Last updated:
1/26/2026
Years published: 1988, 1989, 2002, 2007, 2020, 2026
NORD gratefully acknowledges Jerry Vockley, MD, PhD, Cleveland Family Endowed Chair in Pediatric Research and Professor of Human Genetics, University of Pittsburgh and Chief of Genetic and Genomic Medicine 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 (called a variant) in a gene that provides instructions for making an enzyme called isovaleryl-CoA dehydrogenase. Because of this change, the enzyme does not work properly or may be missing altogether. This enzyme normally helps the body break down leucine, a building block of protein found in many foods. When the enzyme does not work, harmful substances build up in the blood and cause symptoms. The disorder can present with acute intermittent attacks in infancy or later in childhood. These sudden (acute) episodes can include vomiting, poor appetite or refusal to eat, extreme tiredness (listlessness), abnormal blood test results (lab values), and a strong odor described as smelling like sweaty feet. Chronic symptoms include failure to thrive (a child not growing or gaining weight as they should compared to their peers), and developmental delay. Management for this disease includes a carefully controlled low protein diet that limits foods high in leucine (leucine restriction), avoiding triggers of acute attacks, and supplementation (taking supplements) with carnitine and/or glycine. Though there is no cure, as a patient ages, acute attacks become less frequent.
Isovaleric acidemia is a rare metabolic disorder that ranges in severity from no symptoms (asymptomatic) to mild or life-threatening symptoms. How severe the condition is depends on the specific gene change (variant) and whether certain triggers can cause sudden episodes (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 noticed in sweat or earwax (cerumen) due to a buildup of isovaleric acid in the body. Patients may develop an aversion early to protein-rich foods.
Acute, early symptoms present soon after birth with increasing lethargy (sluggishness or drowsiness), poor appetite and/or feeding, and vomiting, progressing to coma. These symptoms are caused by dangerous chemical imbalances in the baby’s body, including too much acid, high ammonia levels, and other toxic substances derived from isovaleric acid. Ongoing (prolonged) stress on the body’s metabolism (metabolic stress) can also lower blood cell counts, including infection-fighting white blood cells (neutropenia) and other cell types (pancytopenia). Patients may also present with lowered body temperature (hypothermia). After resolution of this first attack, the patient typically shows the chronic intermittent form of the disease unless the initial illness caused serious damage to the brain or nervous system (severe neurologic damage).
After the newborn period, chronic intermittent symptoms are usual. Patients can have slowed growth rates (failure to thrive), developmental delay, learning difficulties (intellectual disability), or problems affecting the nervous system, such as seizures or muscle stiffness (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. Affected people can exhibit ongoing (chronic) symptoms later in life, even if they did not become seriously ill as newborns.
Because early symptoms in newborns (neonatal symptoms) are now better recognized, babies in the United States and many other countries are routinely screened for this condition with newborn screening. If isovaleric acidemia is 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 now identified by newborn screening in many countries. Follow-up testing by DNA sequencing can sometimes help doctors estimate how severe the condition may be (disease severity). Multiple mutations (gene variants) have been identified in the IVD gene causing isovaleric acidemia. A common c.932C>T (p.A282V) variant causes abnormal lab results (biochemical findings) but does not lead to symptoms or illness.
Isovaleric acidemia is a genetic disorder inherited in an autosomal recessive pattern, meaning a child must inherit a non-working copy of the gene from both parents to develop the condition.
If an individual receives one working and one non-working gene for the disease, the person will be a carrier but usually will not show symptoms.
The risk for two carrier parents to pass on the non-working gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier, like the parents, is 50% with each pregnancy. The chance that a child receives working genes from both parents is 25%. The risk is the same for males and females.
In patients with isovaleric acidemia, there is a variant in the IVD gene that prevents an enzyme called isovaleryl-Co-enzyme A (CoA) dehydrogenase from working properly. 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 person per 526,000 in Western populations, and the incidence is 1 person per 250,000 in the U.S.
In the United States and other developed countries, isovaleric acidemia is routinely identified by newborn screening via a blood test called tandem mass spectrometry (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 body cells (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 (variants or sometimes called mutations) identified in the first child.
Treatment
While there is no cure for isovaleric acidemia, the 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 the management of organic acidemias. Frequency of follow-up is determined by the severity of the disease and the frequency of acute attacks. The 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.
Supplements such as L-carnitine or glycine help the kidneys remove harmful acids from the blood. Patients typically require a carefully managed low-protein diet to avoid overconsumption of the amino acid leucine. However, patients need sufficient protein in their diet to meet the body’s increasing demands, which increase with growth. It might be impossible for patients with severe disease to eat enough natural protein to meet bodily requirements. In this case, the use of special medical formulas (medical foods) that do not include leucine is necessary. A dietician should be available also to 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 to provide glucose via intravenous fluids. Other metabolic abnormalities (chemical imbalances), such as high ammonia levels, may also need treatment. A return to the patient’s standard diet can usually be achieved over the course of a few days.
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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/.
Ensenauer, R., et al., A common mutation is associated with a mild, potentially asymptomatic phenotype in patients with isovaleric acidemia diagnosed by newborn screening. Am J Hum Genet, 2004. 75(6): p. 1136–42.
D’Annibale, O.M., et al., Characterization of variants of uncertain significance in isovaleryl-CoA dehydrogenase identified through newborn screening: An approach for faster analysis. Mol Genet Metab, 2021. 134(1-2): p. 29–36.
Thimm, E., et al., Practical Considerations for the Diagnosis and Management of Isovaleryl-CoA-Dehydrogenase Deficiency (Isovaleric Acidemia): Systematic Search and Review and Expert Opinions. International Journal of Neonatal Screening, 2025. 11(4).
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.
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The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
View reportGeneReviews has an article on this condition covering diagnosis, management, and inheritance. Each article is written by one or more experts on the specific disease and is reviewed by other specialists. The article contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. The GeneReviews database is managed by the University of Washington.
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