Epidemiology of SBCAD Deficiency in Hmong-Americans

描述（由申请人提供）： 本项目的总体目标是调查威斯康星州苗族-美国人群中2-甲基丁酰辅酶A脱氢酶缺乏症（SBCADD）的患病率、自然史、生化和分子特征。SBCADD是一种罕见的先天性异亮氨酸代谢缺陷，可能导致神经发育障碍，现在可以通过国家授权的新生儿筛查计划使用串联质谱法进行鉴定。在威斯康星州最初45个月的新生儿MBADD筛查中，发现了23例病例，均为苗族血统的婴儿。虽然程序是在地方常规新生儿筛查SBCADD，既不自然的历史，这种缺陷也不早期左旋肉碱治疗和饮食干预的效用是已知的。拟议项目有三个具体目标：（1）分析2001年4月至2009年3月的新生儿筛查数据，以便：（a）估计SBCADD在威斯康星州的苗族和其他婴儿中的患病率，（B）描述新生儿血液样本中C5-酰基肉毒碱浓度的分布，和（c）进行分子研究以评估该群体中常见SBCADD突变的存在，并评估用于检测该疾病的当前新生儿筛查截止值;（2）通过使用三种设计进行神经发育和功能结果的观察性研究来检验SBCADD是苗族-美国人群中的良性突变的假设：（a）通过新生儿筛查和匹配对照确定的病例的前瞻性队列研究，（B）SBCADD及其在纳入前瞻性队列研究的婴儿的家庭成员中的结果的横断面研究，以及（c）相关性分析，以检验持续的C5-无环肉碱血液水平预测不良发育结果的假设;以及（3）进行探索性研究，以确定与SBCADD不良结果相关的因素，如果观察到此类结果的话;需要检查的潜在因素包括饮食，触发事件，如疾病，疫苗接种，压力和禁食事件，以及分子变异和潜在的基因-环境相互作用。这项工作的公共卫生意义在于，研究结果将提供评估新生儿筛查阈值和政策所需的关键信息。这一发现也可能促使未来研究早期治疗和饮食限制的有效性，以防止SBCADD儿童的发育障碍。

DESCRIPTION (provided by applicant): The overall goal of this project is to investigate the prevalence, natural history, and biochemical and molecular characteristics of 2-Methylbutyrl-CoA Dehydrogenase Deficiency (SBCADD) in the Hmong- American population of Wisconsin. SBCADD is a rare inborn error of isoleucine metabolism that may cause neurodevelopmental impairments and can now be identified by state-mandated newborn screening programs using tandem mass spectrometry. During the initial 45 months of newborn screening for MBADD in Wisconsin, 23 cases have been detected, all in infants of Hmong descent. Though procedures are in place for routine newborn screening for SBCADD, neither the natural history of this deficiency nor the utility of early l-carnitine treatment and dietary intervention are known. The proposed project has three specific aims: (1) To analyze newborn screening data from 4/2001-3/2009 to: (a) estimate the prevalence of SBCADD in Hmong and other infants in Wisconsin, (b) describe the distribution of C5-acylcarnitine concentrations in newborn blood specimens, and (c) conduct molecular studies to evaluate the existence of a common SBCADD mutation in this population and to evaluate the current newborn screening cut-off value for detecting this disorder; (2) To test the hypothesis that SBCADD is a benign mutation in the Hmong- American population by conducting observational studies of neurodevelopmental and functional outcomes using three designs: (a) a prospective cohort study of cases identified by newborn screening and matched controls, (b) a cross-sectional study of SBCADD and its outcomes in family members of the infants enrolled in the prospective cohort study, and (c) a correlational analysis to test the hypothesis that persistent C5- acycarnitine blood levels are predictive of adverse developmental outcomes; and (3) To conduct exploratory studies to identify factors associated with adverse outcomes of SBCADD, if such outcomes are observed; potential factors to be examined include diet, triggering events such as illnesses, vaccinations, stress and fasting episodes, and molecular variations and potential gene-environment interactions. The public health significance of this work is that the findings will provide critical information needed to evaluate newborn screening thresholds and policies. The findings may also prompt future studies of the efficacy of early treatment and dietary restriction to prevent developmental disabilities in children with SBCADD.