Isobutyryl-CoA Dehydrogenase Deficiency

Background

Isobutyryl-CoA Dehydrogenase (IBDH) is an enzyme involved in the metabolism of Valine, a branched-chain amino acid. Deficiency of IBDH was recently described and only a few patients have been identified. The gene for IBDH (ACAD8), located on chromosome 9, has been cloned and mutations have been identified in several patients.

Clinical

The clinical features of IBDH deficiency are poorly defined and may have a highly variable presentation. The first patient described with this disease had failure to thrive and developed dilated cardiomyopathy associated with anemia at 11 months of age. Plasma carnitine levels were profoundly decreased. Several other patients have been identified by newborn screening and appear “asymptomatic”. Long-term clinical follow-up, however, is lacking and the true clinical spectrum of the disease is yet to be determined.

Testing

Newborns can be screened for IBDH deficiency using tandem mass spectrometry analysis of a dried blood spot. The finding of elevated 4-carbon acylcarnitine (C4) indicates either IBDH deficiency or short-chain acyl-CoA dehydrogenase deficiency. C4-acylcarnitine may also be seen in Multiple Acyl-CoA Dehydrogenase Deficiency (MADD), but this is usually accompanied by other acylcarnitine metabolites. To differentiate and make a diagnosis of IBDH deficiency, further testing with urine organic acid analysis is required. Urine from a patient suspected of IBDH deficiency may reveal an elevation of isobutyrylglycine or be normal, whereas patients with Short-Chain Acyl-CoA Dehydrogenase deficiency (SCAD) excrete ethylmalonic acid. Plasma free carnitine levels may be low. Identification of mutations in the ACAD8 gene should permit genetic counseling and prenatal diagnosis.

Treatment

The proper treatment of IBDH deficiency is not yet established, because of the wide variation in clinical phenotype and lack of long-term follow-up. Asymptomatic patients may not require specific treatment, whereas those patients who are symptomatic and have low plasma carnitine may benefit from carnitine supplementation.

Because the diagnosis of IBDH deficiency is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

Inheritance

This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.

References

Koeberl DD, Young SP, Gregersen NS, et al. Rare disorders of metabolism with elevated butyryl- and isobutyryl-carnitine detected by tandem mass spectrometry newborn screening. Pediatr Res 54:219-23, 2003.

Nguyen TV, Andresen BS, Corydon TJ, et al. Identification of isobutyryl-CoA dehydrogenase and its deficiency in humans. Mol Genet Metab 77:68-79, 2002.

Roe CR, Cederbaum SD, Roe DS, et al. Isolated isobutyryl-CoA dehydrogenase deficiency: an unrecognized defect in human valine metabolism. Mol Genet Metab 65:264-271, 1998.

Sass JO, Sander S, Zschocke J. Isobutyryl-CoA dehydrogenase deficiency: isobutyrylglycinuria and ACAD8 gene mutations in two infants. J Inherit Metab Dis 27:741-745, 2004.

Web Sites

SaveBabies.org
Site established and maintained by parents of newborns affected with a rare genetic defect, with information for parents and professionals and links to other informative sites.

National Newborn Screening and Genetics Resource Center
Provides information and resources in the area of newborn screening and genetics to benefit health professionals, the public health community, consumers and government officials.

Disclaimers
The analyses conducted by PerkinElmer Genetics produce results that can be used by qualified physicians in the diagnosis of disorders described herein. Evidence of these conditions will be detected in the vast majority of affected individuals; however, due to genetic variability, age of the patient at the time of specimen collection, quality of the specimen, health status of the patient, and other variables, such conditions may not be detected in all affected patients. PerkinElmer Genetics makes no warranty whatsoever, express or implied, including any warranty as to accuracy, completeness or timeliness, concerning the information contained herein, and you should not assume that such information is complete or the most up-to-date information available. PerkinElmer Genetics shall not be liable for any loss, claim or damages caused in whole or in part by our provision of, or your use of, any of the information contained herein. As a general statement, this information was drawn from published literature and is not drawn from our patient population or screening experience. The information contained herein is not intended to be a substitute for professional medical advice and should not be used for the diagnosis or treatment of any medical condition. A licensed physician should be consulted for diagnosis and treatment of any and all medical conditions.

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