The impact of ethnicity on the clinical presentations of spinocerebellar ataxia type 3
Introduction
In a variety of sporadic neurodegenerative diseases, it is well-established that ethnicity can affect disease phenotypes in Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) [[1], [2], [3], [4], [5], [6], [7]]. These studies provided a unique window to probe the interplay of factors of gene, environment, socioeconomic status, and access to care, in late onset, sporadic neurodegenerative disorders. While a recent study has demonstrated that ethnicity may influence disease penetrance in LRRK2-PD [8], it remains unclear whether ethnicity also plays a key role in monogenetic, ataxic disorders.
CAG-repeat disorders, including spinocerebellar ataxias (SCAs) and Huntington's disease (HD), are a group of neurodegenerative disorders with a strong genetic influence. Often, the length of pathological CAG repeats inversely correlates with AAO. Thus, CAG repeat diseases are often considered as prototypical disorders of neurodegeneration with a robust genetic predisposition [9]. Our overarching aim is to investigate the contribution of ethnicity in monogenetic, neurodegenerative disorders. We choose SCA3 as a disease model because SCA3 is the most common of the CAG-repeat ataxias, and occurs across different ethnicities [10]. SCA3 is caused by an expanded CAG repeat in exon 10 of ATXN3 [11]. We recruited a multi-ethnicity cohort that consisted of Caucasians, African Americans and Asians in multi-center settings in order to compare clinical presentations in SCA3 patients of different ethnicities. This will inform the contribution of ethnicity in monogenetic, neurodegenerative disorders.
Section snippets
Patients
257 molecularly-confirmed SCA3 patients were included in the present study with two large cohorts: 1) the Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA) natural history study in the North America [12] with 66 Caucasians, 43 African Americans, and 17 Asian Americans and 2) the SCA3 study in China with 131 native Han Chinese. The clinical data of Caucasians, African Americans and Asian Americans were from the CRC-SCA cohort constitutes patients from 12 medical centers across
The demographic features of SCA3 patients
The basic demographics of the SCA3 participants were shown in Table 1. There were no significant differences in SCA3 patients of different ethnicities with respect to gender, AAO, and depression symptoms. Compared to Caucasians and African Americans, Asians had the youngest age at the baseline enrollment and the shortest disease duration. Asians also had significantly lower SARA scores than Caucasians or African Americans. Interestingly, in contrast to their low SARA scores, Asians had the
Discussion
We found that Asians have the latest AAO, compared to African Americans and Caucasians, whereas African Americans have the most severe ataxia, compared to Asians and Caucasians, suggesting that Asians appear to have the mildest ataxia phenotypes while African Americans have the most severe phenotypes in SCA3. On the other hand, Caucasian SCA3 patients more commonly have depression. We also found that Asians have the shortest disease duration at the enrollment, which might suggest the ethnic
Study funding
The CRC-SCA natural history study was supported by the Rare Disease Clinical Research Network (RDCRN) (RC1NS068897), and the National Ataxia Foundation. Dr. Kuo is supported by the NINDS K08 NS083738, Louis V. Gerstner Jr. Scholarship, American Brain Research Training Fellowship, Parkinson Disease Foundation, American Parkinson's Disease Association, Rare Disease Clinical Research Network (RDCRN) (RC1NS068897), International Essential Tremor Foundation, and NIEHS pilot grant ES009089, the Smart
Declaration of competing interest
Dr. Zesiewicz has served as a clinical advisor for Steminent Biotherapeutics, and she has received travel reimbursement from the department of neurology at University of Southern Florida; has received travel reimbursement for a Biohaven Pharmaceuticals meeting. Dr. Zesiewicz has served on the editorial board for Neurodegenerative Disease Management and Tremor and other Hyperkinetic Movements, and has received research support for her division for approximately 20 clinical trials for Parkinson's
Acknowledgements
The authors sincerely thank the participants for their help and willingness to participate in this study. We also thank the reviewers for their helpful comments.
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