背景:粘多糖病II(MPSII)是一种罕见的,由艾杜糖醛酸-2-硫酸酯酶基因(IDS)的致病变体引起的X连锁溶酶体贮积病,其特征是疾病谱高度可变。MPSII的严重程度是很难预测仅基于IDS变异;而一些基因型与特定的表型相关,大多数基因型的病程仍然未知。本研究旨在通过将来自科学文献的信息与来自MPSII的两项临床研究的数据相结合来完善基因型表型分类。
方法:基因型,认知,和来自MPSII的两项临床研究(NCT01822184,NCT02055118)中的88名患者的行为数据,通过半自动多阶段审查过程,结合生物医学文献中已发表的IDS变异信息进行事后分析.差异能力量表,第二版(DAS-II)和VinelandAdaptiveBehaviorScales™,第二版(VABS-II)用于测量认知功能和适应行为。
结果:IDS变体最常见的类别是错义(47/88,占总变体的53.4%)。平均(标准差[SD])基线DAS-II一般概念能力(GCA)和VABS-II适应行为综合(ABC)得分分别为74.0(16.4)和82.6(14.7),分别。所有确定的IDS完全缺失/大重排(n=7)和大缺失(n=1)与已发表的“严重”或“预测的严重”进行性神经疾病表型有关,以中枢神经系统受累为特征。在由多个参与者组成的类别中,平均基线DAS-IIGCA评分(SD)在完全缺失/大重排者中最低64.0(9.1,n=4),在剪接位点变异者中最高83.8(14.2,n=4).平均基线VABS-IIABC评分(SD)在具有不可分类变异79.3(4.9,n=3)的患者中最低,在具有剪接位点变异87.2(16.1,n=5)的患者中最高。在具有多个参与者的变体类别中。
结论:研究中大多数患者的MPSII表型根据分类分为“严重”或“预测严重”。正如文献报道的那样。IDS完全缺失/大重排变异的患者平均DAS-IIGCA评分低于其他变异的患者,以及低VABS-IIABC,确认与早期进行性“严重”(神经病理性)疾病有关。这些数据提供了改善MPSII表型分类和基因型-表型关系表征的起点。
Mucopolysaccharidosis II (MPS II) is a rare, X-linked lysosomal storage disease caused by pathogenic variants of the iduronate-2-sulfatase gene (IDS) and is characterized by a highly variable disease spectrum. MPS II severity is difficult to predict based on IDS variants alone; while some genotypes are associated with specific phenotypes, the disease course of most genotypes remains unknown. This study aims to refine the genotype-phenotype categorization by combining information from the scientific literature with data from two clinical studies in MPS II.
Genotype, cognitive, and behavioral data from 88 patients in two clinical studies (NCT01822184, NCT02055118) in MPS II were analyzed post hoc in combination with published information on IDS variants from the biomedical literature through a semi-automated multi-stage review process. The Differential Ability Scales, second edition (DAS-II) and the Vineland Adaptive Behavior Scales™, second edition (VABS-II) were used to measure cognitive function and adaptive behavior.
The most common category of IDS variant was missense (47/88, 53.4% of total variants). The mean (standard deviation [SD]) baseline DAS-II General Conceptual Ability (GCA) and VABS-II Adaptive Behavior Composite (ABC) scores were 74.0 (16.4) and 82.6 (14.7), respectively. All identified IDS complete deletions/large rearrangements (n = 7) and large deletions (n = 1) were associated with a published \'severe\' or \'predicted severe\' progressive neuronopathic phenotype, characterized by central nervous system involvement. In categories comprising more than one participant, mean baseline DAS-II GCA scores (SD) were lowest among individuals with complete deletions/large rearrangements 64.0 (9.1, n = 4) and highest among those with splice site variants 83.8 (14.2, n = 4). Mean baseline VABS-II ABC scores (SD) were lowest among patients with unclassifiable variants 79.3 (4.9, n = 3) and highest among those with a splice site variant 87.2 (16.1, n = 5), in variant categories with more than one participant.
Most patients in the studies had an MPS II phenotype categorized as \'severe\' or \'predicted severe\' according to classifications, as reported in the literature. Patients with IDS complete deletion/large rearrangement variants had lower mean DAS-II GCA scores than those with other variants, as well as low VABS-II ABC, confirming an association with the early progressive \'severe\' (neuronopathic) disease. These data provide a starting point to improve the classification of MPS II phenotypes and the characterization of the genotype-phenotype relationship.