Glutaric Aciduria Type I

Disease Overview

Summary

Glutaric aciduria type I (GA1) is a rare inherited metabolic condition. GA1 affects how the body breaks down certain proteins, and harmful substances can build up in the brain if treatment is not started early.

GA1 It is caused by a deficiency of an enzyme (a helper protein) called glutaryl-CoA dehydrogenase (GCDH). Enzymes are proteins that help the body carry out chemical reactions. GCDH normally works inside the mitochondria, which are the parts of the cell that produce energy.

GA1 belongs to a group of conditions called cerebral organic acidemias, meaning disorders in which certain organic acids build up in the body and can affect the brain.

In people with GA1, the GCDH enzyme does not work properly or is completely absent. This enzyme is needed to break down lysine, an amino acid found in many protein-containing foods. When lysine cannot be processed correctly, several related substances (including glutaric acid, 3-hydroxyglutaric acid, and glutaconic acid) build up in the body, which can be harmful to the brain. Another substance, glutarylcarnitine (C5DC), also increases but is not toxic.

There are two main biochemical (based on lab findings) forms of GA1, often called high excretors and low excretors, based on how much glutaric acid is passed in the urine and reflect how well the enzyme is still working. People with low excretor GA1 may produce smaller amounts of glutaric acid, which can make the condition harder to detect.

Early signs in newborns may be subtle and nonspecific. Some babies have an unusually large head size (macrocephaly) or low muscle tone (hypotonia). Without treatment, most affected children experience a sudden and severe brain illness called an acute encephalopathic crisis. This often occurs in the first three years of life and is usually triggered by fever, infection, or other situations in which the body is under stress and begins breaking down its own tissues for energy (called catabolic stress). These crises can cause damage to a deep area of the brain called the striatum (seen as injury on both sides of this area, called bilateral striatal lesions). Bilateral striatal lesions can lead to long-term movement problems such as dystonia, which involves involuntary muscle contractions and abnormal postures. Although less common, these acute events have been reported up to six years of age.

Some individuals develop brain injury more gradually, without a clearly identifiable crisis. In addition, babies with GA1 may sometimes develop subdural hemorrhages, meaning bleeding that collects around the brain, between the brain and skull. Because of this, GA1 has occasionally been mistaken for abusive head trauma (non-accidental injury).

Early diagnosis and treatment greatly improve outcomes. For this reason, GA1 has been added to newborn screening programs in many countries, allowing treatment to begin shortly after birth. However, it is important to note that some individuals with the low excretor form may not be detected through newborn screening because their C5DC levels may fall within the normal range on screening tests.

Introduction

For approximately 80–90% of individuals with glutaric aciduria type 1(GA1), serious movement problems can be prevented if the condition is diagnosed early through newborn screening and treatment is started immediately. Treatment focuses on reducing the buildup of harmful substances and protecting the brain.

Treatment usually includes a low-lysine diet to limit the amino acid that cannot be properly broken down. This is a specialized amino acid supplement that is in a special medical formula that does not contain lysine, has less tryptophan, and enriched with arginine to support normal growth. This also includes carnitine supplements taken by mouth, which help remove toxic substances from the body.

Emergency treatment during illness, such as fever or infection, is very important to prevent metabolic stress (when the body is under strain from illness) that could trigger brain injury.

If treatment is delayed or not followed consistently, movement symptoms may develop either suddenly or gradually during infancy or early childhood, usually before six years of age. These symptoms can vary widely in severity from one individual to another.

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Synonyms

GA1
glutaric acidemia type I
glutaric aciduria type I
glutaryl-CoA dehydrogenase deficiency
GCDHD
Glutaryl-coenzyme A dehydrogenase deficiency

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Signs & Symptoms

Glutaric aciduria type 1 (GA1) often affects the brain areas that control movement, especially in early childhood if the condition is not treated.

Babies with glutaric aciduria Type 1 (GA1) are usually born appearing healthy. Early signs can be subtle and may include macrocephaly, meaning a head size larger than expected for age, or hypotonia, which refers to low muscle tone. Because an enlarged head circumference is one of the earliest signs of GA1, newborns with macrocephaly should be evaluated for this condition.

