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Disease Profile

Isovaleric acidemia

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

1-9 / 100 000

US Estimated

Europe Estimated

Age of onset

Adolescent

ICD-10

E71.1

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease.

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype.

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder.

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

Isovaleric acid CoA dehydrogenase deficiency; IVA; Isovaleryl CoA carboxylase deficiency;

Categories

Congenital and Genetic Diseases; Metabolic disorders; Newborn Screening

Summary

Isovaleric acidemia (IVA) occurs when the body cannot breakdown certain parts of the proteins found in food. This can cause a build-up of toxic substances which can lead to bouts of serious illness known as metabolic crises. There are two types of IVA. The acute, neonatal type has more severe symptoms that begin in the newborn period. In the chronic, intermittent type symptoms appear during childhood and can come and go. Symptoms include poor feeding, tremor, vomiting, low muscle tone, and lack of energy (lethargy). These may get worse over time and lead to coma and possibly death. One characteristic sign of IVA is an odor of sweaty feet during illness. IVA occurs due to variants in the IVD gene and is inherited in an autosomal recessive pattern. Diagnosis of IVD is based on the symptoms, clinical exam, and blood and urine testing. The results of genetic testing may help confirm the diagnosis. Treatment is focused on managing the symptoms and involves a special protein-restricted diet and medications that rid the body of excess isovaleric acid.[1][2][3][4]

Symptoms

The following list includes the most common signs and symptoms in people with isovaleric acidemia (IVA). These features may be different from person to person. Some people may have more symptoms than others and they can range from mild to severe. This list does not include every symptom that has been described in the condition.

Symptoms may include:[1][2] 

  • Poor feeding
  • Vomiting
  • Lack of energy
  • Low muscle tone
  • Tremor
  • Odor of sweaty feet

The symptoms of IVA can range from mild to very severe. In severe cases, these symptoms start a few days after birth. These symptoms sometimes progress to more serious medical problems, including seizures, coma, and possibly death. In other cases, the symptoms of IVA appear during childhood and can be triggered by prolonged periods without food (fasting), infections, or eating an increased amount of protein-rich foods. Although IVA can be life-threatening in infancy, with treatment, many children with IVA have normal growth and development.[4]

Some people have a form of IVA which does not cause any symptoms of the condition.

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Global developmental delay
0001263
Metabolic acidosis
0001942
30%-79% of people have these symptoms
Seizure
0001250
5%-29% of people have these symptoms
Cerebellar hemorrhage
0011695
Percent of people who have these symptoms is not available through HPO
Autosomal recessive inheritance
0000007
Bone marrow hypocellularity
Bone marrow failure
0005528
Coma
0001259
Dehydration
0001944
Hyperglycinuria
High urine glycine levels
0003108
Ketoacidosis
0001993
Lethargy
0001254
Leukopenia
Decreased blood leukocyte number
Low white blood cell count

[ more ]

 0001882
Pancytopenia
Low blood cell count
0001876
Thrombocytopenia
Low platelet count
0001873
Vomiting
Throwing up
0002013

Cause

Isovaleric acidemia occurs when the IVD gene is not working correctly.[2] DNA changes known as pathogenic variants are responsible for making genes work incorrectly or sometimes, not at all.

Diagnosis

Isovaleric acidemia (IVA) is diagnosed based on the symptoms, clinical exam, and blood and urine testing. The results of genetic testing may help confirm the diagnosis.[1][4] 

IVA can also be diagnosed on the newborn screen. However, some people found to have IVA on a newborn screen may never develop symptoms.[4]

Testing Resources

  • The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

    Newborn Screening

    • An ACTion (ACT) sheet is available for this condition that describes the short-term actions a health professional should follow when an infant has a positive newborn screening result. ACT sheets were developed by experts in collaboration with the American College of Medical Genetics.
    • An Algorithm flowchart is available for this condition for determining the final diagnosis in an infant with a positive newborn screening result. Algorithms are developed by experts in collaboration with the American College of Medical Genetics.
    • Baby's First Test is the nation's newborn screening education center for families and providers. This site provides information and resources about screening at the local, state, and national levels and serves as the Clearinghouse for newborn screening information.
    • The Newborn Screening Coding and Terminology Guide has information on the standard codes used for newborn screening tests. Using these standards helps compare data across different laboratories. This resource was created by the National Library of Medicine.
    • National Newborn Screening and Global Resource Center (NNSGRC) provides information and resources in the area of newborn screening and genetics to benefit health professionals, the public health community, consumers and government officials.

