Newborn Screening and Biomarkers for Mucopolysaccharidoses

描述(由申请人提供)：这个项目寻求应用粘多糖病(MPS)的生物标记物来开发一种创新的新生儿筛查系统(NBS)来治疗这组溶酶体储存疾病。背景：MPS是由于糖胺多聚糖(GAG)的过度积聚引起的，这种积聚是由于催化其降解的酶活性不足而引起的。有11种已知的酶缺乏导致7种不同形式的MPS，总体发病率约为25000例活产儿中的1例，这意味着在美国每年约有200名新生儿患者。未降解的储存物质在溶酶体内的积聚会引起不同的临床症状。一般来说，如果不治疗，临床情况会进展，导致不可逆转的发育延迟、全身性骨骼畸形和/或过早死亡。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。如果在早期阶段开始治疗，接受这些疗法治疗的MPS患者的生活质量会显著提高。早期发现(通过国家统计局)将使这些和其他新疗法的治疗效益最大化。然而，传统的MPS实验室筛查方法是为了测量尿液总GAG(硫酸乙酰肝素：HS，硫酸角蛋白：KS，硫酸皮肤素：DS，硫酸软骨素：CS)，不适用于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中的NBS进行两层分离的方法。第一级筛查将根据干血斑点同时检测特定的GAG标记物(DS、HS和KS)，确定所有类型MPS的“高危”人群。随后的第二级单项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。筛查每种类型的MPS的费用将会很高，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，将MPS作为一组合并发病率约为1：25,000的新生儿进行筛查，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方法能够同时检测一组MPS，在NBS中具有广阔的应用前景。拟议研究计划的前景：我们将建立MPS的NBS方法，同时测定三种主要的GAG(DS、HS和KS)作为生物标志物。除了国家统计局的应用外，我们还将测量GAG作为生物标记物，用于评估疾病严重程度并监测长期临床过程中不断演变的治疗方法的效果。 与公共卫生相关：粘多糖病(MPS)是一组先天性代谢疾病，由溶酶体酶活性不足引起，导致硫酸皮肤素、硫酸肝素、硫酸软骨素和硫酸角蛋白等糖胺多聚糖(一系列糖链)在多个器官中积聚，导致全身骨骼畸形、腹部器官增大、听力丧失、瓣膜心脏病、精神发育迟滞和过早死亡。我们的研究方案致力于开发一种新的MPS新生儿筛查方法，使早期诊断和潜在的治疗成为可能，防止严重的不可逆转的损害，并导致更好的生活质量。我们建议进行一项针对MPS的新生儿筛查试点研究，以评估我们的创新方法。

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. PUBLIC HEALTH RELEVANCE: Mucopolysaccharidoses (MPS) are a group of inborn errors of metabolism caused by deficiency of lysosomal enzyme activities, leading to accumulation of glycosaminoglycans (a chain of sugars) such as dermatan sulfate, heparan sulfate, chondroitin sulfate, and keratan sulfate in multiple organs causing systemic bone deformities, enlarged abdominal organs, hearing loss, valvular heart disease, mental retardation and early death. Our research proposal addresses development of a novel newborn screening method for MPS that enables early diagnosis and potential treatment, preventing serious irreversible damage and leading to a better quality of life. We propose to perform a newborn screening pilot study for MPS to evaluate our innovative method.