Between about 3 months and 3 years of age, many untreated children develop a serious event called an acute encephalopathic crisis (a sudden and severe brain illness). This is a sudden episode of brain dysfunction that is often triggered by situations that place stress on the body, known as catabolic conditions – times when the body breaks down its own tissues for energy. These triggers can be fever from infections, fever after vaccinations, or surgery. During these crises, damage occurs in the striatum, a deep part of the brain that helps control movement.

This brain injury can lead to a severe and permanent movement disorder, most commonly dystonia. Dystonia causes abnormal muscle tightening that leads to twisting movements or unusual postures. These movement problems are often complex, difficult to manage, and can be associated with significant disability, affecting walking, speaking, or daily activities. In severe cases, this brain injury can also be life-threatening.

Affected children may show symptoms that resemble cerebral palsy, including frequent abnormal body positions caused by poor muscle control. They may have involuntary movements that are slow and writhing (athetosis) or quick and jerky movements (chorea) involving the arms, legs, trunk, head, or neck. Controlling voluntary (intentional) movements can become very difficult, and painful muscle spasms may occur. Repeated stress on the body, such as infections with fever, can worsen symptoms. In some children, however, brain injury can occur even without a clear triggering illness.

Early warning signs of an acute encephalopathic crisis may include:

Irritability

Jitteriness or shakiness

Nausea, vomiting, or diarrhea

Low muscle tone (hypotonia)

Poor appetite or difficulty feeding

Unusual sleepiness or low energy

Muscle weakness

Possible permanent neurologic effects of an acute encephalopathic crisis include:

Involuntary, uncontrolled movements (dyskinesia)

Sustained abnormal postures due to increased muscle tone (dystonia)

Involuntary movements of the face, mouth, or tongue (orofacial dyskinesia)

A combination of jerky and writhing movements (choreoathetosis)

Involuntary shaking movements of the eyes (nystagmus)

Difficulties with thinking or learning (cognitive impairment) – This is variable and not seen in many patients.

Loss of previously learned skills (developmental regression)

Severe muscle spasms causing backward arching of the body (opisthotonus)

Coma

In addition to sudden onset crises, some people develop brain injury more gradually over time, (called insidious onset). This has been reported in up to 50% of symptomatic children identified through newborn screening and is most often linked to not fully following dietary treatment recommendations. These children typically develop a milder form of dystonic movement disorder, and brain imaging shows a characteristic pattern of injury limited to a specific part of the striatum called the dorsolateral putamen. New onset of striatal injury has not been reported after 6 years of age.

In addition to the striatum, some people with GA1show other brain changes on imaging tests such as MRI scans called extrastriatal abnormalities. These can include underdevelopment of the front and side (temporal) regions of the brain (frontotemporal hypoplasia), widening of fluid-filled spaces around the brain (cerebrospinal fluid spaces), enlargement of the Sylvian fissure (a deep groove on the side of the brain), or abnormalities in the brain’s white matter, which helps transmit signals between brain regions.

Although people with high excretor (HE) and low excretor (LE) forms of GA1 have a similar risk of striatal injury, those with the HE form more often show extrastriatal brain abnormalities (brain changes outside the movement control areas). They also tend to have higher levels of harmful metabolic byproducts (toxic metabolites) in the brain, larger head size, a higher risk of subdural hemorrhages (bleeding between the brain and the skull), and poorer cognitive outcomes.

Some people are diagnosed later in life, during adolescence or adulthood. These late-onset cases may present with less specific neurologic symptoms such as nerve damage in the arms or legs (polyneuropathy), bladder control problems, headaches, tremor, seizures, or changes in thinking or memory (cognitive decline). In these cases, typical striatal injury may be absent.

