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Congenital hyperammonemia, type I

MedGen UID:
907954
Concept ID:
C4082171
Disease or Syndrome
Synonyms: Carbamoyl phosphate synthetase 1 deficiency; Carbamoyl phosphate synthetase I deficiency disease; Carbamoyl-phosphate synthase I deficiency; Carbamyl phosphate synthetase (CPS) deficiency; CPS 1 deficiency; CPS I DEFICIENCY; Hyperammonemia due to carbamoyl phosphate synthetase 1 deficiency
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): CPS1 (2q34)
 
Monarch Initiative: MONDO:0009376
OMIM®: 237300
Orphanet: ORPHA147

Definition

Carbamoyl phosphate synthetase I deficiency is an autosomal recessive inborn error of metabolism of the urea cycle which causes hyperammonemia. There are 2 main forms: a lethal neonatal type and a less severe, delayed-onset type (summary by Klaus et al., 2009). Urea cycle disorders are characterized by the triad of hyperammonemia, encephalopathy, and respiratory alkalosis. Five disorders involving different defects in the biosynthesis of the enzymes of the urea cycle have been described: ornithine transcarbamylase deficiency (311250), carbamyl phosphate synthetase deficiency, argininosuccinate synthetase deficiency, or citrullinemia (215700), argininosuccinate lyase deficiency (207900), and arginase deficiency (207800). [from OMIM]

Additional description

From MedlinePlus Genetics
Carbamoyl phosphate synthetase I deficiency is an inherited disorder that causes ammonia to accumulate in the blood (hyperammonemia). 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.

In the first few days of life, infants with carbamoyl phosphate synthetase I deficiency typically exhibit the effects of hyperammonemia, which may include unusual sleepiness, poorly regulated breathing rate or body temperature, unwillingness to feed, vomiting after feeding, unusual body movements, seizures, or coma. Affected individuals who survive the newborn period may experience recurrence of these symptoms if diet is not carefully managed or if they experience infections or other stressors. They may also have delayed development and intellectual disability.

In some people with carbamoyl phosphate synthetase I deficiency, signs and symptoms may be less severe and appear later in life.  https://medlineplus.gov/genetics/condition/carbamoyl-phosphate-synthetase-i-deficiency

Clinical features

From HPO
Stroke disorder
MedGen UID:
52522
Concept ID:
C0038454
Disease or Syndrome
Sudden impairment of blood flow to a part of the brain due to occlusion or rupture of an artery to the brain.
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.
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.
Protein avoidance
MedGen UID:
326521
Concept ID:
C1839531
Finding
Cerebral edema
MedGen UID:
2337
Concept ID:
C0006114
Pathologic Function
Abnormal accumulation of fluid in the brain.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Coma
MedGen UID:
1054
Concept ID:
C0009421
Disease or Syndrome
The complete absence of wakefulness and consciousness, which is evident through a lack of response to any form of external stimuli.
Lethargy
MedGen UID:
7310
Concept ID:
C0023380
Sign or Symptom
A state of disinterest, 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.
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.
Irritability
MedGen UID:
397841
Concept ID:
C2700617
Mental Process
A proneness to anger, i.e., a tendency to become easily bothered or annoyed.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Respiratory alkalosis
MedGen UID:
1411
Concept ID:
C0002064
Pathologic Function
Alkalosis due to excess loss of carbon dioxide from the body.
Low plasma citrulline
MedGen UID:
326522
Concept ID:
C1839532
Finding
A decreased concentration of citrulline in the blood.
Episodic ammonia intoxication
MedGen UID:
333343
Concept ID:
C1839541
Finding
Hypoargininemia
MedGen UID:
892673
Concept ID:
C4025095
Finding
A decreased concentration of arginine in the blood.
Hyperammonemia
MedGen UID:
1802066
Concept ID:
C5574662
Laboratory or Test Result
An increased concentration of ammonia in the blood.

Recent clinical studies

Etiology

Zhang Z, Tong F, Chen C, Zhang T, Qian G, Yang X, Huang X, Yang R, Zhao Z
Zhejiang Da Xue Xue Bao Yi Xue Ban 2023 Nov 14;52(6):721-726. doi: 10.3724/zdxbyxb-2023-0359. PMID: 37986659Free PMC Article
Foschi FG, Morelli MC, Savini S, Dall'Aglio AC, Lanzi A, Cescon M, Ercolani G, Cucchetti A, Pinna AD, Stefanini GF
World J Gastroenterol 2015 Apr 7;21(13):4063-8. doi: 10.3748/wjg.v21.i13.4063. PMID: 25852294Free PMC Article
Falik-Zaccai TC, Kfir N, Frenkel P, Cohen C, Tanus M, Mandel H, Shihab S, Morkos S, Aaref S, Summar ML, Khayat M
Genet Med 2008 Dec;10(12):903-9. doi: 10.1097/GIM.0b013e31818d0e0f. PMID: 19092443
Huang HP, Chien YH, Huang LM, Ni YH, Chang MH, Ho MC, Lee PH, Hwu WL
J Formos Med Assoc 2005 Sep;104(9):623-9. PMID: 16276436
Saudubray JM, Touati G, Delonlay P, Jouvet P, Narcy C, Laurent J, Rabier D, Kamoun P, Jan D, Revillon Y
Eur J Pediatr 1999 Dec;158 Suppl 2:S55-9. doi: 10.1007/pl00014323. PMID: 10603100

