3-Methylglutaconyl-CoA Hydratase Deficiency

Background

3-Methyl Glutaconyl-CoA Hydratase is an enzyme involved in the metabolism of the amino acid Leucine. It is located in mitochondria along with other associated enzymes of leucine catabolism. Deficiency of the enzyme leads to impaired leucine breakdown and massive excretion of 3-methylglutaconic acid. The gene has been cloned and some mutations identified in affected patients.

Clinical

Few patients have been described with this disorder, but the disease seems to have a wide range of clinical severity. Some patients develop acute life-threatening cardiopulmonary symptoms soon after birth, whereas others have a more chronic picture with psychomotor retardation, hypotonia, failure to thrive, microcephaly, seizures, and spasticity. Some patients have acute episodes of vomiting, metabolic acidosis and lethargy progressing to coma. Carnitine levels are variably low. Recurrent acidosis is occasionally seen with prolonged fasting and/or intercurrent illness. Speech retardation was the isolated neurological manifestation in one family.

Testing

Newborn screening for this disorder can be performed on a dried blood spot by tandem mass spectrometry. Infants with this disorder have increased C5-hydroxy acylcarnitine (C5-OH). This finding, however, is not specific to 3-Methyl Glutaconyl-CoA Hydratase Deficiency and the diagnosis requires additional testing. Urinary organic acid analysis reveals elevations of 3-methylglutaconate and 3-hydroxyisovalerate. The diagnosis can be confirmed with measurement of hydratase enzyme activity in lymphocytes or fibroblasts. Measurement of metabolites in amniotic fluid or enzyme assay of amniocytes may be useful for prenatal diagnosis. Knowledge of gene mutations in a family offers the potential for reliable prenatal diagnosis.

Treatment

Treatment of 3-Methylglutaconyl-CoA Hydratase Deficiency involves reducing protein intake, particularly the branched-chain amino acid Leucine. Carnitine supplementation may be indicated. Prolonged fasting should be avoided, because it can exacerbate the abnormal biochemical findings.

Because the diagnosis and therapy of 3-Methylglutaconyl-CoA Hydratase 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

IJlst L, Loupatty FJ, Ruiter JP, et al. 3-Methylglutaconic aciduria type I is caused by mutations in AUH. Am J Hum Genet. 71:1463, 2002.

Ly TB, Peters V, Gibson KM, et al. Mutations in the AUH gene cause 3-methylglutaconic aciduria type I. Hum Mutat. 21:401, 2003.

Sweetman, L. and Williams, J.C. Branched Chain Organic Acidurias. In: The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al., ed., McGraw-Hill.

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.

This information is copyrighted and is only for your personal, non-commercial use, provided that all copyright and other proprietary notices are retained on any copies made of it. The information may not be modified in any way or reproduced or distributed or used for any public or commercial purpose unless expressly permitted. Any use or display of the enclosed information for any purpose is prohibited.