Development of a newborn screening follow-up algorithm for the diagnosis of isobutyryl-CoA dehydrogenase deficiency.
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.
Oglesbee
Devin
D
Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
He
Miao
M
Majumder
Nilanjana
N
Vockley
Jerry
J
Ahmad
Ayesha
A
Angle
Brad
B
Burton
Barbara
B
Charrow
Joel
J
Ensenauer
Regina
R
Ficicioglu
Can H
CH
Keppen
Laura Davis
LD
Marsden
Deborah
D
Tortorelli
Silvia
S
Hahn
Si Houn
SH
Matern
Dietrich
D
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
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