• Disease Overview
  • Synonyms
  • Signs & Symptoms
  • Causes
  • Affected Populations
  • Disorders with Similar Symptoms
  • Diagnosis
  • Standard Therapies
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Glutaric Aciduria Type I

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Last updated: 8/24/2023
Years published: 1987, 1990, 1994, 2004, 2019, 2023


Acknowledgment

NORD gratefully acknowledges Bridget McClain and Ashby Martin, NORD Editorial Interns from the University of Notre Dame; Barb Calhoun, MSN, RN, NP, Nurse Practitioner and Outreach Coordinator, Boler-Parseghian Center for Rare and Neglected Diseases at the University of Notre Dame; and Nikolas Boy, MD, Metabolic Pediatrician, Centre for Child and Adolescent Medicine, Division of Child Neurology and Metabolic Medicine, Heidelberg University Hospital, for assistance in the preparation of this report.


Disease Overview

Summary


Glutaric aciduria type I (GA1) is a rare hereditary metabolic disorder caused by a deficiency of the mitochondrial enzyme glutaryl-CoA dehydrogenase (GCDH). It is in the group of disorders known as cerebral organic acidemias. Individuals with this condition have deficiency or absence of GCDH enzyme that is involved in the lysine metabolism. GCDH deficiency results in increased concentrations of potentially neurotoxic metabolites, glutaric acid (GA), 3-hydroxy glutaric acid (3-OH-GA) and glutaconic acid within body tissues, especially within the brain, and also non-toxic glutarylcarnitine (C5DC). Two biochemical subtypes have been defined, high (HE) and low excretors (LE), depending on residual enzyme activity and the amount of GA in the urine.

Newborns may show unspecific clinical signs like enlarged head circumference (macrocephaly) or decreased muscle tone (hypotonia). Without treatment, most affected children develop an acute encephalopathic crisis (AEC) following episodes of fever or other catabolic conditions resulting in bilateral striatal injury and consequently, dystonic movement disorder (MD), within the first three years of life. Single acute-onset events have been reported up to the age of six years. Besides acute-onset, individuals with insidious-onset type of striatal injury without an apparent crisis have also been described. Sometimes babies with GA1 have been mistaken to have been abused because they may present with subdural hemorrhages (SDH).

Since early diagnosis and treatment dramatically improve outcome and prognosis, GA1 has been included in the newborn screening (NBS) panel in a constantly growing number of countries worldwide which is essential for early intervention. Importantly, some low excretor patients may be missed by newborn screening due to normal C5DC concentrations.

Introduction


For 80-90% of people with GA1, motor symptom development is preventable, but this requires early diagnosis by NBS and metabolic treatment according to guideline recommendations from birth on. Metabolic treatment consists of a low lysine diet with supplementation of a lysine-free, tryptophane-reduced and arginine-fortified amino acid supplement and oral carnitine supplementation as well as intermittent emergency treatment during episodes that are likely to induce catabolism, such as fever. If treatment is delayed or inadequate, motor symptoms begin to manifest acutely or insidiously during infancy or early childhood (before the age of 6) and are often highly variable.

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Synonyms

  • GA1
  • glutaric acidemia type I
  • glutaric aciduria type I
  • glutaryl-CoA dehydrogenase deficiency
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Signs & Symptoms

Babies with GA1 are born healthy and may only have unspecific signs like macrocephaly or muscular hypotonia at birth. Macrocephaly is one of the earliest signs of GA1 so newborns with an enlarged head circumference should be evaluated for GA1. Especially during the age of 3 months to 3 years, most affected untreated babies develop an acute encephalopathic crisis which is triggered by catabolic conditions such as febrile infections, febrile reactions to vaccinations or surgery. These crises result in striatal injury and a complex, mostly dystonic, irreversible and severe movement disorder which is associated with high morbidity and mortality. These babies can experience several symptoms resembling those of cerebral palsy, such as frequently assuming odd positions due to disordered muscle tone (dystonia), involuntary and ceaseless slow, sinuous, writhing (athetotic) or jerky (choreic) movements of the trunk and limbs. Controlling the movement of hands, arms, feet, legs, head and neck may become very hard and muscle spasms may occur. Repeated stress on the body (such as infection and fever) can cause symptoms to worsen, but in some children, brain damage will occur without a triggering fever.

