Project Title: Epidemiology of SBCAD Deficiency in Hmong-Americans Principal Investigator: Maureen Durkin, PhD The overall goal of this project is to investigate the prevalence, natural history, and biochemical and molecular characteristics of 2-Methylbutyrl-CoA Dehydrogenase Deficiency or Short Branched Chain CoA Dehydrogenase Deficiency (SBCADD) in the Hmong-American population of Wisconsin. SBCADD is an 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 33 months of newborn screening for SBCADD in Wisconsin, 17 cases were detected, all in infants of Hmong decent. 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. This project has three specific aims: (1) To analyze newborn screening data from 4/2001-3/2008 to: (a) estimate the prevalence of SBCADD in Hmong-American and other infants in Wisconsin, (b) describe the distribution of C5-acylcarnitine concentrations in newborn blood specimens screening positive and negative for SBCADD, & (c) conduct molecular studies of SBCADD mutations in this population and evaluate the existence of a common mutation; (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 & its outcomes in family members of the infants enrolled in the prospective cohort study, & (c) a correlational analysis to test the hypothesis that variations in C5-acycarnitine concentrations in newborn blood specimens positive for SBCADD 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 findings will provide critical information for evaluating newborn screening thresholds and policies. They may also prompt future studies of the efficacy of early treatment and dietary restriction for SBCADD, and further molecular studies depending on whether the hypothesis of a common mutation is supported or refuted.

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