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Hyperammonemia, type III(NAGSD)

MedGen UID:
120649
Concept ID:
C0268543
Disease or Syndrome
Synonyms: Hyperammonemia due to N-acetylglutamate synthase deficiency; N-Acetylglutamate Synthase Deficiency; NAG synthetase deficiency; NAGSD
SNOMED CT: N-Acetylglutamate synthase deficiency (57119000); NAGS - N-Acetylglutamate synthase deficiency (57119000); NAGS deficiency (57119000); Hyperammonemia, type III (57119000); N-acetylglutamate synthetase deficiency (57119000); Amino acid acetyltransferase deficiency (57119000); N-acetylglutamate transferase deficiency (57119000); AGA deficiency (57119000); Congenital AGA deficiency (57119000)
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): NAGS (17q21.31)
 
Monarch Initiative: MONDO:0009377
OMIM®: 237310
Orphanet: ORPHA927

Definition

N-acetylglutamate synthase deficiency is an autosomal recessive disorder of the urea cycle. The clinical and biochemical features of the disorder are indistinguishable from carbamoyl phosphate synthase I deficiency (237300), since the CPS1 enzyme (608307) has an absolute requirement for NAGS (Caldovic et al., 2007). [from OMIM]

Additional description

From MedlinePlus Genetics
N-acetylglutamate synthase deficiency is a disorder that causes abnormally high levels of ammonia to accumulate in the blood. Ammonia, which is formed when proteins are broken down in the body, is toxic if the levels become too high. The brain is especially sensitive to the effects of excess ammonia.

The signs and symptoms of N-acetylglutamate synthase deficiency often become evident in the first few days of life. An infant with this condition may be lacking in energy (lethargic) or unwilling to eat, and have difficulty controlling his or her breathing rate or body temperature. Severely affected babies may experience seizures or unusual body movements, or go into a coma. Complications of N-acetylglutamate synthase deficiency may include developmental delay and intellectual disability.

In some affected individuals, signs and symptoms of N-acetylglutamate synthase deficiency do not appear until later in life. Some people with this form of the disorder notice that eating high-protein foods, such as meat, affects how they feel, although they may not know why. In many affected adults, illness or other stress can trigger episodes of vomiting, lack of coordination, headaches, confusion, behavioral changes, or coma.  https://medlineplus.gov/genetics/condition/n-acetylglutamate-synthase-deficiency

Clinical features

From HPO
Aggressive behavior
MedGen UID:
1375
Concept ID:
C0001807
Individual Behavior
Aggressive behavior can denote verbal aggression, physical aggression against objects, physical aggression against people, and may also include aggression towards oneself.
Coma
MedGen UID:
1054
Concept ID:
C0009421
Disease or Syndrome
Complete absence of wakefulness and content of conscience, which manifests itself as a lack of response to any kind of external stimuli.
Confusion
MedGen UID:
3587
Concept ID:
C0009676
Mental or Behavioral Dysfunction
Lack of clarity and coherence of thought, perception, understanding, or action.
Lethargy
MedGen UID:
7310
Concept ID:
C0023380
Sign or Symptom
A state of disinterestedness, listlessness, and indifference, resulting in difficulty performing simple tasks or concentrating.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Vomiting
MedGen UID:
12124
Concept ID:
C0042963
Sign or Symptom
Forceful ejection of the contents of the stomach through the mouth by means of a series of involuntary spasmic contractions.
Hyperammonemia
MedGen UID:
113136
Concept ID:
C0220994
Disease or Syndrome
An increased concentration of ammonia in the blood.
Cognitive impairment
MedGen UID:
90932
Concept ID:
C0338656
Mental or Behavioral Dysfunction
Abnormal cognition with deficits in thinking, reasoning, or remembering.
Respiratory distress
MedGen UID:
96907
Concept ID:
C0476273
Sign or Symptom
Respiratory distress is objectively observable as the physical or emotional consequences from the experience of dyspnea. The physical presentation of respiratory distress is generally referred to as labored breathing, while the sensation of respiratory distress is called shortness of breath or dyspnea.
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.
Increased level of L-glutamic acid in blood
MedGen UID:
1641276
Concept ID:
C4703634
Finding
An increase in the level of L-glutamic acid in the blood.