Diagnosis

Zhang Z, Tong F, Chen C, Zhang T, Qian G, Yang X, Huang X, Yang R, Zhao Z
Zhejiang Da Xue Xue Bao Yi Xue Ban 2023 Nov 14;52(6):721-726. doi: 10.3724/zdxbyxb-2023-0359. PMID: 37986659Free PMC Article
Wang S, Chen J, Zhu X, Huang T, Xu H, Ying G, Qian H, Lin W, Tung Y, Khan KU, Guo H, Zheng G, Lu H, Zhang G
BMC Med Genomics 2023 Jun 26;16(1):145. doi: 10.1186/s12920-023-01569-w. PMID: 37365635Free PMC Article
Zhang L, Zou Y, Lu Y, Li Z, Gao F
Bioorg Chem 2023 Jan;130:106253. Epub 2022 Nov 5 doi: 10.1016/j.bioorg.2022.106253. PMID: 36356370
Choi Y, Oh A, Lee Y, Kim GH, Choi JH, Yoo HW, Lee BH
Clin Chim Acta 2022 Feb 1;526:55-61. Epub 2021 Dec 29 doi: 10.1016/j.cca.2021.11.029. PMID: 34973183
Martínez AI, Pérez-Arellano I, Pekkala S, Barcelona B, Cervera J
Mol Genet Metab 2010 Dec;101(4):311-23. Epub 2010 Aug 6 doi: 10.1016/j.ymgme.2010.08.002. PMID: 20800523

Therapy

Imataka G, Ishii J, Ando Y, Yoshihara S, Takagi Y, Nitta A, Arisaka O, Yoshihara S
Eur Rev Med Pharmacol Sci 2020 Oct;24(19):10051-10053. doi: 10.26355/eurrev_202010_23220. PMID: 33090410
Khoja S, Nitzahn M, Hermann K, Truong B, Borzone R, Willis B, Rudd M, Palmer DJ, Ng P, Brunetti-Pierri N, Lipshutz GS
Mol Genet Metab 2018 Aug;124(4):243-253. Epub 2018 Apr 12 doi: 10.1016/j.ymgme.2018.04.001. PMID: 29801986Free PMC Article
Papadia C, Osowska S, Cynober L, Forbes A
Clin Nutr 2018 Dec;37(6 Pt A):1823-1828. Epub 2017 Oct 16 doi: 10.1016/j.clnu.2017.10.009. PMID: 29107336
Diez-Fernandez C, Häberle J
Expert Opin Ther Targets 2017 Apr;21(4):391-399. Epub 2017 Feb 20 doi: 10.1080/14728222.2017.1294685. PMID: 28281899
Enns GM, Berry SA, Berry GT, Rhead WJ, Brusilow SW, Hamosh A
N Engl J Med 2007 May 31;356(22):2282-92. doi: 10.1056/NEJMoa066596. PMID: 17538087

Prognosis

Zhang Z, Tong F, Chen C, Zhang T, Qian G, Yang X, Huang X, Yang R, Zhao Z
Zhejiang Da Xue Xue Bao Yi Xue Ban 2023 Nov 14;52(6):721-726. doi: 10.3724/zdxbyxb-2023-0359. PMID: 37986659Free PMC Article
Wang S, Chen J, Zhu X, Huang T, Xu H, Ying G, Qian H, Lin W, Tung Y, Khan KU, Guo H, Zheng G, Lu H, Zhang G
BMC Med Genomics 2023 Jun 26;16(1):145. doi: 10.1186/s12920-023-01569-w. PMID: 37365635Free PMC Article
Zhang S, Hu Y, Wu Z, Zhou X, Wu T, Li P, Lian Q, Xu S, Gu J, Chen L, Wu G, Zhang T, Tang J, Xue J
Int J Radiat Oncol Biol Phys 2023 Apr 1;115(5):1244-1256. Epub 2022 Nov 22 doi: 10.1016/j.ijrobp.2022.11.022. PMID: 36423742
Choi Y, Oh A, Lee Y, Kim GH, Choi JH, Yoo HW, Lee BH
Clin Chim Acta 2022 Feb 1;526:55-61. Epub 2021 Dec 29 doi: 10.1016/j.cca.2021.11.029. PMID: 34973183
Yang X, Shi J, Lei H, Xia B, Mu D
Medicine (Baltimore) 2017 Jun;96(26):e7365. doi: 10.1097/MD.0000000000007365. PMID: 28658158Free PMC Article

Clinical prediction guides

Zhang Z, Tong F, Chen C, Zhang T, Qian G, Yang X, Huang X, Yang R, Zhao Z
Zhejiang Da Xue Xue Bao Yi Xue Ban 2023 Nov 14;52(6):721-726. doi: 10.3724/zdxbyxb-2023-0359. PMID: 37986659Free PMC Article
Yang X, Shi J, Lei H, Xia B, Mu D
Medicine (Baltimore) 2017 Jun;96(26):e7365. doi: 10.1097/MD.0000000000007365. PMID: 28658158Free PMC Article
Ali EZ, Khalid MK, Yunus ZM, Yakob Y, Chin CB, Abd Latif K, Hock NL
Eur J Pediatr 2016 Mar;175(3):339-46. Epub 2015 Oct 6 doi: 10.1007/s00431-015-2644-z. PMID: 26440671
Pekkala S, Martínez AI, Barcelona B, Yefimenko I, Finckh U, Rubio V, Cervera J
Hum Mutat 2010 Jul;31(7):801-8. doi: 10.1002/humu.21272. PMID: 20578160
Scaglia F, Brunetti-Pierri N, Kleppe S, Marini J, Carter S, Garlick P, Jahoor F, O'Brien W, Lee B
J Nutr 2004 Oct;134(10 Suppl):2775S-2782S; discussion 2796S-2797S. doi: 10.1093/jn/134.10.2775S. PMID: 15465784

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, Carbamoyl Phosphate Synthetase I (CPS I) Deficiency, 2012

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