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Glutaric aciduria, type 1(GA1)

MedGen UID:
124337
Concept ID:
C0268595
Disease or Syndrome
Synonyms: GA I; Glutaric acidemia type 1; Glutaric acidemia type I; Glutaricacidemia Type 1; Glutaricaciduria, type I; Glutaryl-CoA dehydrogenase deficiency
SNOMED CT: Glutaric aciduria, type 1 (76175005); Glutaric acidemia, type 1 (76175005); GA I (76175005); Glutaryl-coenzyme A dehydrogenase deficiency (360416003); Glutaryl-CoA dehydrogenase deficiency (360416003); Glutaric aciduria type I (76175005)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): GCDH (19p13.13)
 
Monarch Initiative: MONDO:0009281
OMIM®: 231670
Orphanet: ORPHA25

Disease characteristics

Excerpted from the GeneReview: Glutaric Acidemia Type 1
The phenotypic spectrum of untreated glutaric acidemia type 1 (GA-1) ranges from the more common form (infantile-onset disease) to the less common form (later-onset disease – i.e., after age 6 years). Of note, the GA-1 phenotype can vary widely between untreated family members with the same genotype, primarily as a function of the age at which the first acute encephalopathic crisis occurred: three months to six years in infantile-onset GA-1 and after age six years in later-onset GA-1. Characteristically these crises result in acute bilateral striatal injury and subsequent complex movement disorders. In the era of newborn screening (NBS), the prompt initiation of treatment of asymptomatic infants detected by NBS means that most individuals who would have developed manifestations of either infantile-onset or later-onset GA-1 remain asymptomatic; however, they may be at increased risk for other manifestations (e.g., renal disease) that are becoming apparent as the understanding of the natural history of treated GA-1 continues to evolve. [from GeneReviews]
Authors:
Austin Larson  |  Steve Goodman   view full author information

Additional descriptions

From OMIM
Glutaric acidemia I is an autosomal recessive metabolic disorder characterized by gliosis and neuronal loss in the basal ganglia and a progressive movement disorder that usually begins during the first year of life (Goodman et al., 1995). Hedlund et al. (2006) provided a detailed review of the clinical and biochemical aspects of glutaric acidemia type I.  http://www.omim.org/entry/231670
From MedlinePlus Genetics
Glutaric acidemia type I (also called glutaric aciduria type I) is an inherited disorder in which the body is unable to process certain proteins properly. It is classified as an organic acid disorder, which is a condition that leads to an abnormal buildup of particular acids known as organic acids. Abnormal levels of organic acids in the blood (organic acidemia), urine (organic aciduria), and tissues can be toxic and can cause serious health problems.

People with glutaric acidemia type I have inadequate levels of an enzyme that helps break down the amino acids lysine, hydroxylysine, and tryptophan, which are building blocks of protein. Excessive levels of these amino acids and their intermediate breakdown products can accumulate and cause damage to the brain, particularly the basal ganglia, which are regions that help control movement. Intellectual disability may also occur.

The severity of glutaric acidemia type I varies widely; some individuals are only mildly affected, while others have severe problems. In most cases, signs and symptoms first occur in infancy or early childhood, but in a small number of affected individuals, the disorder first becomes apparent in adolescence or adulthood.

Some babies with glutaric acidemia type I are born with unusually large heads (macrocephaly). Affected individuals may have difficulty moving and may experience spasms, jerking, rigidity, or decreased muscle tone. Some individuals with glutaric acidemia have developed bleeding in the brain or eyes that could be mistaken for the effects of child abuse. Strict dietary control may help limit progression of the neurological damage. Stress caused by infection, fever or other demands on the body may lead to worsening of the signs and symptoms, with only partial recovery.  https://medlineplus.gov/genetics/condition/glutaric-acidemia-type-i