Recent clinical studies

Etiology

Madigan T, Block DR, Carey WA, Kaemingk BD, Patel R
J Appl Lab Med 2020 Mar 1;5(2):363-369. doi: 10.1093/jalm/jfz001. PMID: 32445380Free PMC Article
Janeiro P, Jotta R, Ramos R, Florindo C, Ventura FV, Vilarinho L, Tavares de Almeida I, Gaspar A
Eur J Pediatr 2019 Mar;178(3):387-394. Epub 2019 Jan 7 doi: 10.1007/s00431-018-03315-2. PMID: 30617651
Medeiros WM, Carvalho AC, Peres P, De Luca FA, Gun C
Eur J Prev Cardiol 2014 Feb;21(2):135-44. Epub 2012 Sep 5 doi: 10.1177/2047487312460520. PMID: 22952290
Wolfe LA, He M, Vockley J, Payne N, Rhead W, Hoppel C, Spector E, Gernert K, Gibson KM
J Inherit Metab Dis 2010 Dec;33 Suppl 3(0 3):S481-7. Epub 2010 Nov 19 doi: 10.1007/s10545-010-9246-8. PMID: 21088898Free PMC Article

Diagnosis

Madigan T, Block DR, Carey WA, Kaemingk BD, Patel R
J Appl Lab Med 2020 Mar 1;5(2):363-369. doi: 10.1093/jalm/jfz001. PMID: 32445380Free PMC Article
Janeiro P, Jotta R, Ramos R, Florindo C, Ventura FV, Vilarinho L, Tavares de Almeida I, Gaspar A
Eur J Pediatr 2019 Mar;178(3):387-394. Epub 2019 Jan 7 doi: 10.1007/s00431-018-03315-2. PMID: 30617651
Medeiros WM, Carvalho AC, Peres P, De Luca FA, Gun C
Eur J Prev Cardiol 2014 Feb;21(2):135-44. Epub 2012 Sep 5 doi: 10.1177/2047487312460520. PMID: 22952290
Wolfe LA, He M, Vockley J, Payne N, Rhead W, Hoppel C, Spector E, Gernert K, Gibson KM
J Inherit Metab Dis 2010 Dec;33 Suppl 3(0 3):S481-7. Epub 2010 Nov 19 doi: 10.1007/s10545-010-9246-8. PMID: 21088898Free PMC Article
Watanabe A
J Gastroenterol Hepatol 2000 Sep;15(9):969-79. doi: 10.1046/j.1440-1746.2000.02283.x. PMID: 11059925

Therapy

Medeiros WM, Carvalho AC, Peres P, De Luca FA, Gun C
Eur J Prev Cardiol 2014 Feb;21(2):135-44. Epub 2012 Sep 5 doi: 10.1177/2047487312460520. PMID: 22952290

Prognosis

Janeiro P, Jotta R, Ramos R, Florindo C, Ventura FV, Vilarinho L, Tavares de Almeida I, Gaspar A
Eur J Pediatr 2019 Mar;178(3):387-394. Epub 2019 Jan 7 doi: 10.1007/s00431-018-03315-2. PMID: 30617651
Adamovic T, Jouvet P, Vobecky S, Garel L, Rougemont AL, Alvarez F
Minerva Anestesiol 2011 May;77(5):554-7. Epub 2011 Mar 2 PMID: 21540812
Wolfe LA, He M, Vockley J, Payne N, Rhead W, Hoppel C, Spector E, Gernert K, Gibson KM
J Inherit Metab Dis 2010 Dec;33 Suppl 3(0 3):S481-7. Epub 2010 Nov 19 doi: 10.1007/s10545-010-9246-8. PMID: 21088898Free PMC Article
Watanabe A
J Gastroenterol Hepatol 2000 Sep;15(9):969-79. doi: 10.1046/j.1440-1746.2000.02283.x. PMID: 11059925

Clinical prediction guides

Janeiro P, Jotta R, Ramos R, Florindo C, Ventura FV, Vilarinho L, Tavares de Almeida I, Gaspar A
Eur J Pediatr 2019 Mar;178(3):387-394. Epub 2019 Jan 7 doi: 10.1007/s00431-018-03315-2. PMID: 30617651
Grimaldi M, Karaca M, Latini L, Brioudes E, Schalch T, Maechler P
Hum Mol Genet 2017 Sep 15;26(18):3453-3465. doi: 10.1093/hmg/ddx213. PMID: 28911206
Wolfe LA, He M, Vockley J, Payne N, Rhead W, Hoppel C, Spector E, Gernert K, Gibson KM
J Inherit Metab Dis 2010 Dec;33 Suppl 3(0 3):S481-7. Epub 2010 Nov 19 doi: 10.1007/s10545-010-9246-8. PMID: 21088898Free PMC Article
Watanabe A
J Gastroenterol Hepatol 2000 Sep;15(9):969-79. doi: 10.1046/j.1440-1746.2000.02283.x. PMID: 11059925

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, Decreased Citrulline, 2022
    • ACMG Algorithm, 2022
      American College of Medical Genetics and Genomics, Algorithm, Decreased Citrulline, 2022
    • ACMG ACT, 2012
      American College of Medical Genetics and Genomics, Transition to Adult Health Care ACT Sheet, N-Acetylglutamate Synthase (NAGS) Deficiency, 2012

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