Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
J Transl Med. 2022 May 14;20(1):226. doi: 10.1186/s12967-022-03428-1.
In polyglutamine (polyQ) diseases, the identification of modifiers and the construction of prediction model for progression facilitate genetic counseling, clinical management and therapeutic interventions.
Data were derived from the longest longitudinal study, with 642 examinations by International Cooperative Ataxia Rating Scale (ICARS) from 82 SCA3 participants. Using different time scales of disease duration, we performed multiple different linear, quadratic and piece-wise linear growth models to fit the relationship between ICARS scores and duration. Models comparison was employed to determine the best-fitting model according to goodness-of-fit tests, and the analysis of variance among nested models.
An acceleration was detected after 13 years of duration: ICARS scores progressed 2.445 (SE: 0.185) points/year before and 3.547 (SE: 0.312) points/year after this deadline. Piece-wise growth model fitted better to studied data than other two types of models. The length of expanded CAG repeat (CAGexp) in ATXN3 gene significantly influenced progression. Age at onset of gait ataxia (AOga), a proxy for aging process, was not an independent modifier but affected the correlation between CAGexp and progression. Additionally, gender had no significant effect on progression rate of ICARS. The piece-wise growth models were determined as the predictive models, and ICARS predictions from related models were available.
We first confirmed that ICARS progressed as a nonlinear pattern and varied according to different stages in SCA3. In addition to ATXN3 CAGexp, AOga or aging process regulated the progression by interacting with CAGexp.
在多聚谷氨酰胺（polyQ）疾病中，修饰因子的鉴定和进展预测模型的构建有助于遗传咨询、临床管理和治疗干预。
数据来源于最长的纵向研究，共有 82 名 SCA3 参与者接受了 642 次国际合作共济失调评分量表（ICARS）检查。我们使用不同的疾病持续时间时间尺度，对线性、二次和分段线性生长模型进行了多次不同的拟合，以确定 ICARS 评分与持续时间之间的关系。根据拟合优度检验和嵌套模型之间的方差分析，采用模型比较来确定最佳拟合模型。
在持续 13 年后发现了加速现象：在这个截止日期之前，ICARS 评分每年进展 2.445（SE：0.185）分，而在截止日期之后每年进展 3.547（SE：0.312）分。分段生长模型比其他两种模型更适合研究数据。ATXN3 基因中扩展的 CAG 重复（CAGexp）长度显著影响进展。步态共济失调发病年龄（AOga），是衰老过程的一个替代指标，不是独立的修饰因子，但影响 CAGexp 与进展之间的相关性。此外，性别对 ICARS 的进展率没有显著影响。分段生长模型被确定为预测模型，并且可以提供相关模型的 ICARS 预测。
我们首次证实，ICARS 的进展呈非线性模式，并且根据 SCA3 的不同阶段而有所不同。除了 ATXN3 CAGexp，AOga 或衰老过程通过与 CAGexp 相互作用来调节进展。
