Multiple Acyl-CoA Dehydrogenase Deficiency

Background

Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) is also known as Glutaric Acidemia Type II (GA-II). It is associated with deficiency of several mitochondrial dehydrogenase enzymes that utilize Flavin Adenine Dinucleotide (FAD) as cofactor, at least 9 of which are known. These include the acyl-CoA dehydrogenases of fatty acid ß-oxidation, and enzymes that degrade glutaric acid, isovaleric acid, and sarcosine (a precursor to glycine). During these dehydrogenation reactions, reduced FAD contributes its electrons to the oxidized form of Electron Transfer Flavoprotein (ETF) and subsequently to the respiratory chain to produce ATP. The reduced form of ETF is recycled to oxidized ETF by action of ETF- ubiquinone oxidoreductase (ETF-QO, also known as ETF dehydrogenase). Deficiency of ETF or ETF-QO therefore results in decreased activity of many FAD-dependent dehydrogenases and the combined metabolic derangements seen in MADD. Some MADD patients have had normal ETF and ETF-QO, suggesting the existence of genetic defects in other unidentified proteins.

Clinical

Three clinical presentations are reported for MADD. Two newborn presentations are seen – one with congenital anomalies, and one without. Those with congenital anomalies are often premature, and develop symptoms in the first 24–48 hours consisting of hypotonia, hepatomegaly, severe nonketotic hypoglycemia, metabolic acidosis and variable body odor of sweaty feet. Dysmorphic facial features and dysplastic, cystic kidneys are present. Plasma carnitine levels are low. Those patients with no congenital anomalies have similar symptoms and metabolic abnormalities. With both neonatal presentations, most patients do not live past a few weeks, though some older survivors succumb at a few months of age from hypertrophic cardiomyopathy. Heart, liver and kidneys are infiltrated with fat. The third cohort of patients has a mild and/or later onset with variable symptoms including lipid storage myopathy.

Testing

Newborn screening using a dried blood spot has identified MADD patients by detecting elevated acylcarnitine (C4, C5, C8, C10, and C16). Severe hypoglycemia without ketosis is a cardinal finding. Analysis of the urine for abnormal organic acids in a suspected patient usually reveals elevated glutaric acid, and always shows elevated 2-hydroxyglutaric acid which is pathognomonic. Plasma and urine sarcosine levels are elevated in the milder patients, but not in the severe neonatal cases. Cultured fibroblasts and amniocytes have been used to measure dehydrogenase substrate oxidation. Mutations have been identified in the genes for ETF and ETF-QO. Prenatal diagnosis has been performed by finding elevated glutaric acid and elevated acylcarnitines in amniotic fluid. Prenatal diagnosis by DNA analysis is restricted to those families in which the mutation(s) is known.

Treatment

There is no effective treatment for the severe forms of MADD that present in the neonatal period. Patients with later onset less severe symptoms may respond to riboflavin (a precursor to FAD) and L-carnitine supplementation. Dietary restriction of fats and protein has had variable results.

Because the diagnosis and therapy of MADD 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

Frerman, F.E. and Goodman, S.I. Defects of Electron Transfer Flavoprotein and Electron Transfer Flavoprotein-Ubiquinone Oxidoreductase. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill. Chapter 103, pg. 2357 - 2365.

Goodman, S.I., Reale, M. and Berlow, S. Glutaric acidemia type II: A form with deleterious intrauterine effects. J Pediatrics 102:411, 1983.

Goodman, S.I., Stene, D.O., McCabe, E.R.B, et al. Glutaric aciduria type II: Clinical, biochemical and morphologic considerations. J Pediatrics 100:946, 1982.

Harpey, J.P., Charpentier, C., Goodman, S.I., et al. Multiple acyl-CoA dehydrogenase deficiency occurring in pregnancy and caused by a defect in riboflavin metabolism in the mother. J Pediatrics 103:394, 1983.

Mitchell, G., Saudubray, J.M., Gubler, M.C., et al. Congenital anomalies in Glutaric aciduria type 2. J Pediatrics 104:961, 1984.

Stockler, S., Radner, H., Felizitas, K., et al. Symmetric hypoplasia of the temporal cerebral lobes in an infant with Glutaric aciduria type II (multiple acyl-CoA dehydrogenase deficiency). J Pediatrics 124:601, 1994.

Sweetman, L., Nyhan, W.L., Trauner, D.A., et al. Glutaric aciduria type II. J Pediatrics 96:1020, 1980. 

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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