Clinical early signs suggesting an “acute encephalopathic crisis” may comprise:

• Irritability
• Jitteriness
• Nausea, vomiting, diarrhea
• Hypotonia (low muscle tone)
• Poor appetite or difficulty feeding
• Lack of energy/sleepy
• Muscle weakness

Possible irreversible neurologic symptoms of an acute encephalopathic crisis are:

• Dyskinesia-disorder of involuntary muscle movements
• Dystonia – fixed abnormal postures due to abnormally increased muscle tone
• Orofacial dyskinesia
• Choreoathetosis—irregular migrating contractions, twisting, writhing
• Abnormality of eye movement- nystagmus (involuntary shaking of the eyes)
• Cognitive impairment (highly variable and not seen in many patients)
• Developmental regression
• Opisthotonus- full body spasms
• Coma

Besides acute-onset, individuals with insidious onset type of striatal injury have been reported in up to 50% of symptomatic patients in NBS cohorts, primarily associated with deviations from dietary treatment recommendations. These patients show a milder degree of dystonic MD and a characteristic striatal injury pattern restricted to the dorsolateral putamen.
After age 6 years, a new onset of striatal injury has not been reported.

Besides striatal pathology, all GA1 patients additionally may develop numerous extrastriatal MRI abnormalities, such as frontotemporal hypoplasia, widening of anterior temporal CSF spaces and the Sylvian fissure or white matter abnormalities.

Although HE and LE patients have the same risk for developing striatal injury, HE patients show increased frequency of extra-striatal abnormalities, higher intracerebral concentrations of GA and 3-OHGA, larger head circumference, increased SDH and a poorer cognitive outcome.

Some patients have been diagnosed in adolescence or adulthood (late-onset) with unspecific neurologic symptoms, such as polyneuropathy, incontinence, headache, dementia, tremor or epilepsy, without striatal injury.

GA1 is associated with an increased risk of developing traumatic or incidental SDH and hygroma. SDH manifests mostly during the first 3 years of life, with a peak in late infancy and affecting primarily HE patients, usually associated with additional characteristic neuroradiologic abnormalities on MRI. In recent years, other neurologic disease manifestations have been reported such as chronic kidney disease in adolescent and adult patients.

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Causes

GA1 is caused by pathogenic variants in the GCDH gene that leads to deficiency of the enzyme, glutaryl-CoA dehydrogenase or GCDH. This enzyme is responsible for metabolizing the amino acids lysine, hydroxylysine and tryptophan. Pathogenic variants in GCDH prevent production of the enzyme resulting in abnormal levels of glutaric, 3-hydroxyglutaric and (to a lesser extent) glutaconic acids These products accumulate and cause damage to an area of the brain called the basal ganglia that regulates motor movement.

GA1 is inherited as an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the mutated gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

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Affected populations

GA1 is a rare inborn error of metabolism that affects males as often as females. It has been estimated that there are about 140 patients with this type of organic aciduria in the United States. GA1 occurs in approximately 1 of every 100,000 births. Five genetic isolates are known with a high carrier frequency (up to 1:10) and incidence (up to 1:250 newborns): the Old Order Amish Community in Lancaster County, Pennsylvania, United States, the Oji-Cree First Nations in Manitoba and Western Ontario, Canada, the Irish Travelers in the Republic of Ireland and United Kingdom, the Lumbee in North Carolina, United States and the Xhosa in South Africa.

