Epidemiology of SBCAD Deficiency in Hmong-Americans

描述(由申请人提供)： 该项目的总体目标是调查威斯康星州苗族美国人中2-甲基丁酰-辅酶A脱氢酶缺乏症(SBCADD)的患病率、自然病史、生化和分子特征。SBCADD是一种罕见的先天性异亮氨酸代谢错误，可能会导致神经发育障碍，现在可以通过使用串联质谱仪的国家强制新生儿筛查计划来识别。在威斯康星州最初45个月的新生儿MBADD筛查期间，发现了23例，均为苗族血统的婴儿。尽管SBCADD的常规新生儿筛查程序已经到位，但这种缺陷的自然病史和早期L-卡尼汀治疗和饮食干预的有效性都不清楚。拟议的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：(A)估计SBCADD在苗族和威斯康星州其他婴儿中的患病率，(B)描述C5-酰肉碱在新生儿血液样本中的浓度分布，以及(C)进行分子研究，以评估在这些人群中是否存在共同的SBCADD突变，并评估目前检测这种疾病的新生儿筛查截止值；(2)通过使用三种设计对神经发育和功能结果进行观察性研究，以检验SBCADD是苗族美国人中良性突变的假设：(A)对新生儿筛查和匹配对照确定的病例进行前瞻性队列研究，(B)对在前瞻性队列研究中登记的婴儿的家庭成员进行SBCADD及其结果的横断面研究，以及(C)进行相关性分析，以检验持续的C5-Acycarnitine血液水平预测不利的发育结果的假设；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；要检查的潜在因素包括饮食、引发疾病的事件、疫苗接种、压力和禁食发作、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。这一发现还可能促使未来研究早期治疗和饮食限制对预防SBCADD儿童发育障碍的效果。

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.