Newborn Screening and Biomarkers for Mucopolysaccharidoses

描述（由申请人提供）：该项目旨在将粘多糖（MPS）的生物标志物应用于开发这组溶酶体储存疾病的创新新生儿筛查（NBS）系统。背景：MPS是由于催化糖胺聚糖降解的酶活性缺乏而导致糖胺聚糖（GAG）过度积累所致。有11种已知的酶缺乏症引起7种不同形式的MPS，总发病率约为25，000例活产中的1例，表明美国每年约有200例新生儿患者。未降解的储存物质在溶酶体中的积累引起不同的临床症状。一般来说，如果不治疗，临床病症会进展，导致不可逆的发育迟缓、全身骨骼畸形和/或早期死亡。这些MPS疾病可能通过酶替代疗法或造血干细胞移植治疗。当治疗在早期阶段开始时，接受这些治疗的MPS患者的生活质量显著改善。早期检测（通过NBS）将使这些和其他新疗法的治疗效益最大化。然而，MPS的常规实验室筛查方法旨在测量尿总GAG（硫酸乙酰肝素：HS、硫酸角质素：KS、硫酸皮肤素：DS、硫酸软骨素：CS），不能应用于NBS血液样本。我们描述了一个两层的方法，通过使用高效液相色谱串联质谱（LC/MS/MS）的MPS的NBS。一级筛选将基于使用干血斑同时测定特定GAG标志物（DS、HS和KS），确定所有类型MPS的“风险增加”人群。随后的第二层个体酶测定提供了明确的诊断。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、灵敏、特异和廉价的筛查方法。每种MPS的筛查费用都很高，而且令人望而却步，因为发病率从大约1：100，000到不到1：2，000，000不等。然而，MPS筛查作为一个组合发病率约为1：25，000出生的群体，与现有筛查计划目前针对的其他遗传性疾病相当。新的LC/MS/MS方法能够同时检测一组MPS，并有望用于NBS。建议研究计划的观点：我们将建立一种NBS方法，同时测定三种主要的GAG（DS，HS和KS）作为生物标志物。除了NBS应用外，我们还将测量GAG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.