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Diagnosis

GA1 Is diagnosed by the characteristic metabolites GA, 3-OH-GA, glutaconic acid and glutarylcarnitine (C5DC) detected in body fluids (urine, plasma, CSF) and tissues using gas chromatography/mass spectrometry (GC/MS) or electrospray-ionization tandem mass spectrometry (MS/MS). As neonatal diagnosis and start of treatment significantly improves neurologic outcome, GA1 has been included in MS/MS based NBS disease panels in many countries worldwide.

Abnormal newborn screening results should be confirmed by quantitative analysis of GA and 3-OH-GA in urine and/or blood with GC/MS, variant analysis of the GCDH gene and/or GCDH enzyme analysis in leukocytes or fibroblasts. The diagnosis is confirmed by significantly reduced enzyme activity and/or detection of two disease-causing GCDH gene variants.

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Standard Therapies

Metabolic treatment
Following the guideline-recommended treatment is associated with the best neurological outcome. Evidence-based treatment recommendations have been developed since 2003, resulting in a first guideline publication in 2007 and three revisions since then, the last in 2022.

Today, GA1 is considered to be a treatable condition. Metabolic treatment consists of a low lysine diet with supplementation of a lysine-free, trytophane-reduced, amino acid mixture, oral supplementation of L-carnitine and an intensified emergency treatment during episodes of intercurrent illness or surgical interventions. It has been recommended by an international guideline group for all patients up to 6 years.

Children with GA1 can develop normally if a thorough treatment plan is followed properly, but treatment must begin from a very early age (from the newborn period before symptoms occur and onwards). If not promptly and properly treated, GA1 will typically cause serious, irreversible, neurologic damage that can permanently affect control of voluntary muscle movement and can severely impact life and shorten life expectancy, especially if damage occurs before the age of 6. The long-term outcome is still incompletely understood. Neurologic disease or extracerebral manifestations like chronic kidney disease may occur in adulthood and variable extrastriatal MRI changes may progress after age 6 years. Therefore, protein control using natural protein with a low lysine content and avoidance of lysine-rich food is advisable after age 6 years.

Genetic counseling is recommended for families of children with GA1.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/

For information about clinical trials sponsored by private sources, contact: www.centerwatch.com

For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/

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References

TEXTBOOKS
Goodman SI, Frerman FE. Organic acidemias due to defects in lysine oxidation: 2-ketoadipic acidemia and glutaric acidemia. In: Scriver CR, Beaudet AL, Sly WS, et al. Eds. The Metabolic Molecular Basis of Inherited Disease. 7th ed. McGraw-Hill Companies. New York, NY; 1995:1451-60.

JOURNAL ARTICLES
Boy N, Mühlhausen C, Maier EM, et al. Recommendations for diagnosing and managing individuals with glutaric aciduria type 1: Third revision. J Inherit Metab Dis. 2023;46(3):482-519. doi:10.1002/jimd.12566

Boy N, Mengler K, Heringer-Seifert J, Hoffmann GF, Garbade SF, Kölker S. Impact of newborn screening and quality of therapy on the neurological outcome in glutaric aciduria type 1: a meta-analysis. Genet Med. 2021;23(1):13-21. doi:10.1038/s41436-020-00971-4

Märtner EMC, Thimm E, Guder P, et al. The biochemical subtype is a predictor for cognitive function in glutaric aciduria type 1: a national prospective follow-up study [published correction appears in Sci Rep. 2021 Oct 12;11(1):20618]. Sci Rep. 2021;11(1):19300. Published 2021 Sep 29. doi:10.1038/s41598-021-98809-9

Peters V, Morath M, Mack M, et al. Formation of 3-hydroxyglutaric acid in glutaric aciduria type I: in vitro participation of medium chain acyl-CoA dehydrogenase. JIMD Rep. 2019;47(1):30–34. Published 2019 Mar 26. doi:10.1002/jmd2.12026

Boy N, Mengler K, Thimm E, et al. Newborn screening: A disease-changing intervention for glutaric aciduria type 1. Ann Neurol. 2018 May;83(5):970-979. doi: 10.1002/ana.25233. Epub 2018 Apr 30.

