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

Abstract

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.

• Authors: 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
• Journal: Genetics in medicine : official journal of the American College of Medical Genetics (Genet Med) Vol. 9 Issue 2 Pg. 108-16 (Feb 2007) ISSN: 1098-3600 [Print] United States
• PMID: 17304052 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• acylcarnitine
• Acyl-CoA Dehydrogenases
• Oxidoreductases Acting on CH-CH Group Donors
• ACAD8 protein, human
• 2-methylacyl-CoA dehydrogenase
• Carnitine

Topics

• Acyl-CoA Dehydrogenases (genetics)
• Algorithms
• Carnitine (analogs & derivatives, blood, urine)
• Diagnosis, Differential
• Genetic Testing (methods)
• Humans
• Infant, Newborn
• Oxidoreductases Acting on CH-CH Group Donors (deficiency, genetics)
• United States