| Background Isovaleric Acidemia results from a defect in the metabolism of the amino acid, Leucine. The first patient with Isovaleric Acidemia was described in 1966 and the deficiency of Isovaleryl-CoA Dehydrogenase activity was found a few years later. Isovaleryl-CoA Dehydrogenase functions in the inner mitochondrial matrix. The gene is located on chromosome 15.
Clinical
Isovaleryl-CoA Dehydrogenase deficiency has two general presentations. The first occurs within days or weeks of life as an acute, overwhelming illness with vomiting and ketoacidosis progressing to lethargy, coma and death in greater than 50% of the patients. Other laboratory findings include variable hyperammonemia, hypocalcemia, neutropenia, thrombocytopenia, and pancytopenia. A second cohort has onset later in the first year of life or after. These patients develop chronic, intermittent illnesses brought on by infection or a large protein intake. Laboratory findings will be as noted above, but perhaps not so severe. Both groups are susceptible to infection. The patient commonly has a distinctive odor of “sweaty feet” during an illness because of the volatile isovaleric acid that accumulates.
Testing
Newborns can be screened for Isovaleric Acidemia using tandem mass spectrometry analysis of a heel-stick dried blood spot specimen. The finding of elevated five-carbon acylcarnitine (C5) indicates either Isovaleryl-CoA Dehydrogenase deficiency or 2-MethylButyryl-CoA Dehydrogenase deficiency. To differentiate the two diseases, further testing is required. Urine organic acid analysis of a patient with Isovaleric Acidemia will reveal an elevation of isovalerylglycine with lesser elevation of 3-hydroxyisovaleric acid. The odiferous Isovalerate is found in a urine specimen only during acute illness when its levels are significant. Due to its volatility (thus producing the odor), it is lost prior to and during specimen preparation for urine organic acid determination. In contrast, patients with 2-MethylButyryl-CoA Dehydrogenase deficiency have 2-methylbutyrate and 2-methylbutyrylglycine in their urine. Prenatal diagnosis is possible by measuring isovalerylglycine in amniotic fluid and by measuring isovaleryl-CoA dehydrogenase enzyme activity in chorionic villus specimens or cultured amniocytes. The activity can also be measured in fibroblasts and leukocytes.
Treatment
Treatment of patients with Isovaleric Acidemia involves reducing protein intake, particularly the branched-chain amino acid Leucine. During an acute episode, aggressive use of glucose and electrolytes is necessary. Glycine supplementation has proven beneficial because this amino acid is conjugated to isovalerate, forming the less harmful isovalerylglycine. Carnitine treatment is similarly effective. Strict dietary control and aggressive treatment have resulted in normal development in some patients. However, many patients with Isovaleric Acidemia show neurologic abnormalities from acute illness. Because the diagnosis and therapy of Isovaleric Acidemia is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist and dietician. 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
Fries, M.H., Rinaldo, P., Schmidt-Sommerfeld, E., et al. Isovaleric acidemia: Response to a Leucine load after three weeks of supplementation with Glycine, L-carnitine and combined glycine-carnitine therapy. J Pediatrics 129:449, 1998. Millington, D.S., Roe, C.R., Maltby, D.A., et al. Endogenous catabolism is the major source of toxic metabolites in isovaleric acidemia. J Pediatrics 110:56, 1987. Roe, C.R., Millington, D.S., Maltby, D.A., et al. L-Carnitine therapy in isovaleric acidemia. J Clinical Investigation 74:2290, 1984. 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, pgs. 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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