Zahoor Muhammad Yasir, Cheema Huma Arshad, Ijaz Sadaqat, Anjum Muhammad Nadeem, Ramzan Khushnooda, Bhinder Munir Ahmad
Molecular Biology and Forensic Laboratory, Institute of Biochemistry and Biotechnology, University of Veterinary and Animal Sciences, Lahore, Pakistan.
Department of Pediatric Gastroenterology and Hepatology, The Children's Hospital and The Institute for Child Health, Lahore, Pakistan.
J Pediatr Endocrinol Metab. 2019 Nov 26;32(11):1221-1227. doi: 10.1515/jpem-2019-0188.
Background Mucopolysaccharidosis type 1 (MPS1) is a rare debilitating multisystem lysosomal disorder resulting due to the deficiency of α-L-iduronidase enzyme (IDUA), caused by recessive mutations in the IDUA gene. Lack or improper amount of the IDUA enzyme results in the improper metabolism of mucopolysaccharides or glycosaminoglycans (GAGs). These large sugar molecules accumulate in lysosomes within cells leading to different systemic complications. The estimated global incidence of MPS1 is 1:100,000 live births for the Hurler and 1:800,000 for the Scheie phenotypes. Methods Thirteen MPS1-affected children from 12 unrelated cohorts were enrolled. All coding and flanking regions of the IDUA gene were sequenced. Bioinformatics tools were used for data analysis and protein prediction for clinical correlations. Results Six IDUA gene mutations were mapped co-segregating with the recessive pattern of inheritance including a novel variant. A novel missense variant c.908T > C (p.L303P) was mapped in two affected siblings in a cohort in the homozygous form. The variant c.1469T > C (p.L490P) was mapped in five unrelated patients and c.784delC (p.H262Tfs55) was mapped in three unrelated patients, while mutations c.1598C > G (p.P533R), c.314G > A (p.R105Q) and c.1277ins9 (p.[A394-L395-L396]) were mapped in a single patient each. Conclusions Multisystem disorders and a wide range of clinical presentation impede the evaluation of patients as well as make it difficult to differentiate between different phenotypes of MPS. Early and accurate diagnosis is crucial for the disease management and implementation of an expanded new-born genetic screening program for inborn errors of metabolism including MPS1. We recommend c.784delC (p.H262Tfs55) and c.1469T > C (p.L490P) as first-line genetic markers for the molecular diagnosis of MPS1 in Pakistan.
1型粘多糖贮积症（MPS1）是一种罕见的、使人衰弱的多系统溶酶体疾病，由α-L-艾杜糖醛酸酶（IDUA）缺乏所致，该酶缺乏是由IDUA基因的隐性突变引起的。IDUA酶的缺乏或数量不当会导致粘多糖或糖胺聚糖（GAGs）代谢异常。这些大的糖分子在细胞内的溶酶体中积累，导致不同的全身并发症。据估计，全球范围内，Hurler型MPS1的发病率为1:100,000活产儿，Scheie型为1:800,000。方法：招募了来自12个不相关队列的13名受MPS1影响的儿童。对IDUA基因的所有编码区和侧翼区进行测序。使用生物信息学工具进行数据分析和蛋白质预测，以建立临床相关性。结果：共定位了6个与隐性遗传模式共分离的IDUA基因突变，包括一个新的变异。在一个队列中的两名受影响的同胞中发现了一个纯合形式的新错义变异c.908T＞C（p.L303P）。变异c.1469T＞C（p.L490P）在5名不相关患者中被定位，c.784delC（p.H262Tfs55）在3名不相关患者中被定位，而突变c.1598C＞G（p.P533R）、c.314G＞A（p.R105Q）和c.1277ins9（p.[A394-L395-L396]）分别在一名患者中被定位。结论：多系统疾病和广泛的临床表现妨碍了对患者的评估，也难以区分MPS的不同表型。早期准确诊断对于疾病管理以及实施包括MPS1在内的先天性代谢缺陷的扩大新生儿基因筛查计划至关重要。我们建议将c.784delC（p.H262Tfs55）和c.1469T＞C（p.L490P）作为巴基斯坦MPS1分子诊断的一线遗传标记。
