title: Development of a newborn screening follow-up algorithm for the diagnosis of isobutyryl-CoA dehydrogenase deficiency.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Devin
authors.initials: D
authors.lastname: Oglesbee
authors.forename: Miao
authors.initials: M
authors.lastname: He
authors.forename: Nilanjana
authors.initials: N
authors.lastname: Majumder
authors.forename: Jerry
authors.initials: J
authors.lastname: Vockley
authors.forename: Ayesha
authors.initials: A
authors.lastname: Ahmad
authors.forename: Brad
authors.initials: B
authors.lastname: Angle
authors.forename: Barbara
authors.initials: B
authors.lastname: Burton
authors.forename: Joel
authors.initials: J
authors.lastname: Charrow
authors.forename: Regina
authors.initials: R
authors.lastname: Ensenauer
authors.forename: Can H
authors.initials: CH
authors.lastname: Ficicioglu
authors.forename: Laura Davis
authors.initials: LD
authors.lastname: Keppen
authors.forename: Deborah
authors.initials: D
authors.lastname: Marsden
authors.forename: Silvia
authors.initials: S
authors.lastname: Tortorelli
authors.forename: Si Houn
authors.initials: SH
authors.lastname: Hahn
authors.forename: Dietrich
authors.initials: D
authors.lastname: Matern
mesh_terms: D044944:Acyl-CoA Dehydrogenases / Q000235:genetics; D000465:Algorithms; D002331:Carnitine / Q000031:analogs & derivatives / Q000097:blood / Q000652:urine; D003937:Diagnosis, Differential; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D007231:Infant, Newborn; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000172:deficiency* / Q000235:genetics*; D014481:United States
chemical_list: C116917:acylcarnitine; D044944:Acyl-CoA Dehydrogenases; D044925:Oxidoreductases Acting on CH-CH Group Donors; C122081:ACAD8 protein, human; C038808:2-methylacyl-CoA dehydrogenase; D002331:Carnitine