We're celebrating
40 years!
Last updated:
October 02, 2020
Years published: 1988, 1989, 2002, 2007, 2020
NORD gratefully acknowledges Sukhdeep Jatana, MDCM Candidate, McGill University School of Medicine, and Jerry Vockley, MD, PhD, Cleveland Family Endowed Chair in Pediatric Research and Professor of Human Genetics, University of Pittsburgh; Chief of Medical Genetics and Director of the Center for Rare Disease Therapy, UPMC Children’s Hospital of Pittsburgh, for assistance in the preparation of this report.
Summary
Isovaleric acidemia is a hereditary metabolic disorder, caused by a change (mutation) in the gene encoding the enzyme isovaleryl-CoA dehydrogenase, resulting in deficient or absent activity. This enzyme is responsible for helping break down leucine, an amino acid, and its deficiency leads to a buildup of chemicals in the blood that cause symptoms. The disorder can present with acute intermittent attacks in infancy or later in childhood. The acute attacks are characterized by vomiting, refusal to eat, listlessness, abnormal lab values, and a sweaty foot odor. Chronic symptoms include failure to thrive and developmental delay. Management for this disease includes a low protein diet with leucine restriction, avoiding triggers of acute attacks, and supplementation with carnitine and/or glycine. Though there is no cure, but as patients age, acute attacks become less frequent.
Isovaleric acidemia is a rare metabolic disorder that ranges in severity from asymptomatic to mild or life-threatening symptoms depending on the mutation and factors predisposing acute attacks. Two major clinical scenarios are often described, an acute form and a chronic intermittent form, but in reality the disease is best thought of as a continuous spectrum from asymptomatic to life threatening. A characteristic ‘sweaty feet’ odor is often present in patient sweat or cerumen due to a buildup of isovaleric acid. Patients may develop aversion early to protein-rich foods.
Acute, early symptoms present soon after birth with increasing lethargy, poor feeding and vomiting, progressing to coma. These findings are related to chemical imbalances in the baby including an increase in acid, ammonia, and specific toxic compounds derived from isovaleric acid. Prolonged metabolic stress can lead to low levels of certain types of white blood cells (neutropenia) and other cell types (pancytopenia). Patients may also present with lowered body temperature (hypothermia). After resolution of this first attack, patients typically show the chronic intermittent form of the disease unless severe neurologic damage has occurred due to the original presentation.
After the newborn period chronic intermittent symptoms are usual. Patients can have slowed growth rates (failure to thrive), developmental delay, intellectual disability or symptoms affecting the nervous system such as seizures and spasticity, most commonly related to early acute damage. Patients can also experience acute attacks similar to the newborn period, typically triggered by other illnesses such as infections. Patients can exhibit a chronic picture even if a newborn acute attack has not occurred. Recognition of acute neonatal symptoms has led to newborn screening for isovaleric acidemia in the United States and many other developed studies. If identified prior to the development of symptoms, outcomes are generally better, with normal growth and development. About half of babies identified through newborn screening have a very mild deficiency that remains asymptomatic and requires no therapy.
Isovaleric acidemia is a genetic disorder inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
In patients with isovaleric acidemia, there is a mutation in the IVD gene that inactivates the enzyme isovaleryl-Co-enzyme A (CoA) dehydrogenase. This enzyme is needed for the breakdown of the amino acid leucine into energy.
Isovaleric acidemia is a rare disorder that presents either soon after birth or during infancy. It may present up to adolescence. It affects an equal number of males and females. The prevalence of this condition is 1 per 526,000 in Western populations and the incidence is 1 per 250,000 in the US.
In the United States and some developed countries, isovaleric acidemia is routinely identified by newborn screening through a blood test called tandem mass spectrometry, often designated as MS/MS. In other countries, the diagnosis must be suspected clinically before it can be diagnosed. Laboratory studies that can be useful in symptomatic patients include checking for high levels of acid and ketones (ketoacidosis) in blood, high levels of glycine in the blood or urine (hyperglycinemia and hyperglycinuria), high levels of ammonia (hyperammonemia), or low levels of certain white blood cells (neutropenia), platelets (thrombocytopenia) or all blood cell types (pancytopenia). The diagnosis is then confirmed by DNA testing. Less commonly, certain types of cells from the body (white blood cells, skin cells) may be sampled from the patient and tested to confirm decreased or deficient activity of the enzyme isovaleryl-CoA dehydrogenase.
