Yee Karen S, Alexanderian David, Merberg David, Natarajan Madhusudan, Wang Scarlett, Wu Yuna, Whiteman David A H
Takeda Development Center Americas, Inc., Cambridge, MA, USA.
Takeda Development Center Americas, Inc., Lexington, MA, USA.
Mol Genet Metab. 2023 Nov;140(3):107652. doi: 10.1016/j.ymgme.2023.107652. Epub 2023 Jul 13.
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.
黏多糖贮积症II型（MPS II）是一种罕见的X连锁溶酶体贮积病，由艾杜糖醛酸-2-硫酸酯酶基因（IDS）的致病变异引起，其疾病谱高度可变。仅根据IDS变异难以预测MPS II的严重程度；虽然某些基因型与特定表型相关，但大多数基因型的疾病进程仍不清楚。本研究旨在通过将科学文献中的信息与两项MPS II临床研究的数据相结合，完善基因型-表型分类。
通过半自动多阶段审查过程，对两项MPS II临床研究（NCT01822184、NCT02055118）中88例患者的基因型、认知和行为数据进行事后分析，并结合生物医学文献中已发表的IDS变异信息。使用第二版差异能力量表（DAS-II）和第二版文兰适应行为量表（VABS-II）来测量认知功能和适应行为。
IDS变异最常见的类别是错义变异（47/88，占总变异的53.4%）。DAS-II一般概念能力（GCA）和VABS-II适应行为综合评分（ABC）的平均（标准差[SD]）基线分数分别为74.0（16.4）和82.6（14.7）。所有鉴定出的IDS完全缺失/大片段重排（n = 7）和大片段缺失（n = 1）均与已发表的“严重”或“预测严重”进行性神经病变表型相关，其特征为中枢神经系统受累。在包含不止一名参与者的类别中，完全缺失/大片段重排个体的DAS-II GCA平均基线分数（SD）最低，为64.0（9.1，n = 4），而剪接位点变异个体的分数最高，为83.8（14.2，n = 4）。在包含不止一名参与者的变异类别中，无法分类变异患者的VABS-II ABC平均基线分数（SD）最低，为79.3（4.9，n = 3），而剪接位点变异患者的分数最高，为87.2（16.1，n = 5）。
根据文献报道，研究中的大多数患者的MPS II表型根据分类被归类为“严重”或“预测严重”。与其他变异患者相比，IDS完全缺失/大片段重排变异患者的DAS-II GCA平均分数较低，VABS-II ABC分数也较低，这证实了其与早期进行性“严重”（神经病变）疾病的关联。这些数据为改善MPS II表型分类和基因型-表型关系的特征描述提供了一个起点。