Clinical features

From HPO
Ketonuria
MedGen UID:
56402
Concept ID:
C0162275
Finding
High levels of ketone bodies (acetoacetic acid, beta-hydroxybutyric acid, and acetone) in the urine. Ketone bodies are insignificant in the blood and urine of normal individuals in the postprandial or overnight-fasted state.
Glutaric aciduria
MedGen UID:
75695
Concept ID:
C0268594
Disease or Syndrome
The concentration of glutaric acid in the urine, normalized for urine concentration, is above the upper limit of normal.
Elevated urine 3-hydroxyglutaric level
MedGen UID:
1841727
Concept ID:
C5826565
Finding
The concentration of 3-hydroxyglutaric acid in the urine, normalized for urine concentration, is above the upper limit of normal.
Subdural hemorrhage
MedGen UID:
6775
Concept ID:
C0018946
Pathologic Function
Hemorrhage occurring between the dura mater and the arachnoid mater.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Dystonic disorder
MedGen UID:
3940
Concept ID:
C0013421
Sign or Symptom
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Hydrocephalus
MedGen UID:
9335
Concept ID:
C0020255
Disease or Syndrome
Hydrocephalus is an active distension of the ventricular system of the brain resulting from inadequate passage of CSF from its point of production within the cerebral ventricles to its point of absorption into the systemic circulation.
Spastic diplegia
MedGen UID:
44181
Concept ID:
C0023882
Disease or Syndrome
Spasticity (neuromuscular hypertonia) primarily in the muscles of the legs, hips, and pelvis.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Choreoathetosis
MedGen UID:
39313
Concept ID:
C0085583
Disease or Syndrome
Involuntary movements characterized by both athetosis (inability to sustain muscles in a fixed position) and chorea (widespread jerky arrhythmic movements).
Encephalopathy
MedGen UID:
39314
Concept ID:
C0085584
Disease or Syndrome
Encephalopathy is a term that means brain disease, damage, or malfunction. In general, encephalopathy is manifested by an altered mental state.
Opisthotonus
MedGen UID:
56246
Concept ID:
C0151818
Sign or Symptom
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Inability to walk
MedGen UID:
107860
Concept ID:
C0560046
Finding
Incapability to ambulate.
Acute encephalopathy
MedGen UID:
224930
Concept ID:
C1306587
Disease or Syndrome
A life-threatening disorder characterized by delirium, seizures, and neuromuscular changes.
Developmental regression
MedGen UID:
324613
Concept ID:
C1836830
Disease or Syndrome
Loss of developmental skills, as manifested by loss of developmental milestones.
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
Infantile encephalopathy
MedGen UID:
343542
Concept ID:
C1856408
Finding
Encephalopathy with onset in the infantile period.
Lateral ventricle dilatation
MedGen UID:
383904
Concept ID:
C1856409
Pathologic Function
Irritability
MedGen UID:
397841
Concept ID:
C2700617
Mental Process
A proneness to anger, i.e., a tendency to become easily bothered or annoyed.
Enlarged sylvian cistern
MedGen UID:
866575
Concept ID:
C4020921
Finding
An increase in size of the subarachnoid space associated with the lateral cerebral sulcus (Sylvian fissure).
Symmetrical progressive peripheral demyelination
MedGen UID:
870524
Concept ID:
C4024972
Disease or Syndrome
A symmetric and progressive loss of myelin from the internode regions along myelinated nerve fibers of the peripheral nervous system.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Rigidity
MedGen UID:
7752
Concept ID:
C0026837
Sign or Symptom
Continuous involuntary sustained muscle contraction. When an affected muscle is passively stretched, the degree of resistance remains constant regardless of the rate at which the muscle is stretched. This feature helps to distinguish rigidity from muscle spasticity.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Macrocephaly
MedGen UID:
745757
Concept ID:
C2243051
Finding
Occipitofrontal (head) circumference greater than 97th centile compared to appropriate, age matched, sex-matched normal standards. Alternatively, a apparently increased size of the cranium.
Hypoglycemia
MedGen UID:
6979
Concept ID:
C0020615
Disease or Syndrome
A decreased concentration of glucose in the blood.
Ketosis
MedGen UID:
7206
Concept ID:
C0022638
Disease or Syndrome
Presence of elevated levels of ketone bodies in the body.
Metabolic acidosis
MedGen UID:
65117
Concept ID:
C0220981
Pathologic Function
Metabolic acidosis (MA) is characterized by a fall in blood pH due to a reduction of serum bicarbonate concentration. This can occur as a result of either the accumulation of acids (high anion gap MA) or the loss of bicarbonate from the gastrointestinal tract or the kidney (hyperchloremic MA). By definition, MA is not due to a respirary cause.
Hyperketonemia
MedGen UID:
66722
Concept ID:
C0235430
Disease or Syndrome
An increase in the level of ketone bodies (acetoacetic acid, beta-hydroxybutyric acid, and acetone) in the blood.
Elevated circulating glutaric acid concentration
MedGen UID:
871132
Concept ID:
C4025603
Finding
An increased concentration of glutaric acid in the blood.
Elevated circulating glutarylcarnitine concentration
MedGen UID:
1781232
Concept ID:
C5539595
Finding
Concentration of glutarylcarnitine in the blood circulation above the upper limit of normal.
Reduced peroxisomal glutaryl-CoA oxidase activity
MedGen UID:
1842072
Concept ID:
C5826590
Finding
Diminished enzyme activity of peroxisomal glutaryl-CoA oxidase, an enzyme that metabolizes glutaryl-CoA (a metabolite of L-lysine, L-hydroxy-lysine and L-tryptophan) by dehydrogenation to glutaconyl-CoA directly followed by decarboxylation of this to crotonyl-CoA.

