Background
3-Hydroxy-3-MethylGlutaryl-CoA (HMG-CoA) Lyase has a dual function in the breakdown of Leucine and in regulating production of ketone bodies. It is located predominantly in mitochondria, but is also found in peroxisomes. In the last step in Leucine metabolism, it cleaves 3-hydroxy-3-methylglutaryl-CoA, producing acetyl-CoA and acetoacetate, one of the ketone bodies. HMG-CoA Lyase Deficiency was first described in 1971 and more than 60 patients have subsequently been diagnosed.
Clinical HMG-CoA Lyase Deficiency typically presents within the first week of life, though some patients have onset later in the first year. The onset of symptoms is initiated by fasting, infection, dietary protein load, or simply the stress of birth. Symptoms progress from vomiting, lethargy, trachypnea and dehydration to coma and possibly death. Hepatomegaly and neurologic abnormalities are seen on physical exam. Laboratory studies reveal non-ketotic hypoglycemia, metabolic acidosis, hyperammonemia and elevated liver transaminases. Abnormal urine organic acids are present as well as the distinctive elevated plasma acylcarnitine species.
Testing Newborns can be screened for HMG-CoA Lyase Deficiency using tandem mass spectrometry analysis of a dried blood spot. The finding of elevated six-carbon dicarboxylic acylcarnitine (C6-DC) and C5-hydroxy acylcarnitine (C5-OH), suggests the metabolic defect. To make a diagnosis, further testing is required. Urine organic acid analysis of a patient with HMG-CoA Lyase Deficiency will reveal elevation of 3-hydroxy-3-methylglutaric, 3-methylglutaconic and 3-hydroxyisovaleric acids. A diagnosis should be confirmed by measurement of HMG-CoA Lyase enzyme activity in fibroblasts or leukocytes. Prenatal diagnosis is possible by measuring 3-hydroxy-3-methylglutaric acid in amniotic fluid and by assaying HMG-CoA Lyase enzyme activity in cultured amniocytes and chorionic villi cells. Mutations in the HMG-CoA Lyase gene on chromosome 1 have been identified in a number of patients and prenatal diagnosis can be accomplished using DNA analysis.
Treatment Acute symptoms of HMG-CoA Lyase Deficiency should be treated with IV glucose, bicarbonate for the metabolic acidosis and restriction of protein (Leucine). During an acute episode, patients may require assisted ventilation. For the long-term treatment, affected patients should avoid fasting and restrict protein intake.
Because the diagnosis and therapy of HMG-CoA Lyase 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 Duran, M., Schutgens, R.B.H., Ketel, A., et al. 3-Hydroxy-3-MethylGlutaryl-CoA Lyase deficiency: Postnatal management following prenatal diagnosis by analysis of maternal urine. J Pediatrics 95:1004, 1979. Mitchell, G. and Fukao, T. Inborn Errors of Ketone Body Metabolism. In: The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al., ed., McGraw-Hill. Chapter 102:2327-2356. Schutgens, R.B.H., Heymans, H., Ketel, A., et al. Lethal hypoglycemia in a child with a deficiency of 3-Hydroxy-3-MethylGlutaryl-CoA Lyase. J Pediatrics 94:89, 1979. 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. Chapter 93:2125-2163. 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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