cn.
Abstract
BACKGROUND: Spinocerebellar ataxia type 3 (SCA3) is the most common subtype of SCAs worldwide. SCA3 homozygote is defined as expanded CAG repeats in both alleles that might exhibit severe phenotype due to gene dosage effect. However, a study on the systematic comparison of clinical phenotypes between homozygotes and heterozygotes to indicate these verity of phenotypes of homozygotes is still lacking. METHODS: A total of 14 SCA3 homozygotes (3 Chinese participants and 11 participants from various ethnicity in different published studies) and 143 Chinese heterozygotes of SCA3 were recruited for this study. The 95% confidence intervals (CIs) of age at onset and disease severity expected from heterozygous patients were analyzed to detect the phenotypic differences between homozygotes and heterozygotes. RESULTS: Almost all the homozygotes (13 of 14) were found to present a significant earlier age at onset compared with heterozygotes, because age at onset of most homozygotes was lower than the 95% CIs of age at onset of heterozygotes. Also, the clinical severity in most of the homozygotes (3 of 4) with identified clinical phenotypes was higher than the 95% CIs of severity in heterozygotes, indicating more severe clinical phenotypes in SCA3 homozygotes. CONCLUSIONS: The homozygosity for SCA3 could lead to an earlier age of onset and putative severe clinical features. The findings of the present study suggested an influence of gene dosage on SCA3 phenotypes.
BACKGROUND:Spinocerebellar ataxia type 3 (SCA3) is the most common subtype of SCAs worldwide. SCA3 homozygote is defined as expanded CAG repeats in both alleles that might exhibit severe phenotype due to gene dosage effect. However, a study on the systematic comparison of clinical phenotypes between homozygotes and heterozygotes to indicate these verity of phenotypes of homozygotes is still lacking. METHODS: A total of 14 SCA3 homozygotes (3 Chinese participants and 11 participants from various ethnicity in different published studies) and 143 Chinese heterozygotes of SCA3 were recruited for this study. The 95% confidence intervals (CIs) of age at onset and disease severity expected from heterozygous patients were analyzed to detect the phenotypic differences between homozygotes and heterozygotes. RESULTS: Almost all the homozygotes (13 of 14) were found to present a significant earlier age at onset compared with heterozygotes, because age at onset of most homozygotes was lower than the 95% CIs of age at onset of heterozygotes. Also, the clinical severity in most of the homozygotes (3 of 4) with identified clinical phenotypes was higher than the 95% CIs of severity in heterozygotes, indicating more severe clinical phenotypes in SCA3 homozygotes. CONCLUSIONS: The homozygosity for SCA3 could lead to an earlier age of onset and putative severe clinical features. The findings of the present study suggested an influence of gene dosage on SCA3 phenotypes.