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Isovaleric Acidemia

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Guidance for primary care clinicians receiving a positive newborn screen result for isovaleric acidemia

Other Names

Isovaleric acid-CoA dehydrogenase deficiency
Isovaleryl-CoA dehydrogenase deficiency
IVA

ICD-10 Coding

E71.110, Isovaleric acidemia

Disorder Category

Organic acidemia

Screening

Abnormal Finding

Elevated C5 (isovaleryl carnitine)

Tested By

Tandem mass spectrometry (MS/MS); sensitivity=NA; specificity=NA

Description

Isovaleric acidemia (IVA) is caused by a genetic deficiency of the enzyme isovaleryl-CoA dehydrogenase, which is involved in the metabolism of the branched-chain amino acid leucine found in dietary protein. This results in the inability to break down isovaleric acid and the subsequent accumulation of toxic isovaleryl-CoA derivatives. The clinical presentation is highly variable, ranging from asymptomatic to severely affected. It may present either in the neonatal period as an acute episode of fulminant metabolic acidosis and hyperammonemia in the acute neonatal form or later as a chronic intermittent form associated with failure to thrive and developmental delay with/without recurrent acidotic episodes.

Clinical Characteristics

With early diagnosis and ongoing treatment of isovaleric acidemia, most affected children have the potential for normal growth and development.
Without treatment, children with the chronic intermittent form may suffer neurologic damage, although most are developmentally normal. Those with the acute neonatal form will present in the first few days or weeks of life. The acute neonatal form carries significant morbidity/mortality if not adequately treated quickly. In many cases, the neonatal presentation occurs before the return of newborn screening results. After the neonatal period, children may be healthy between metabolic crises, but episodes can be triggered by consuming too much protein or during infectious illnesses.
Initial symptoms may include:
  • A "sweaty feet" odor
  • Vomiting
  • Lethargy progressing to coma
  • Lab findings:
    • Ketoacidosis
    • Neutropenia, thrombocytopenia, anemia

Incidence

Incidence in the United States is approximately 1:159,000 [Therrell: 2014]

Inheritance

Autosomal recessive

Primary Care Management

Next Steps After a Positive Screen

  • Contact the family and evaluate the infant for poor feeding, vomiting, lethargy, and odor of sweaty feet.
  • Provide emergency treatment and referral for symptoms of poor feeding or vomiting.
  • Continue breastfeeding if the infant appears healthy. If not, discuss with Metabolic Genetics whether the child should be admitted to the hospital for treatment (breastmilk contains fewer proteins than regular formulas).
  • If there are any clinical symptoms, obtain BMP to check CO2 and anion gap and urine analysis (for ketones).

Confirming the Diagnosis

If the Diagnosis is Confirmed

  • Evaluate and continue ongoing collaborative management - consult Medical Genetics (see NW providers [1]).
  • Educate the family about signs, symptoms, and the need for urgent care if the infant becomes ill. See Isovaleric Acidemia - Information for Parents (STAR-G) for additional information.
  • Consider a low-protein, low-leucine, and high-carbohydrate diet for affected children.
  • Most patients require oral L-carnitine and glycine for some affected children.
  • Patients need intravenous calories (glucose, intralipids) and bicarbonate during metabolic crisis episodes.

    Resources

    Information & Support

    For Professionals

    Isovaleric Acidemia Acute Illness Protocol (NECMP)
    A guideline for health care professionals treating the sick infant/child who has previously been diagnosed with isovaleric acidemia; developed under the direction of Dr. Harvey Levy, Senior Associate in Medicine/Genetics at Children’s Hospital Boston, and Professor of Pediatrics at Harvard Medical School, for the New England Consortium of Metabolic Programs.

    Isovaleric Acidemia (OMIM)
    Information about clinical features, diagnosis, management, and molecular and population genetics; Online Mendelian Inheritance in Man, authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine

    For Parents and Patients

    Isovaleric Acidemia - Information for Parents (STAR-G)
    A fact sheet, written by a genetic counselor and reviewed by metabolic and genetic specialists, for families who have received an initial diagnosis of a newborn disorder; Screening, Technology and Research in Genetics.

    Isovaleric Acidemia (GARD)
    Symptoms, causes, support groups, and clinical studies; Genetic and Rare Diseases Information Center.

    Isovaleric Acidemia: A Guide for Parents (PacNoRGG) (PDF Document 1.4 MB)
    Eight-page guide that includes an overview, social concerns, sample treatment plan, glossary, regional resources, and references; sponsored by the Pacific Northwest Regional Genetics Group.

    Isovaleric Acidemia: A Guide for Parents (PacNoRGG) (Spanish) (PDF Document 187 KB)
    Spanish translation of an 8-page guide that includes an overview, social concerns, sample treatment plan, glossary, regional resources, and references; sponsored by the Pacific Northwest Regional Genetics Group.

    Tools

    ACT Sheet for Elevated C5 Acylcarnitine (ACMG) (PDF Document 290 KB)
    Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical Genetics.

    Confirmatory Algorithm for Elevated C5 (ACMG) (PDF Document 194 KB)
    An algorithm of the basic steps involved in determining the final diagnosis of an infant with a positive newborn screen; American College of Medical Genetics.

    Services for Patients & Families Nationwide (NW)

    For services not listed above, browse our Services categories or search our database.

    * number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

    Helpful Articles

    PubMed search for isovaleric acidemia, last 5 years.

    Authors & Reviewers

    Initial publication: March 2007; last update/revision: July 2023
    Current Authors and Reviewers:
    Author: Brian J. Shayota, MD, MPH
    Reviewer: Nancy C. Rose, MD
    Authoring history
    2023: update: Brian J. Shayota, MD, MPHA
    2015: first version: Nicola Longo, MD, Ph.D.A
    AAuthor; CAContributing Author; SASenior Author; RReviewer

    Page Bibliography

    Therrell BL Jr, Lloyd-Puryear MA, Camp KM, Mann MY.
    Inborn errors of metabolism identified via newborn screening: Ten-year incidence data and costs of nutritional interventions for research agenda planning.
    Mol Genet Metab. 2014;113(1-2):14-26. PubMed abstract / Full Text