Development of a newborn screening follow-up algorithm for the diagnosis of isobutyryl-CoA dehydrogenase deficiency

Devin Oglesbee, Miao He, Nilanjana Majumder, Jerry Vockley, Ayesha Ahmad, Brad Angle, Barbara Burton, Joel Charrow, Regina Ensenauer, Can H. Ficicioglu, Laura Davis Keppen, Deborah Marsden, Silvia Tortorelli, Si Houn Hahn, Dietrich Matern

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


PURPOSE: Isobutyryl-CoA dehydrogenase deficiency is a defect in valine metabolism and was first reported in a child with cardiomyopathy, anemia, and secondary carnitine deficiency. We identified 13 isobutyryl-CoA dehydrogenase-deficient patients through newborn screening due to an elevation of C4-acylcarnitine in dried blood spots. Because C4-acylcarnitine represents both isobutyryl- and butyrylcarnitine, elevations are not specific for isobutyryl-CoA dehydrogenase deficiency but are also observed in short-chain acyl-CoA dehydrogenase deficiency. To delineate the correct diagnosis, we have developed a follow-up algorithm for abnormal C4-acylcarnitine newborn screening results based on the comparison of biomarkers for both conditions. METHODS: Fibroblast cultures were established from infants with C4-acylcarnitine elevations, and the analysis of in vitro acylcarnitine profiles provided confirmation of either isobutyryl-CoA dehydrogenase or short-chain acyl-CoA dehydrogenase deficiency. Isobutyryl-CoA dehydrogenase deficiency was further confirmed by molecular genetic analysis of the gene encoding isobutyryl-CoA dehydrogenase (ACAD8). Plasma acylcarnitines, urine acylglycines, organic acids, and urine acylcarnitine results were compared between isobutyryl-CoA dehydrogenase- and short-chain acyl-CoA dehydrogenase-deficient patients. RESULTS: Quantification of C4-acylcarnitine in plasma and urine as well as ethylmalonic acid in urine allows the differentiation of isobutyryl-CoA dehydrogenase-deficient from short-chain acyl-CoA dehydrogenase-deficient cases. In nine unrelated patients with isobutyryl-CoA dehydrogenase deficiency, 10 missense mutations were identified in ACAD8. To date, 10 of the 13 isobutyryl-CoA dehydrogenase-deficient patients remain asymptomatic, two were lost to follow-up, and one patient required frequent hospitalizations due to emesis and dehydration but is developing normally at 5 years of age. CONCLUSION: Although the natural history of isobutyryl-CoA dehydrogenase deficiency must be further defined, we have developed an algorithm for rapid laboratory evaluation of neonates with an isolated elevation of C4-acylcarnitine identified through newborn screening.

Original languageEnglish (US)
Pages (from-to)108-116
Number of pages9
JournalGenetics in Medicine
Issue number2
StatePublished - Feb 2007


  • ACAD8
  • Acylcarnitine analysis
  • Isobutyryl-CoA dehydrogenase deficiency
  • Newborn screening
  • Tandem mass spectrometry

ASJC Scopus subject areas

  • Genetics(clinical)


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