Genotype-phenotype correlation in 667 Chinese families with spinocerebellar ataxia type 3

Du, Yi-Chu; Dong, Yi; Cheng, Haixia; Li, Quan-Fu; Yang, Lu; Shao, Ya-Ru; Yin, Ming; Wang, Ni; Gan, Shi‐Rui; Wu, Zhi‐Ying

doi:10.1016/j.parkreldis.2020.07.024

Cited by 7 publications

(5 citation statements)

References 26 publications

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“…SCA3 is characterized by the accumulation of aggregates composed of polyglutamine (polyQ) ataxin-3 (ATXN3) proteins translated from expanded CAG trinucleotide repeats in the ATXN3 gene [2]. Although SCA3 is defined as a single disorder caused by the repeat expansion mutation in ATXN3, multiple phenotypes may exist within one family sparking the study of genotype-phenotype correlations [3]. The exact underlying pathogenic mechanisms of SCA3 and fundamental treatment for preventing the disease remain active topics of investigation.…”

Section: Introductionmentioning

confidence: 99%

Urine levels of the polyglutamine ataxin-3 protein are elevated in patients with spinocerebellar ataxia type 3

Koike

Jansen-West

Al-Shaikh

et al. 2021

Parkinsonism & Related Disorders

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Section: Introductionmentioning

confidence: 99%

Urine levels of the polyglutamine ataxin-3 protein are elevated in patients with spinocerebellar ataxia type 3

Koike

Jansen-West

Al-Shaikh

et al. 2021

Parkinsonism & Related Disorders

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“…Similarly, these previous studies also found that the distribution of AAO and the CAGexp at ATXN3 gene in Chinese population were different from those in Western populations. 30,31 These discrepancies between different populations confirmed that ethnic or geographic origin is an important factor for disease onset in polyQ disease. The CAG repeat length of the expanded allele at the causative genes has different contributions among different populations.…”

Section: Discussionmentioning

confidence: 85%

“…Similarly, these previous studies also found that the distribution of AAO and the CAGexp at ATXN3 gene in Chinese population were different from those in Western populations. 30,31…”

Section: Discussionmentioning

confidence: 99%

“…The distributions of AAO, sex, and the CAG repeat length of ATXN3 in our SCA3/MJD populations were also similar to that of other Chinese cohorts. [29][30][31] The final cohort was established by excluding patients with ATXN3 CAGexp lengths outside of the typical range in the initial cohort. Except for the CAGexp length range, no obvious differences were detected in clinical and genotypic data between the 2 cohorts (table 1).…”

Section: Description Of the Populationsmentioning

confidence: 99%

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New Model for Estimation of the Age at Onset in Spinocerebellar Ataxia Type 3

et al. 2021

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ObjectivesThe aim of this study was to develop an appropriate parametric survival model to predict patient's age at onset (AAO) for spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) populations from mainland China.MethodsWe compared the efficiency and performance of 6 parametric survival analysis methods (exponential, weibull, log-gaussian, gaussian, log-logistic, and logistic) based on cytosine-adenine-guanine (CAG) repeat length at ATXN3 to predict the probability of AAO in the largest cohort of patients with SCA3/MJD. A set of evaluation criteria, including −2 log-likelihood statistic, Akaike information criterion (AIC), bayesian information criterion (BIC), Nagelkerke R-squared (Nagelkerke R^2), and Cox-Snell residual plot, were used to identify the best model.ResultsAmong these 6 parametric survival models, the logistic model had the lowest −2 log-likelihood (6,560.12), AIC (6,566.12), and BIC (6,566.14) and the highest value of Nagelkerke R^2 (0.54), with the closest graph to the bisector Cox-Snell residual graph. Therefore, the logistic survival model was the best fit to the studied data. Using the optimal logistic survival model, we indicated the age-specific probability distribution of AAO according to the CAG repeat size and current age.ConclusionsWe first demonstrated that the logistic survival model provided the best fit for AAO prediction in patients with SCA3/MJD from mainland China. This optimal model can be valuable in clinical and research. However, the rigorous clinical testing and practice of other independent cohorts are needed for its clinical application. A unified model across multiethnic cohorts is worth further exploration by identifying regional differences and significant modifiers in AAO determination.

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“…SCAs can present with a wide spectrum of symptoms and signs. Our previous studies have revealed impressive genetic and clinical variation between populations on SCA2 and SCA3 [7,8]. Elaborating the genotypic and phenotypic features of SCA1 based on the Chinese population is of great importance for disease recognition and inter-population comparison.…”

Section: Introductionmentioning

confidence: 99%

Genetic and clinical profiles in a large cohort of Chinese individuals with spinocerebellar ataxia type 1

Shao

Dong

et al. 2022

Preprint

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Background Spinocerebellar ataxia type 1 (SCA1) is the third most common type of spinocerebellar ataxia in China. However, data about Chinese SCA1 patients are limited. This study aims to provide a detailed description of the phenotype and genotype of Chinese SCA1 individuals and guide the clinical practice. Methods A total of 110 SCA1 individuals from 79 pedigrees and 123 unrelated normal controls were recruited. Sanger sequencing, SfaNI restriction and TA cloning were used for the determination of the CAG repeat size and the intrinsic structure. Clinical data including scale scores, magnetic resonance imaging and electromyography were collected. Results Interrupted pathogenic alleles occurred in 5.5% of the SCA1 individuals and caused later disease onset (p < 0.0001). The average age at onset (AAO) was 38.1 ± 10.1 years, inversely correlated with the expanded CAG repeats (expCAGs), best fitted with exponential models. The mean ± SD of the longest uninterrupted expCAG repeat number was 48.3 ± 4.6 and could explain 65.4% of the AAO variance, making an increasement of 28.0% compared to the total CAG repeats. Longer disease duration and larger expCAG size were associated with higher scale scores and smaller brainstem relative volumes. Conclusions This study described the genetic and clinical profiles of Chinese SCA1 individuals, revealed the impact of interruptions in expCAGs to AAO and made an inter-population comparison.

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Genotype-phenotype correlation in 667 Chinese families with spinocerebellar ataxia type 3

Cited by 7 publications

References 26 publications

Urine levels of the polyglutamine ataxin-3 protein are elevated in patients with spinocerebellar ataxia type 3

Urine levels of the polyglutamine ataxin-3 protein are elevated in patients with spinocerebellar ataxia type 3

New Model for Estimation of the Age at Onset in Spinocerebellar Ataxia Type 3

Genetic and clinical profiles in a large cohort of Chinese individuals with spinocerebellar ataxia type 1

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