Isovaleric Acidemia is a hereditary metabolic disorder. It is characterized by a deficiency of the enzyme isovaleryl CoA dehydrogenase. The disorder occurs in both an acute and a chronic intermittent form. In the acute form of Isovaleric Acidemia, vomiting, refusal to eat, and listlessness usually occur. With treatment and low protein diet, the disorder becomes chronically intermittent, and a nearly normal life is possible.
Isovaleric Acidemia is a rare metabolic disorder that occurs in an acute and a chronic intermittent form. The disorder may start any time between the first week of life and adolescence. It is characterized by attacks of vomiting, lack of appetite and listlessness. Infants with Isovaleric Acidemia become increasingly listless, and they sometimes shake or tremble. They often have a lower than normal body temperature (hypothermia). In most cases, a strong odor like that of “sweaty feet” occurs. Intermittent episodes are usually triggered by upper respiratory infections or excessive eating of high protein foods. Severe acidity and the presence of ketone bodies in blood and body tissues (ketoacidosis) usually follows and patients may lapse into a coma.
Ketoacidotic episodes tend to occur frequently in early infancy and young childhood, but their frequency usually diminishes as the patient grows older. Children with Isovaleric Acidemia often show a natural aversion to protein foods, even at a young age.
Isovaleric Acidemia is a genetic disorder inherited through autosomal recessive genes. Symptoms are the result of a deficiency of the enzyme isovaleric co-enzyme A (CoA) dehydrogenase, which is needed for the breakdown of the amino acid leucine. Human traits, including the classic genetic diseases, are the product of the interaction of two genes for that condition, one received from the father and one from the mother. In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but generally will not show symptoms of the disorder. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. On average, fifty percent of their children will be carriers of the disease, while 25 percent will receive a normal copy of the gene from each parent for that trait. The risks are the same for each pregnancy.
Isovaleric Acidemia is a rare disorder affecting males and females in equal numbers, usually beginning during infancy.
In some cases, Isovaleric Acidemia may be diagnosed before birth (prenatally) by measuring the concentration of abnormal metabolites in amniotic fluid or the activity of the isovaleryl-CoA dehydrogenase enzyme in fluid or tissue samples obtained from the fetus or uterus during pregnancy (amniocentesis or chorionic villus sampling [CVS]. During amniocentesis, a sample of fluid surrounding the developing fetus is removed and analyzed. CVS involves the removal and examination of tissue from a portion of the placenta. The disorder can be identified at birth through expanded newborn screening with tandem mass spectrometry.
In most affected infants, the disorder is diagnosed or confirmed in the first weeks of life, based upon a thorough clinical evaluation, a detailed patient and family history, and a variety of specialized tests. Laboratory studies (assays) are typically conducted on certain white blood cells (leukocytes) or cultured skin cells (fibroblasts) to confirm deficient activity of the isovaleryl-CoA dehydrogenase enzyme. Additional laboratory studies may reveal excessive levels of acids and increased accumulations of ketone bodies in bodily tissues and fluids (ketoacidosis); increased levels of glycine in the blood and urine (hyperglycinemia and hyperglycinuria); high levels of ammonia in the blood (hyperammonemia); and/or decreased levels of circulating platelets and white blood cells (thrombocytopenia and neutropenia).
The disorder is treated by a diet with moderate restriction of the amino acid leucine and supplementation of L-carnitine. Administration of glycine at 150-300 mg/day is life-saving and may permit normal growth and development. Other treatment is symptomatic and supportive. Genetic counseling is recommended for families of children with Isovaleric Acidemia.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
Sweetman L, Williams JD. Branched chain organic acidurias in The Metabolic and Molecular Basis of Inherited Disease. Scriver C, Beaudet AL, Sly W, Valle D, eds. (McGraw-Hill, New York, 2001), pp. 2125-64.
Mohsen A-W, Vockley J. Biochemical characteristics of recombinant human isovaleryl-CoA dehydrogenase pre-treated with ethylenediaminetetraacetate in Flabins and Flavoproteins. Rudolf Weber, New York, 1999: 515-18.
Vockley J, Rogan PK, Anderson BD, et al. Exon skipping in IVD RNA processing in isovaleric academia caused by point mutations in the coding region of the IVD gene. Am J Hum Genet. 2000;66:356-67.
Mohsen AW, Anderson BD, Volchenboum SL, et al. Characterization of molecular defects in isovaleryl-CoA dehydrogenase in patients with isovaleric academia. Biochemistry. 1998;37:10325-35.
Vockley J, Parimoo B, Tanaka K. Molecular characterization of four different classes of mutations in the isovaleryl-CoA dehydrogenase gene responsible for isovaleric academia. Am J Hum Genet. 1991;40:147-57.
de Sousa C, Chalmers RA, Stacey TE, Tracey BM, Weaver CM, Bradley D.. The response to L-carnitine and glycine therapy in isovaleric acidaemia. Eur J Ped. 1986;144:451-56.
Hine DG, Hack AM, Goodman SI, Tanaka K. Stable isotope dilution analysis of isovalerylglycine in amniotic fluid and urine and its application for the prenatal diagnosis of isovaleric academia. Pediatr Res. 1986;20:222-26.
Hine DG, Tanaka K. The identification and the excretion pattern of isovaleryl glucuronide in the urine of patients with isovaleric academia. Pediatr Res. 1984;18:508-12.
Budd MA, Tanaka K, Holmes LB, Efron ML, Crawford JD, Isselbacher KJ. Isovaleric academia: clinical features of a new genetic defect of leucine metabolism. N Engl J Med. 1967;277:321-27.
FROM THE INTERNET
McKusick VA, ed. Online Mendelian Inehritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 243500; Last Update: 4/10/2000.
The information in NORD’s Rare Disease Database is for educational purposes only and is not intended to replace the advice of a physician or other qualified medical professional.
The content of the website and databases of the National Organization for Rare Disorders (NORD) is copyrighted and may not be reproduced, copied, downloaded or disseminated, in any way, for any commercial or public purpose, without prior written authorization and approval from NORD. Individuals may print one hard copy of an individual disease for personal use, provided that content is unmodified and includes NORD’s copyright.
National Organization for Rare Disorders (NORD)
55 Kenosia Ave., Danbury CT 06810 • (203)744-0100