Glutaric Acidemia Type 1
Other Names
GA1, GA-1, GA I
GCDH deficiency
Glutaric aciduria, type 1
Glutaryl-CoA dehydrogenase deficiency
Screening
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]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
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
- Contact the family immediately and evaluate the infant for macrocephaly, hypotonia, and/or signs of decompensation.
- To confirm the diagnosis, work with the following service(s): Newborn Screening Services (see UT providers [3]).
- For evaluation and ongoing collaborative management, consult the following service(s): Pediatric Genetics (see UT providers [7]).
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 UT providers [7]); 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)
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
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 nonprofit organization that provides information, support, events, connections with other parents, a discussion board,
and nutrition and recipe ideas.
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)
Information for families that includes description, frequency, causes, inheritance, other names, and additional resources;
from the National Library of Medicine.
Tools
ACT Sheet for Glutaric Acidemia Type 1 (ACMG) (
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) ( 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 Utah (UT)
| Service Categories | # of providers* in: | UT | NW | Other states (5) (show) | | ID | MT | NM | NV | RI |
|---|---|---|---|---|---|---|---|---|---|---|
| Newborn Screening Services | 3 | 1 | 22 | 4 | 2 | 2 | 1 | |||
| Pediatric Genetics | 7 | 1 | 3 | 7 | 4 | 5 | 4 | |||
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.
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