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Isovaleric Acidemia

Other Names

Isovaleric acid-CoA dehydrogenase deficiency

Isovaleryl-CoA dehydrogenase deficiency

IVA

IVD deficiency

Diagnosis Coding

E71.110, isovaleric acidemia

Disorder Category

An organic acidemia

Screening

Finding

Elevated C5 (isovaleryl carnitine)

Tested By

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

Overview

Lack of isovaleryl-CoA dehydrogenase, which is involved in the metabolism of the branched chain amino acid leucine, results in the inability to break down isovaleric acid and the accumulation of potentially toxic metabolites. Clinical manifestations of the illness include an acute neonatal form, a chronic intermittent form, and a very mild form of unknown clinical significance.

Incidence

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

Inheritance

Autosomal recessive

Maternal & Family History

In most cases, there is no previous family history of this condition. Children develop normally during pregnancy. Mothers with isovaleric acidemia have had normal children.

Prenatal Testing

DNA testing or enzyme analysis by amniocentesis or CVS

Clinical Characteristics

With early diagnosis and ongoing treatment, most affected children will have normal development. Without treatment, children with the chronic, intermittent form may suffer neurologic damage, though most children are developmentally normal. Those children with the acute neonatal form will present in the first few days or weeks of life and about half will die during their first episode. In many cases, the neonatal presentation occurs before the return of newborn screening results. After the neonatal period, symptoms may be triggered by consuming too much protein, and illness. Children may be healthy between metabolic crisis episodes.

Initial symptoms may include:
  • A "sweaty feet" odor
  • Vomiting
  • Lethargy progressing to coma
  • Lab findings:
    • Ketoacidosis
    • Elevated ammonia levels in the blood
    • Neutropenia, thrombocytopenia, anemia

Follow-up Testing after Positive Screen

Quantitative plasma acylcarnitine profile, urine organic acids, and urine acylglycine analysis

Primary Care Management

Upon Notification of the + 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, the child should be admitted to the hospital for treatment (breast milk contains fewer proteins than regular formulas).
  • If in doubt, obtain BMP to check CO2 and anion gap and urine analysis (for ketones).
  • Confirm the diagnosis and work with the following service(s): Newborn Screening Services (see UT providers [3]).
  • Evaluate and continue ongoing collaborative management, consult the following service(s): Pediatric Genetics (see UT providers [6]).

If the Diagnosis is Confirmed

  • 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 low protein, low leucine, and high carbohydrate meals 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.
  • Evaluate and continue ongoing collaborative management; consult the following service(s): Pediatric Genetics (see UT providers [6]).

Specialty Care Collaboration

Provide initial consultation and ongoing collaboration, particularly for dietary management. Facilitate genetic counseling for the family.

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

Resources for Isovaleric Acidemia (Disease InfoSearch)
Compilation of information, articles, research, case studies, and genetics links; from Genetic Alliance.

Genetics in Primary Care Institute (AAP)
Contains health supervision guidelines and other useful resources for the care of children with genetic disorders; American Academy of Pediatrics.

Utah Newborn Screening Program (UDOH)
Provides information about the program, related legislation, training for practices, and newborn conditions; Utah Department of Health.

For Parents and Patients

Support

Organic Acidemia Association (OAA)
A nonprofit organization that provides information, support, events, connections with other parents, a discussion board, and nutrition and recipe ideas.

General

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 (MedlinePlus)
Information for families that includes description, frequency, causes, inheritance, other names, and additional resources; from the National Library of Medicine.

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 Isovaleric Acidemia (ACMG) (PDF Document)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical Genetics.

Confirmatory Algorithm for Isovaleric Acidemia (ACMG) (PDF Document 90 KB)
Resource for clinicians to help confirm diagnosis; American College of Medical Genetics.

Services for Patients & Families in Utah (UT)

Genetics clinic services throughout the US can be found through the Genetics Clinic Services Search Engine (ACMG).

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.

Vockley J, Ensenauer R.
Isovaleric acidemia: new aspects of genetic and phenotypic heterogeneity.
Am J Med Genet C Semin Med Genet. 2006;142C(2):95-103. PubMed abstract / Full Text

Authors & Reviewers

Initial publication: March 2007; last update/revision: December 2015
Current Authors and Reviewers:
Author: Nicola Longo, MD, Ph.D.

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