Glutaric Acidemia Type 1

Other Names

GA1, GA-1, GA I

GCDH deficiency

Glutaric aciduria, type 1

Glutaryl-CoA dehydrogenase deficiency

Diagnosis Coding

E72.3, Disorders of lysine and hydroxylysine metabolism

Disorder Category

An organic acidemia

Screening

Finding

Elevated C5-DC (glutaryl) carnitine

Tested By

Tandem mass spectrometry (MS/MS); sensitivity ~96%; specificity=NA [Boy: 2018]

Overview

In glutaric acidemia type 1 (GA1), defective activity of glutaryl-CoA dehydrogenase, an enzyme necessary for the break-down of lysine, hydroxylysine, and tryptophan, causes an accumulation of glutaric and 3-OH-glutaric acid, which are intermediates in the amino acid catabolism. These toxic metabolites can result in acute encephalopathic crisis that usually presents within the first 6 years of life. Crises result in striatal injury and subsequently lead to complex movement disorders. [Larson: 2019] Mutations in the GCDH gene cause GA1.

Incidence

The incidence is approximately 1:90,000 in the United States. [Therrell: 2014] Certain geographic regions have a higher incidence due to a founder effect. These regions include Ojibway-Cree First Nation Canadians of Manitoba and Ontario, South African Xhosa people, Pennsylvania Amish, Lumbee Native Americans of North Carolina, and Irish Traveler communities in the Republic of Ireland. [Larson: 2019]

Inheritance

Autosomal recessive

Prenatal Testing

DNA testing is possible by amniocentesis if both disease-causing mutations of an affected family member have been identified.

Clinical Characteristics

With early diagnosis and full adherence to treatment, 80-90% of individuals with GA-1 will remain largely asymptomatic. [Viau: 2012] [Boy: 2018] Without treatment, a majority of individuals with early-onset GA-1 will experience an encephalopathic crisis, usually occurring within the first year of life. [Kölker: 2006] [Boy: 2017]

Symptoms are usually triggered by illness (high fever, vomiting, dehydration); crises may also be triggered by vaccinations and surgery. Children may be healthy until the first metabolic crisis. Profuse sweating may occur in some affected children. Acute decompensation has not been reported after 6 years of age, although some undiagnosed patients have presented with a leukoencephalopathy after this age. [Kölker: 2006]

Initial symptoms/signs may include:
  • Macrocephaly
  • Failure to thrive
  • Metabolic ketoacidosis
  • Hypotonia
  • Dystonia and athetosis
After 6 years of age, the risk of acute decompensation (acute dystonia) appears to decrease, and children with normal neurological exam and normal brain MRI are likely to remain healthy. Treatment consists of aggressive emergency management, provision of calories through intravenous glucose and lipids, and carnitine to aid in removal of toxic metabolites. Chronic therapy consists of avoidance of catabolism, a diet low in lysine and tryptophan, and carnitine supplementation.

Follow-up Testing after Positive Screen

Follow-up with a quantitative plasma acylcarnitine profile, urine organic acid and acylglycine analysis, confirmation with gene sequencing. If negative, consider riboflavin transporter deficiency if biochemical abnormalities (plasma acylcarnitine profile) are persistent.

Primary Care Management

Upon Notification of the + Screen

If the Diagnosis is Confirmed

  • Educate the family regarding signs, symptoms, and the need for urgent care when the infant becomes ill (see Glutaric Acidemia Type 1 - Information for Parents (STAR-G) for additional information).
  • Support initiation and maintenance of a low-lysine, low-tryptophan diet.
  • Glucose, intralipids, carnitine, and fluids given intravenously may be indicated during episodes of acute, intercurrent illness.
  • For those identified after irreversible consequences, assist in management, particularly with developmental and educational interventions.

Specialty Care Collaboration

Refer for initial consultation with the following service(s): Pediatric Genetics (see NM providers [4]); and ongoing collaboration if the child is affected. A dietician may work with the family to devise an optimal approach to dietary management. Genetic counseling for the family.

Resources

Information & Support

For Professionals

Glutaric Acidemia Type 1 (OMIM)
Extensive review of literature that provides technical information on genetic disorders; Online Mendelian Inheritance in Man site, hosted by Johns Hopkins University.

For Parents and Patients

Glutaric Acidemia Type 1 - 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 this newborn disorder; Screening, Technology and Research in Genetics.

Organic Acidemia Association (OAA)
A volunteer non-profit organization whose mission is to empower families and health care professionals with knowledge in organic acidemia metabolic disorders.

Resources for Glutaric Acidemia Type 1 (Disease InfoSearch)
Compilation of information, articles, research, case studies, and genetics links; from Genetic Alliance.

Glutaric Acidemia Type 1 (MedlinePlus)
Excellent, detailed review of condition for patients and families; National Library of Medicine and National Institutes of Health.

Tools

ACT Sheet for Glutaric Acidemia Type 1 (ACMG) (PDF Document 346 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical Genetics.

Confirmatory Algorithms for Glutaric Acidemia Type 1 (ACMG) (PDF Document 178 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 in New Mexico (NM)

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.

Authors & Reviewers

Initial publication: March 2007; last update/revision: March 2020
Current Authors and Reviewers:
Author: Chelsea Norman, BS, RDN, CD
Reviewer: Nicola Longo, MD, Ph.D.
Authoring history
2012: revision: Kimberly Hart, MS, LCGCA
2011: first version: Nicola Longo, MD, Ph.D.A
AAuthor; CAContributing Author; SASenior Author; RReviewer

Page Bibliography

Boy N, Mengler K, Thimm E, Schiergens KA, Marquardt T, Weinhold N, Marquardt I, Das AM, Freisinger P, Grünert SC, Vossbeck J, Steinfeld R, Baumgartner MR, Beblo S, Dieckmann A, Näke A, Lindner M, Heringer J, Hoffmann GF, Mühlhausen C, Maier EM, Ensenauer R, Garbade SF, Kölker S.
Newborn screening: A disease-changing intervention for glutaric aciduria type 1.
Ann Neurol. 2018;83(5):970-979. PubMed abstract

Boy N, Mühlhausen C, Maier EM, Heringer J, Assmann B, Burgard P, Dixon M, Fleissner S, Greenberg CR, Harting I, Hoffmann GF, Karall D, Koeller DM, Krawinkel MB, Okun JG, Opladen T, Posset R, Sahm K, Zschocke J, Kölker S.
Proposed recommendations for diagnosing and managing individuals with glutaric aciduria type I: second revision.
J Inherit Metab Dis. 2017;40(1):75-101. PubMed abstract

Kölker S, Garbade SF, Greenberg CR, Leonard JV, Saudubray JM, Ribes A, Kalkanoglu HS, Lund AM, Merinero B, Wajner M, Troncoso M, Williams M, Walter JH, Campistol J, Martí-Herrero M, Caswill M, Burlina AB, Lagler F, Maier EM, Schwahn B, Tokatli A, Dursun A, Coskun T, Chalmers RA, Koeller DM, Zschocke J, Christensen E, Burgard P, Hoffmann GF.
Natural history, outcome, and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency.
Pediatr Res. 2006;59(6):840-7. PubMed abstract

Larson A, Goodman S.
Glutaric Acidemia Type 1.
GeneReviews. 2019. PubMed abstract

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

Viau K, Ernst SL, Vanzo RJ, Botto LD, Pasquali M, Longo N.
Glutaric acidemia type 1: outcomes before and after expanded newborn screening.
Mol Genet Metab. 2012;106(4):430-8. PubMed abstract