In families in whom a previous child has been affected, isovaleric acidemia can be diagnosed before birth (prenatally) by measuring the concentration of abnormal metabolites in amniotic fluid, 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], or testing of fetal tissue or amniocytes for a DNA changes (mutations) identified in the first child
Treatment
While there is no cure of isovaleric acidemia, outcome is usually good if severe neonatal symptoms are avoided or treated rapidly. Patients should be followed regularly by a geneticist or metabolic physician familiar with management of organic acidemias. Frequency of follow-up is determined by the severity of the disease and the frequency of acute attacks. Patient should be monitored for growth, development, and dietary history. Additional testing should include blood acid levels, blood counts, and electrolytes. Additionally, physicians may monitor for complications and do examinations of the nervous system, liver, or other organs.
Supplementation with L-carnitine or glycine allows increased removal of acids form the blood by the kidney. Patients typically require a low protein diet to avoid overconsumption of the amino acid leucine. However, patients need enough protein in their diet to meet the body’s demands, which increase over time with growth. However, it may be impossible for patients with severe disease to eat enough natural protein to meet bodily requirements. In this case, use of medical foods that do not include leucine is necessary. A dietician should be available to also help families with creating a low-protein diet for the patient.
During acute attacks, protein should be reduced or withheld for 24 hours with a subsequent increase in low protein, high sugar foods to maintain calorie intake. If a patient cannot eat, hospitalization is required so that glucose can be provided by intravenous fluids. Other metabolic abnormalities such as high ammonia may need to be corrected depending on the individual patient’s clinical findings. A return to the patient’s standard diet can usually be achieved over the course of a few days.
Information on current clinical trials is posted on the Internet at https://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
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
TEXTBOOKS
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.
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: 2125-64.
Lo SF. Chapter 3 – Organic acid disorders in Biomarkers in Inborn Errors of Metabolism. Garg U, Smith LD, eds. Elsevier, Oxford, 2017: 65-85.
JOURNAL ARTICLES
Couce ML, Aldamiz-Echeverria L, Bueno MA, et al. Genotype and phenotype characterization in a Spanish cohort with isovaleric acidemia. J Hum Genet. 2017;62:355-360. https://pubmed.ncbi.nlm.nih.gov/27904153/.
Vockley J, Ensenauer R. Isovaleric Acidemia: New Aspects of Genetic and Phenotypic Heterogeneity. Am J Med Genet C Semin Med Genet. 2006;142C:95-103. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2652706/.
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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1288088/.
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. https://pubmed.ncbi.nlm.nih.gov/9665741/.
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. https://pubmed.ncbi.nlm.nih.gov/3956533/.
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 acidemia. Pediatr Res. 1986;20:222-26. https://pubmed.ncbi.nlm.nih.gov/3703611/.
Hine DG, Tanaka K. The identification and the excretion pattern of isovaleryl glucuronide in the urine of patients with isovaleric acidemia. Pediatr Res. 1984;18:508-12. https://pubmed.ncbi.nlm.nih.gov/6547525/.
Budd MA, Tanaka K, Holmes LB, Efron ML, Crawford JD, Isselbacher KJ. Isovaleric acidemia: clinical features of a new genetic defect of leucine metabolism. N Engl J Med. 1967;277:321-27. https://pubmed.ncbi.nlm.nih.gov/4378266/.
INTERNET
IVD gene. U.S. National Library of Medicine Genetics Home Reference. Updated August 4, 2020. https://ghr.nlm.nih.gov/gene/IVD. Accessed August 6, 2020.
Bodamer OA. Organic acidemias: An overview and specific defects. In: Post T, ed. UpToDate. Waltham, Mass. Updated January 19, 2020. https://www.uptodate.com/contents/organic-acidemias-an-overview-and-specific-defects#:~:text=Organic%20acidemias%2C%20also%20known%20as,of%20organic%20acids%20in%20urine. Accessed August 1, 2020.
Isovaleric acidemia. NIH Genetic and Rare Diseases Information Center. Updated August 1, 2020. https://rarediseases.info.nih.gov/diseases/465/isovaleric-acidemia#ref_3423. Accessed August 1, 2020.
Isovaleric acidemia (IVA). European registry and network for Intoxication type Metabolic Diseases. Updates 2018. https://www.e-imd.org/diseases/organic-acidurias-oads/isovaleric-acidemia-iva. Accessed August 1, 2020.
Isovaleric Acidemia – Acute Illness Protocol. New England Consortium of Metabolic Programs. Updated September 16, 2013. https://newenglandconsortium.org/for-professionals/acute-illness-materials/organic-acid-disorders/isovaleric-acidemia/. Accessed August 1, 2020.
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 243500; Updated July 12, 2012. https://omim.org/clinicalSynopsis/243500. Accessed August 1, 2020.
NORD strives to open new assistance programs as funding allows. If we don’t have a program for you now, please continue to check back with us.
NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.
Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.
Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.
Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/