Prevalence and mutation analysis of short/branched chain acyl-CoA dehydrogenase deficiency (SBCADD) detected on newborn screening in wisconsin

Sandra C. Van Calcar, Mei W. Baker, Phillip Williams, Susan A. Jones, Blia Xiong, Mai Choua Thao, Sheng Lee, Mai Khou Yang, Greg M. Rice, William Rhead, Jerry Vockley, Gary Hoffman, Maureen S. Durkin

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Short/branched chain acyl-CoA dehydrogenase deficiency (SBCADD), also called 2-methylbutyryl CoA dehydrogenase deficiency (2-MBCDD), is a disorder of l-isoleucine metabolism of uncertain clinical significance. SBCADD is inadvertently detected on expanded newborn screening by elevated 2-methylbutyrylcarnitine (C5), which has the same mass to charge (m/s) on tandem mass spectrometry (MS/MS) as isovalerylcarnitine (C5), an analyte that is elevated in isovaleric acidemia (IVA), a disorder in leucine metabolism. SBCADD cases identified in the Hmong-American population have been found in association with the c.1165 A>G mutation in the ACADSB gene. The purposes of this study were to: (a) estimate the prevalence of SBCADD and carrier frequency of the c.1165 A>G mutation in the Hmong ethnic group; (b) determine whether the c.1165 A>G mutation is common to all Hmong newborns screening positive for SBCADD; and (c) evaluate C5 acylcarnitine cut-off values to detect and distinguish between SBCADD and IVA diagnoses. During the first 10. years of expanded newborn screening using MS/MS in Wisconsin (2001-2011), 97 infants had elevated C5 values (≥. 0.44. μmol/L), of whom five were Caucasian infants confirmed to have IVA. Of the remaining 92 confirmed SBCADD cases, 90 were of Hmong descent. Mutation analysis was completed on an anonymous, random sample of newborn screening cards (n=1139) from Hmong infants. Fifteen infants, including nine who had screened positive for SBCADD based on a C5 acylcarnitine concentration ≥. 0.44. μmol/L, were homozygous for the c.1165 A>G mutation. This corresponds to a prevalence in this ethnic group of being homozygous for the mutation of 1.3% (95% confidence interval 0.8-2.2%) and of being heterozygous for the mutation of 21.8% (95% confidence interval 19.4-24.3%), which is consistent with the Hardy-Weinberg equilibrium. Detection of homozygous individuals who were not identified on newborn screening suggests that the C5 screening cut-off would need to be as low as 0.20. μmol/L to detect all infants homozygous for the ACADSB c.1165 A>G mutation. However, lowering the screening cut-off to 0.20 would also result in five "false positive" (non-homozygous) screening results in the Hmong population for every c.1165 A>G homozygote detected. Increasing the cut-off to 0.60. μmol/L and requiring elevated C5/C2 (acetylcarnitine) and C5/C3 (propionylcarnitine) ratios to flag a screen as abnormal would reduce the number of infants screening positive, but would still result in an estimated 5 infants with SBCADD per year who would require follow-up and additional biochemical testing to distinguish between SBCADD and IVA diagnoses. Further research is needed to determine the clinical outcomes of SBCADD detected on newborn screening and the c.1165 A>G mutation before knowing whether the optimal screening cut-off would minimize true positives or false negatives for SBCADD associated with this mutation.

Original languageEnglish (US)
Pages (from-to)111-115
Number of pages5
JournalMolecular Genetics and Metabolism
Volume110
Issue number1-2
DOIs
StatePublished - Sep 2013
Externally publishedYes

Keywords

  • 2-Methylbutyryl-CoA dehydrogenase deficiency
  • Expanded newborn screening
  • Inborn errors of metabolism
  • Isovaleric acidemia
  • Short/branched chain acyl-CoA dehydrogenase deficiency

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology

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