Professional guidelines

PubMed

Schuurmans IME, Dimitrov B, Schröter J, Ribes A, de la Fuente RP, Zamora B, van Karnebeek CDM, Kölker S, Garanto A
J Inherit Metab Dis 2023 May;46(3):371-390. Epub 2023 Apr 16 doi: 10.1002/jimd.12608. PMID: 37020324
Yahyaoui R, Blasco-Alonso J, Gonzalo-Marín M, Benito C, Serrano-Nieto J, González-Gallego I, Ruiz-Sala P, Pérez B, González-Lamuño D
Genes (Basel) 2020 Aug 29;11(9) doi: 10.3390/genes11091018. PMID: 32872442Free PMC Article
Tuncel AT, Boy N, Morath MA, Hörster F, Mütze U, Kölker S
J Inherit Metab Dis 2018 Sep;41(5):765-776. Epub 2018 Jan 15 doi: 10.1007/s10545-017-0135-2. PMID: 29335813

Curated

American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated C5-DC Acylcarnitine, Glutaric Acidemia Type I (GA I), 2022

American College of Medical Genetics and Genomics, Algorithm, Glutaric Acidemia Type I (GA I): Elevated C5-DC, 2022

Recent clinical studies

Etiology

Bian B, Liu Z, Feng D, Li W, Wang L, Li Y, Li D
AJNR Am J Neuroradiol 2023 Aug;44(8):967-973. Epub 2023 Jul 20 doi: 10.3174/ajnr.A7928. PMID: 37474264Free PMC Article
Boy N, Mühlhausen C, Maier EM, Ballhausen D, Baumgartner MR, Beblo S, Burgard P, Chapman KA, Dobbelaere D, Heringer-Seifert J, Fleissner S, Grohmann-Held K, Hahn G, Harting I, Hoffmann GF, Jochum F, Karall D, Konstantopoulous V, Krawinkel MB, Lindner M, Märtner EMC, Nuoffer JM, Okun JG, Plecko B, Posset R, Sahm K, Scholl-Bürgi S, Thimm E, Walter M, Williams M, Vom Dahl S, Ziagaki A, Zschocke J, Kölker S
J Inherit Metab Dis 2023 May;46(3):482-519. Epub 2022 Nov 17 doi: 10.1002/jimd.12566. PMID: 36221165
Özgedi K DD, Tokgöz Yılmaz S, Gürbüz BB, Si Vri HS, Sennaroğlu G
Metab Brain Dis 2022 Aug;37(6):2121-2132. Epub 2022 Apr 30 doi: 10.1007/s11011-022-00987-6. PMID: 35488943
Chen YC, Huang CY, Lee YT, Wu CH, Chang SK, Cheng HL, Chang PH, Niu DM, Cheng YF
Orphanet J Rare Dis 2020 Dec 1;15(1):337. doi: 10.1186/s13023-020-01571-w. PMID: 33256818Free PMC Article
Roujeau T, Mireau E, Bourgeois M
Handb Clin Neurol 2013;112:905-12. doi: 10.1016/B978-0-444-52910-7.00012-X. PMID: 23622300