GA1 is also associated with an increased risk of subdural hemorrhage (bleeding between the brain and the skull), as well as subdural hygroma, which is a collection of cerebrospinal fluid in the same space. These findings occur most often in the first three years of life, especially in late infancy, and are more common in people with the HE form. They are usually accompanied by other characteristic findings on brain MRI. In recent years, additional complications, such as chronic kidney disease, have also been reported in adolescents and adults with GA1.

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Causes

GA1 is caused by harmful changes (pathogenic variants in the GCDH gene that leads to deficiency of the enzyme, glutaryl-CoA dehydrogenase (GCDH). This enzyme is responsible for breaking down (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, which helps control 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

Glutaric aciduria type 1 (GA1) is a rare inborn error of metabolism (a rare genetic disorder where the body cannot properly process food into energy) that affects males as often as females. In the United States, it is estimated that about 140 people are living with GA1. Overall, GA1 occurs in about 1 in every 100,000 births.

GA1 is more common in certain populations due to shared genetic ancestry. Five genetic isolates (populations that have remained relatively genetically distinct over generations) are known to have a higher carrier frequency (as high as 1 in 10 people carrying one non-working copy of the gene) and a higher incidence of GA1 (up to 1 in 250 newborns being affected. These populations include 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 the United Kingdom; the Lumbee in North Carolina, United States; and the Xhosa in South Africa.

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Disorders with Similar Symptoms

Because GA1 affects brain regions involved in movement control, its signs and symptoms, particularly in infancy and early childhood, can resemble those of several other neurological and metabolic conditions. This can make diagnosis challenging, especially before GA1 is recognized or confirmed through specialized testing.

Conditions that have similar features include brain infections (such as encephalitis), certain metabolic disorders, and movement disorders that affect the same deep brain structures involved in motor control. These conditions may be considered during evaluation and include:

Reye syndrome, a rare condition that can cause sudden brain dysfunction in children

Familial infantile bilateral striatal necrosis, a rare genetic disorder that affects the same movement-related brain regions as GA1

Familial megalocephaly, a genetic condition characterized by an unusually large head size

Post-encephalitic parkinsonism, a movement disorder that can develop after brain inflammation

Dystonic cerebral palsy, a non-progressive movement disorder marked by abnormal muscle tone and postures

In some cases, especially when brain imaging shows bleeding or fluid collections around the brain, GA1 has historically been mistaken for other causes of brain injury. These have included:

Abusive head trauma (previously referred to as “battered child syndrome”), particularly in the presence of chronic subdural effusions (fluid collections)

Sudden infant death syndrome (SIDS), in cases of unexplained infant death before diagnosis

Suspected vaccine-related brain injury, when symptoms followed routine illness or fever after vaccination, although vaccines are not known to cause GA1

From a diagnostic laboratory perspective, certain biochemical findings seen in GA1 may also be observed in other conditions, which is important to consider during evaluation.

Increased levels of 3-hydroxygluataric acid (3‐OH‐GA), which are typical in GA1, have also been reported in individuals with short‐chain 3‐hydroxyacyl CoA dehydrogenase (SCAD) deficiency, patients with renal insufficiency, disorders of long‐chain fatty acid oxidation, mitochondrial disorders, and in ketotic states.

Careful clinical evaluation, brain imaging, and metabolic and genetic testing are essential to distinguish GA1 from these conditions and to ensure appropriate treatment.

Glutaric aciduria type II (GA II) is a totally different disease from GA1. GA II belongs to a group of conditions known as fatty acid oxidation disorders, which affect the body’s ability to break down fats for energy due to deficiencies in specific enzymes. Two forms of this disorder occur during different stages of life.

1) Glutaric aciduria IIA (GA IIA) is the neonatal (newborn) form of glutaricaciduria II. This form of glutaric aciduria II is a very rare, autosomal recessive disorder characterized by the accumulation of large amounts of glutaric acid and other organic acids in the blood and urine. The disorder is caused by dysfunction of the electron-transferring flavoprotein in the mitochondria, a protein that helps cells produce energy from fats.