Boy N, Mühlhausen C, Maier EM, et al. Proposed recommendations for diagnosing and managing individuals with glutaric aciduria type I: second revision. J Inherit Metab Dis. 2017;40(1):75-101. doi:10.1007/s10545-016-9999-9

Mosaeilhy A, Mohamed MM, C GPD, et al. Genotype-phenotype correlation in 18 Egyptian patients with glutaric acidemia type I. Metab Brain Dis. 2017 Oct;32(5):1417-1426. doi: 10.1007/s11011-017-0006-4. Epub 2017 Apr 7. PubMed PMID: 28389991.

Hedlund GL, Longo N, Pasquali M. Glutaric acidemia type 1. Am J Med Genet C Semin Med Genet. 2006 May 15;142C(2):86-94. doi: 10.1002/ajmg.c.30088. Review. PubMed PMID: 16602100; PubMed Central PMCID: PMC2556991.

Bähr O, Mader I, Zschocke J, Dichgans J, Schulz JB. Adult onset glutaric aciduria type I presenting with a leukoencephalopathy. Neurology. 2002 Dec 10;59(11):1802-4. doi: 10.1212/01.wnl.0000036616.11962.3c. PubMed PMID: 12473778.

Kölker S, Ramaekers VT, Zschocke J, Hoffmann GF. Acute encephalopathy despite early therapy in a patient with homozygosity for E365K in the glutaryl-coenzyme A dehydrogenase gene. J Pediatr. 2001 Feb;138(2):277-9. doi: 10.1067/mpd.2001.110303. PubMed PMID: 11174631.

Busquets C, Coll MJ, Merinero B, et al. Prenatal molecular diagnosis of glutaric aciduria type I by direct mutation analysis. Prenat Diagn. 2000 Sep;20(9):761-4. PubMed PMID: 11015709.

Kafil-Hussain NA, Monavari A, Bowell R, Thornton P, Naughten E, O’Keefe M. Ocular findings in glutaric aciduria type 1. J Pediatr Ophthalmol Strabismus. 2000 Sep-Oct;37(5):289-93. PubMed PMID: 11020111.

Zafeiriou DI, Zschocke J, Augoustidou-Savvopoulou P, et al. Atypical and variable clinical presentation of glutaric aciduria type I. Neuropediatrics. 2000 Dec;31(6):303-6. doi: 10.1055/s-2000-12943. PubMed PMID: 11508549.

Baric I, Wagner L, Feyh P, Liesert M, Buckel W, Hoffmann GF. Sensitivity and specificity of free and total glutaric acid and 3-hydroxyglutaric acid measurements by stable-isotope dilution assays for the diagnosis of glutaric aciduria type I. J Inherit Metab Dis.1999 Dec;22(8):867-81. PubMed PMID: 10604139.

Hoffmann GF, Zschocke J. Glutaric aciduria type I: from clinical, biochemical and molecular diversity to successful therapy. J Inherit Metab Dis. 1999 Jun;22(4):381-91. Review. PubMed PMID: 10407775.

Naylor EW, Chace DH. Automated tandem mass spectrometry for mass newborn screening for disorders in fatty acid, organic acid, and amino acid metabolism. J Child Neurol. 1999 Nov;14 Suppl 1:S4-8. doi: 10.1177/0883073899014001021. PubMed PMID: 10593560.

INTERNET
Glutaric Acidemia Type I. MedlinePlus. Last updated September 1, 2019. https://ghr.nlm.nih.gov/condition/glutaric-acidemia-type-i. Accessed Aug 24, 2023.

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Glutaric Acidemia I. Entry Number; 231670. 12/22/2021. https://www.omim.org/entry/231670 Accessed Aug 24, 2023.

Save Babies Through Screening. Glutaric acidemia Type I (GA-I). March 5, 2023. https://www.newbornscreening.info/Parents/organicaciddisorders/GA1.html Accessed Aug 24, 2023.

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