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Glutaric Acidemia Type 1

Other Names

Glutaric aciduria, type 1

GA1, GA-1, GA I

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~90% [Nicola Longo, personal communication, 2007]; specificity=NA [American: 1996]

Overview

In glutaric acidemia type 1 (GA1), inadequate quantities of glutaryl-CoA dehydrogenase limit the ability to break down lysine, hydroxylysine, and tryptophan, leading to excessive levels of their intermediate metabolic products (glutaric and 3-OH-glutaric acid). These and other chemicals can then lead to brain injury, particularly in the basal ganglia.[Hedlund: 2006] Mutations in the GCDH gene cause GA1.

Incidence

Prevalence is about 1:40,000 Caucasian live births and 1:30,000 Swedish live births; n Old Amish and Ojibway populations, the incidence may be as high as 1:300. (Glutaric Acidemia Type 1 - Information for Professionals (STAR-G))

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 treatment, normal outcome is possible. Without treatment, outcomes vary but many will have encephalitis-like crises that may result in developmental delay, neurologic deterioration, and spastic/dystonic cerebral palsy. Otherwise healthy newborns may have macrocephaly sometimes with hypotonia. Acute decompensation usually occurs between 6 and 18 months of age. Symptoms are usually triggered by illness (high fever, vomiting, dehydration). Children may be healthy until the first metabolic crisis. Profuse sweating may occur in some affected children. Acute decompensation has not been reported after 5 years of age, although some undiagnosed patients have presented with a leukoencephalopathy after this age.

Initial symptoms/signs may include:
  • Macrocephaly
  • Failure to thrive
  • Metabolic ketoacidosis
  • Hypotonia
  • Dystonia and athetosis.
After 5 years of age, the risk of acute decompensation (acute dystonia) is low and children with normal neurological exam are likely to remain healthy. Treatment consists in the prompt therapy of fever, gastroenteritis or any condition causing catabolism with intravenous glucose and lipids and carnitine. Chronic therapy consists in a diet low in protein, lysine and tryptophan, and supplemented with carnitine.

Follow-up Testing after Positive Screen

Quantitative plasma acylcarnitine profile, urine organic acid and acylglycine analysis, confirmation with ETF/ETF-QO enzyme assay and/or 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 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

Initial consultation with the following service(s):Pediatric Genetics (see UT providers [6]); 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.

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.

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 (Genetics Home Reference)
Excellent, detailed review of condition for patients and families; sponsored by the U.S. National Library of Medicine.

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.

Services for Patients & Families in Utah (UT)

Genetics clinic services throughout the US can be found through the Genetics Clinic Services Search Engine (ACMG).
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 glutaric acidemia type 1 and neonatal screening, last 5 years.

Authors & Reviewers

Current Authors and Reviewers:
Reviewers: Kimberly Hart, MS, LCGC
Nicola Longo, MD, Ph.D.

Page Bibliography

American Academy of Pediatrics.
Newborn screening fact sheets. American Academy of Pediatrics. Committee on Genetics.
Pediatrics. 1996;98(3 Pt 1):473-501. PubMed abstract

Hedlund GL, Longo N, Pasquali M.
Glutaric acidemia type 1.
Am J Med Genet C Semin Med Genet. 2006;142C(2):86-94. PubMed abstract / Full Text
Glutaric acidemias (GA) comprise different disorders resulting in an increased urinary excretion of glutaric acid. Early diagnosis and therapy reduce the risk of acute dystonia in patients with GA-1.