Newborn Screening and Biomarkers for Mucopolysaccharidoses

描述（由申请人提供）：本项目旨在应用粘多糖病（MPS）的生物标志物来开发一种针对这组溶酶体积存疾病的创新型新生儿筛查（NBS）系统。背景：MPS是由糖胺聚糖（GAGs）过度积累引起的，这是由于催化其降解的酶活性缺乏引起的。有11种已知的酶缺陷导致7种不同形式的MPS，总发病率约为1 / 25,000活产婴儿，这表明美国每年约有200名新生儿患者。溶酶体中未降解储存物质的积累引起不同的临床综合征。一般来说，如果不及时治疗，临床状况会恶化，导致不可逆转的发育迟缓、全身骨骼畸形和/或早期死亡。这些MPS疾病有可能通过酶替代疗法或造血干细胞移植来治疗。在早期阶段开始治疗时，接受这些疗法治疗的MPS患者的生活质量显著提高。早期发现（通过NBS）将使这些和其他新疗法获得最大的治疗效益。然而，传统的MPS实验室筛查方法旨在测量尿液总GAGs（硫酸肝素：HS，硫酸角蛋白：KS，硫酸皮肤蛋白：DS，硫酸软骨素：CS），不能用于NBS血液样本。我们描述了一种利用高效液相色谱串联质谱（LC/MS/MS）对MPS进行NBS检测的两层方法。第一级筛查将根据使用干血点同时检测特定GAG标记物（DS、HS和KS）来确定所有类型MPS的“风险增加”人群。随后的二级个体酶分析提供了明确的诊断。挑战：由于成本效益是国家统计局的关键，因此需要一种高效、敏感、特异和廉价的筛查方法。由于每一种MPS的发病率从约1:10万到不足1:20万不等，因此对每一种MPS进行筛查的费用高昂且令人望而却步。然而，将MPS作为一个组合发病率约为1:25 000的群体进行筛查，将与现有筛查计划目前针对的其他遗传疾病相媲美。新的LC/MS/MS方法可以同时检测一组MPS，对NBS有很大的应用前景。拟研究计划视角：我们将建立一种同时测定三种主要GAGs （DS、HS和KS）作为生物标志物的MPS的NBS方法。除了NBS应用外，我们还将测量GAGs作为生物标志物，用于评估疾病严重程度和监测长期临床过程中不断发展的治疗效果。

DESCRIPTION (provided by applicant): This project seeks to apply biomarkers for mucopolysaccharidoses (MPS) to the development of an innovative newborn screening (NBS) system for this group of lysosomal storages diseases. Background: MPS are caused by excessive accumulation of glycosaminoglycans (GAGs) from a deficiency of enzyme activity catalyzing their degradation. There are 11 known enzyme deficiencies that give rise to seven distinct forms of MPS with an overall incidence of approximately 1 out of 25,000 live births that indicates approximately 200 newborn patients per year in the Unites States. The accumulation of undegraded storage material in lysosomes causes different clinical syndromes. Generally, the clinical conditions progress if untreated, leading to irreversible developmental delay, systemic skeletal deformities and/or early death. These MPS disorders are potentially treatable with enzyme replacement therapy or hematopoietic stem cell transplantation. The quality of life for MPS patients treated with these therapies dramatically improves when treatment begins at an early stage. Early detection (through NBS) will allow maximum therapeutic benefit of these and other novel therapies. However, conventional laboratory screening methods for MPS are designed to measure urinary total GAGs (heparan sulfate: HS, keratan sulfate: KS, dermatan sulfate: DS, chondroitin sulfate: CS) and cannot be applied to NBS blood samples. We describe a two-tiered approach to NBS for MPS by using high performance liquid chromatography tandem mass spectrometry (LC/MS/MS). The first-tier screen will identify an "at increased risk" population for all types of MPS based on simultaneous assay of specific GAG markers (DS, HS and KS) using dried blood spots. The subsequent second-tier individual enzyme assays provide definitive diagnosis. Challenges: Since cost-effectiveness is a key for NBS, a highly efficient, sensitive, specific and inexpensive screening method is required. The cost of screening each type of MPS would be high and prohibitive as the incidence rates range from about 1:100,000 births to less than 1:2,000,000 births. However, screening for MPS as a group with a combined incidence of about 1:25,000 births would be comparable to other genetic disorders currently targeted by existing screening programs. The new LC/MS/MS method enables the simultaneous detection of a group of MPS and is promising for NBS. Perspective in proposed research plan: We will establish a NBS method for MPS with simultaneous determination of three major GAGs (DS, HS and KS) as biomarkers. In addition to the NBS application we will measure GAGs as biomarkers for assessing disease severity and monitoring the effects of evolving therapies over a long clinical course.