2) Glutarica aciduria IIB (GA IIB; ethylmalonic adipicaciduria) is the adult form of glutaricaciduria II. This milder form of the disorder is inherited in an autosomal recessive pattern. It presents in adulthood with excess acidity in the body tissues (metabolic acidosis), and a low blood sugar (hypoglycemia) without an elevated level of ketones in body tissues (ketosis). Large amounts of glutaric acid in the blood and urine are caused by a deficiency of the enzyme multiple acyl-CoA dehydrogenase.

Glutaric aciduria type III is another distinct autosomal recessive condition characterized by accumulation or excretion of glutaric acid and caused by pathogenic variants in the C7ORF10 gene, which plays a role in normal organic acid metabolism. Symptoms vary, and some individuals show no symptoms.

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Diagnosis

GA1 Is diagnosed by identifying a specific pattern of substances in the body that build up when the condition is present. These substances (called metabolites) include glutaric acid (GA), 3-hydroxyglutaric acid (3-OH-GA), glutaconic acid, and blutarylcarnitine (C5DC). They can be detected in body fluids such as urine, blood plasma, or cererbrospinal fluid.

These metabolites are measured using specialized laboratory techniques, including gas chromatography/mass spectrometry (GC/MS) or electrospray-ionization tandem mass spectrometry (MS/MS), which are highly sensitive tests that can detect very small amounts of these substances.

Because early diagnosis and prompt treatment greatly improve neurological outcomes, GA1 has been added to MS/MS-based newborn screening (NBS) panels in many countries worldwide, allowing affected infants to be identified soon after birth.

If a newborn screening result is abnormal, the diagnosis must be confirmed with more detailed testing. This typically includes quantitative measurement of GA and 3-OH-GA in urine and/or blood using GC/MS, genetic testing (variant analysis) of the GCDH gene and/or GCDH enzyme activity in white blood cells (leukocytes) or skin cells grown in the lab (fibroblasts).

The diagnosis of GA1 is confirmed by significantly reduced enzyme activity of the GCDH enzyme and/or identifying two disease-causing variants in the GCDH gene.

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Standard Therapies

Metabolic treatment
Following guideline-recommended treatment is associated with the best neurological outcomes for people with GA1. Evidence-based treatment recommendations have been developed and refined since 2003, resulting in a first international guideline published in 2007 and most recently updated in 2023.

Today, GA1 is considered a treatable condition when managed appropriately. Treatment focuses on reducing the buildup of harmful substances in the body and protecting the brain, especially during early childhood.

Metabolic treatment typically includes:

A low lysine diet, which limits the amino acid that cannot be properly broken down in GA1

A specialized medical formula that does not contain lysine and has reduced tryptophan, helping meet nutritional needs while minimizing harmful byproducts

Oral supplementation with L-carnitine, which helps the body remove toxic substances

An intensified emergency treatment plan during illness, fever, or surgery to prevent metabolic stress that could trigger brain injury

This treatment approach is recommended by international expert guidelines for all patients during early childhood, particularly up to six years of age.

With early diagnosis and consistent treatment beginning in the newborn (neonatal) period – before symptoms appear – many children with GA1 can grow and develop normally. If treatment is delayed or not followed carefully, GA1 can cause serious and irreversible neurological injury, most often affecting movement control, and can shorten life expectancy, especially when brain injury occurs before six years of age.

Long-term outcomes beyond childhood are still being studied. Some individuals may develop neurological symptoms or health problems outside the brain, such as chronic kidney disease, later in life. Changes seen on brain MRI outside the primary movement-control areas (extrastriatal) may also progress after six years of age. For this reason, ongoing dietary management using natural protein sources that are low in lysine and avoiding lysine-rich foods is generally recommended beyond early childhood.

Genetic counseling is recommended for individuals with GA1 and their families to support understanding of inheritance, testing, and family planning

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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 January 5, 2025.

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 January 5, 2025.

Save Babies Through Screening. Glutaric acidemia Type I (GA-I). March 5, 2023. https://www.newbornscreening.info/Parents/organicaciddisorders/GA1.html Accessed March 5, 2023 Accessed January 5, 2025.

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