Diagnosis

Bian B, Liu Z, Feng D, Li W, Wang L, Li Y, Li D
AJNR Am J Neuroradiol 2023 Aug;44(8):967-973. Epub 2023 Jul 20 doi: 10.3174/ajnr.A7928. PMID: 37474264Free PMC Article
Boy N, Mühlhausen C, Maier EM, Ballhausen D, Baumgartner MR, Beblo S, Burgard P, Chapman KA, Dobbelaere D, Heringer-Seifert J, Fleissner S, Grohmann-Held K, Hahn G, Harting I, Hoffmann GF, Jochum F, Karall D, Konstantopoulous V, Krawinkel MB, Lindner M, Märtner EMC, Nuoffer JM, Okun JG, Plecko B, Posset R, Sahm K, Scholl-Bürgi S, Thimm E, Walter M, Williams M, Vom Dahl S, Ziagaki A, Zschocke J, Kölker S
J Inherit Metab Dis 2023 May;46(3):482-519. Epub 2022 Nov 17 doi: 10.1002/jimd.12566. PMID: 36221165
Özgedi K DD, Tokgöz Yılmaz S, Gürbüz BB, Si Vri HS, Sennaroğlu G
Metab Brain Dis 2022 Aug;37(6):2121-2132. Epub 2022 Apr 30 doi: 10.1007/s11011-022-00987-6. PMID: 35488943
Bouchereau J, Schiff M
J Nutr 2020 Oct 1;150(Suppl 1):2556S-2560S. doi: 10.1093/jn/nxaa112. PMID: 33000154
Roujeau T, Mireau E, Bourgeois M
Handb Clin Neurol 2013;112:905-12. doi: 10.1016/B978-0-444-52910-7.00012-X. PMID: 23622300

Therapy

Shlobin NA, Hofmann K, Keating RF, Oluigbo CO
J Inherit Metab Dis 2023 Jul;46(4):543-553. Epub 2023 Jun 13 doi: 10.1002/jimd.12638. PMID: 37254447
Kaur S, Campbell SL, Stockton DW
Am J Med Genet A 2021 Jun;185(6):1854-1857. Epub 2021 Mar 8 doi: 10.1002/ajmg.a.62161. PMID: 33686767Free PMC Article
Bernstein L, Coughlin CR, Drumm M, Yannicelli S, Rohr F
Nutrients 2020 Oct 16;12(10) doi: 10.3390/nu12103162. PMID: 33081139Free PMC Article
Bouchereau J, Schiff M
J Nutr 2020 Oct 1;150(Suppl 1):2556S-2560S. doi: 10.1093/jn/nxaa112. PMID: 33000154
Gokmen-Ozel H, MacDonald A, Daly A, Ashmore C, Preece MA, Hendriksz C, Vijay S, Chakrapani A
J Hum Nutr Diet 2012 Dec;25(6):514-9. Epub 2012 Jul 30 doi: 10.1111/j.1365-277X.2012.01269.x. PMID: 22845646