      Treatment

      Treatment for isovaleric acidemia (IVA) is focused on managing the symptoms and avoiding a metabolic crisis. Early diagnosis and treatment are associated with a better outcome. Treatment involves a special protein-restricted diet and medications to reduce the amount of isovaleric acid in the body. Children with the chronic, intermittent form of IVA should avoid triggers, such as fasting and infections, which can cause a metabolic crisis.[2][3]

      Specialists involved in the care of someone with isovaleric acidemia include:[2]

      • Neurologist
      • Nutritionist
      • Medical geneticist/metabolic geneticist
      • Gastroenterologist
      • Physical therapist

      Management Guidelines

      • Orphanet Emergency Guidelines is an article which is expert-authored and peer-reviewed that is intended to guide health care professionals in emergency situations involving this condition.

        Organizations

        Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

        Organizations Supporting this Disease

          Learn more

          These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

          Where to Start

          • Baby's First Test offers an information page on Isovaleric acidemia.
          • Genetics Home Reference (GHR) contains information on Isovaleric acidemia. This website is maintained by the National Library of Medicine.
          • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.
          • The Screening, Technology And Research in Genetics (STAR-G) Project has a fact sheet on this condition, which was written specifically for families that have received a diagnosis as a result of newborn screening. This fact sheet provides general information about the condition and answers questions that are of particular concern to parents.

            In-Depth Information

            • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
            • The New England Consortium of Metabolic Program has written medical guidelines called acute care protocols for Isovaleric acidemia for health care professionals.
            • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
            • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
            • PubMed is a searchable database of medical literature and lists journal articles that discuss Isovaleric acidemia. Click on the link to view a sample search on this topic.

              References

              1. Szymanska E, Jezela-Stanek A, Bogdanska A, Rokicki D, Ehmke Vel Emczynska-Seliga E, Pajdowska M, Ciara E, Tylki-Szymanska A. Long Term Follow-Up of Polish Patients with Isovaleric Aciduria. Clinical and Molecular Delineation of Isovaleric Aciduria. Diagnostics (Basel). Sep. 23, 2020; 10(10):738. https://pubmed.ncbi.nlm.nih.gov/32977617/.
              2. Grünert SC, Wendel U, Lindner M, Leichsenring M, Schwab KO, Vockley J, Lehnert W, Ensenauer R. Clinical and neurocognitive outcome in symptomatic isovaleric acidemia. Orphanet J Rare Dis. 2012 Jan 25;7:9.. Jan 25, 2012; 7:1-9. https://pubmed.ncbi.nlm.nih.gov/22277694/.
              3. Pinto A, Daly A, Evans S, Almeida MF, Assoun M, Belanger-Quintana A, et al. Dietary practices in isovaleric acidemia: A European survey. Mol Genet Metab Rep. Feb 27, 2017; 12:16-22. https://pubmed.ncbi.nlm.nih.gov/28275552/.
              4. Bodamer OA. Organic acidemias: An overview and specific defects. UpToDate. Updated Jan. 19, 2020; https://www.uptodate.com/contents/organic-acidemias-an-overview-and-specific-defects.
              5. Moorthie S, Cameron L, Sgoo GS, Bonham JR, Burton H. Systematic review and meta-analysis to estimate the birth prevalence of five inherited metabolic diseases. J Inherit Metab Dis. Nov, 2014; 37(6):889-98. https://pubmed.ncbi.nlm.nih.gov/25022222/.
              6. Schlune A, Riederr A, Mayatepek E, Ensenauer R. Aspects of Newborn Screening in Isovaleric Acidemia. Int J Neonatal Screen. Jan 29, 2018; 4(1):7. https://pubmed.ncbi.nlm.nih.gov/33072933/.

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