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 dehydrogenasedeficient patients through newborn screening due to an elevation of C 4 -acylcarnitine in dried blood spots. Because C 4 -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 C 4 -acylcarnitine newborn screening results based on the comparison of biomarkers for both conditions. Methods: Fibroblast cultures were established from infants with C 4 -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 C 4 -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 C 4 -acylcarnitine identified through newborn screening. Genet Med 2007:9(2):108-116.

Isobutyryl-CoA dehydrogenase deficiency with a novel ACAD8 gene mutation detected by tandem mass spectrometry newborn screening

“…Urinary organic acids did not show elevation of butyrylglycine or isobutyrylglycine. The patient was treated with carnitine which reversed the cardiomyopathy and development was normal (5,10).…”

Disorders of Leucine, Isoleucine, and Valine Metabolism

“…The original patient presented with anemia and dilated cardiomyopathy (Roe et al 1998 ). Thus far, at least 22 individuals have been described who are mostly asymptomatic, largely identifi ed via newborn screening (Koeberl et al 2003 ;Sass et al 2004 ;Oglesbee et al 2007 ).…”

Newborn screening: After the thrill is gone

“…She has remained well since. Of the additional patients whom we have had the opportunity to study (all identified through newborn screening), all but one have remained asymptomatic [22]. The symptomatic patient had recurrent episodes of emesis and dehydration with mild intercurrent illness accompanied by dramatic increase in the production of isobutyryl-CoA intermediates and their carnitine derivatives.…”

“…Given our then understanding of isovaleric acidemia it was logical to assume that the severe medical problems exhibited by both patients could be attributed to their enzymatic blocks. However, soon babies with both deficiencies began to be flagged through newborn screening and all was not as straightforward as one might hope [21,22].…”