Prognosis

Yuan Y, Dimitrov B, Boy N, Gleich F, Zielonka M, Kölker S
J Inherit Metab Dis 2023 May;46(3):391-405. Epub 2023 May 2 doi: 10.1002/jimd.12618. PMID: 37078465
Schuurmans IME, Dimitrov B, Schröter J, Ribes A, de la Fuente RP, Zamora B, van Karnebeek CDM, Kölker S, Garanto A
J Inherit Metab Dis 2023 May;46(3):371-390. Epub 2023 Apr 16 doi: 10.1002/jimd.12608. PMID: 37020324
Gürbüz BB, Yılmaz DY, Coşkun T, Tokatlı A, Dursun A, Sivri HS
Eur J Med Genet 2020 Nov;63(11):104032. Epub 2020 Aug 7 doi: 10.1016/j.ejmg.2020.104032. PMID: 32777384
Tuncel AT, Boy N, Morath MA, Hörster F, Mütze U, Kölker S
J Inherit Metab Dis 2018 Sep;41(5):765-776. Epub 2018 Jan 15 doi: 10.1007/s10545-017-0135-2. PMID: 29335813
Roujeau T, Mireau E, Bourgeois M
Handb Clin Neurol 2013;112:905-12. doi: 10.1016/B978-0-444-52910-7.00012-X. PMID: 23622300

Clinical prediction guides

Bian B, Liu Z, Feng D, Li W, Wang L, Li Y, Li D
AJNR Am J Neuroradiol 2023 Aug;44(8):967-973. Epub 2023 Jul 20 doi: 10.3174/ajnr.A7928. PMID: 37474264Free PMC Article
Schuurmans IME, Dimitrov B, Schröter J, Ribes A, de la Fuente RP, Zamora B, van Karnebeek CDM, Kölker S, Garanto A
J Inherit Metab Dis 2023 May;46(3):371-390. Epub 2023 Apr 16 doi: 10.1002/jimd.12608. PMID: 37020324
Özgedi K DD, Tokgöz Yılmaz S, Gürbüz BB, Si Vri HS, Sennaroğlu G
Metab Brain Dis 2022 Aug;37(6):2121-2132. Epub 2022 Apr 30 doi: 10.1007/s11011-022-00987-6. PMID: 35488943
Gürbüz BB, Yılmaz DY, Coşkun T, Tokatlı A, Dursun A, Sivri HS
Eur J Med Genet 2020 Nov;63(11):104032. Epub 2020 Aug 7 doi: 10.1016/j.ejmg.2020.104032. PMID: 32777384
Mohammad SA, Abdelkhalek HS, Ahmed KA, Zaki OK
Pediatr Radiol 2015 Oct;45(11):1696-705. Epub 2015 Jun 26 doi: 10.1007/s00247-015-3395-8. PMID: 26111870

Recent systematic reviews

Boy N, Mengler K, Heringer-Seifert J, Hoffmann GF, Garbade SF, Kölker S
Genet Med 2021 Jan;23(1):13-21. Epub 2020 Sep 28 doi: 10.1038/s41436-020-00971-4. PMID: 32981931Free PMC Article
Vester ME, Bilo RA, Karst WA, Daams JG, Duijst WL, van Rijn RR
Forensic Sci Med Pathol 2015 Sep;11(3):405-15. Epub 2015 Jul 29 doi: 10.1007/s12024-015-9698-0. PMID: 26219480Free PMC Article
Thomason MJ, Lord J, Bain MD, Chalmers RA, Littlejohns P, Addison GM, Wilcox AH, Seymour CA
J Public Health Med 1998 Sep;20(3):331-43. doi: 10.1093/oxfordjournals.pubmed.a024777. PMID: 9793900
Seymour CA, Thomason MJ, Chalmers RA, Addison GM, Bain MD, Cockburn F, Littlejohns P, Lord J, Wilcox AH
Health Technol Assess 1997;1(11):i-iv, 1-95. PMID: 9483156

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • ACMG ACT, 2022
      American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated C5-DC Acylcarnitine, Glutaric Acidemia Type I (GA I), 2022
    • ACMG Algorithm, 2022
      American College of Medical Genetics and Genomics, Algorithm, Glutaric Acidemia Type I (GA I): Elevated C5-DC, 2022

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