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Congenital hyperammonemia, type I

MedGen UID:
907954
Concept ID:
C4082171
Disease or Syndrome
Synonyms: Carbamoyl phosphate synthetase 1 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
Sources: HPO, OMIM, 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).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
 
Gene (location): CPS1 (2q34)
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 GHR
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://ghr.nlm.nih.gov/condition/carbamoyl-phosphate-synthetase-i-deficiency

Clinical features

From HPO
Stroke
MedGen UID:
52522
Concept ID:
C0038454
Disease or Syndrome
A group of pathological conditions characterized by sudden, non-convulsive loss of neurological function due to BRAIN ISCHEMIA or INTRACRANIAL HEMORRHAGES. Stroke is classified by the type of tissue NECROSIS, such as the anatomic location, vasculature involved, etiology, age of the affected individual, and hemorrhagic vs. non-hemorrhagic nature. (From Adams et al., Principles of Neurology, 6th ed, pp777-810)
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
Swelling due to an excessive 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- oder 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
A profound state of unconsciousness associated with depressed cerebral activity from which the individual cannot be aroused. Coma generally occurs when there is dysfunction or injury involving both cerebral hemispheres or the brain stem RETICULAR FORMATION.
Lethargy
MedGen UID:
7310
Concept ID:
C0023380
Sign or Symptom
A general state of sluggishness, listless, or uninterested, with being tired, and having difficulty concentrating and doing simple tasks. It may be related to DEPRESSION or DRUG ADDICTION.
Seizures
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as EPILEPSY or "seizure disorder."
Stroke
MedGen UID:
52522
Concept ID:
C0038454
Disease or Syndrome
A group of pathological conditions characterized by sudden, non-convulsive loss of neurological function due to BRAIN ISCHEMIA or INTRACRANIAL HEMORRHAGES. Stroke is classified by the type of tissue NECROSIS, such as the anatomic location, vasculature involved, etiology, age of the affected individual, and hemorrhagic vs. non-hemorrhagic nature. (From Adams et al., Principles of Neurology, 6th ed, pp777-810)
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.
Intellectual disability
MedGen UID:
334384
Concept ID:
C1843367
Finding
Irritability
MedGen UID:
397841
Concept ID:
C2700617
Mental Process
Feelings of annoyance, impatience, and anger.
Respiratory alkalosis
MedGen UID:
1411
Concept ID:
C0002064
Pathologic Function
A condition in which the blood pH is greater than normal, secondary to impaired gas exchange.
Cerebral edema
MedGen UID:
2337
Concept ID:
C0006114
Pathologic Function
Swelling due to an excessive accumulation of fluid in the brain.
Hyperammonemia
MedGen UID:
113136
Concept ID:
C0220994
Disease or Syndrome
A laboratory test result demonstrating an increased concentration of ammonia in the blood.
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.

Recent clinical studies

Etiology

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
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
Funghini S, Thusberg J, Spada M, Gasperini S, Parini R, Ventura L, Meli C, De Cosmo L, Sibilio M, Mooney SD, Guerrini R, Donati MA, Morrone A
Gene 2012 Feb 10;493(2):228-34. Epub 2011 Dec 7 doi: 10.1016/j.gene.2011.11.052. PMID: 22173106
Serrano M, Martins C, Pérez-Dueñas B, Gómez-López L, Murgui E, Fons C, García-Cazorla A, Artuch R, Jara F, Arranz JA, Häberle J, Briones P, Campistol J, Pineda M, Vilaseca MA
J Child Neurol 2010 Mar;25(3):352-8. Epub 2009 Aug 14 doi: 10.1177/0883073809340696. PMID: 19684305
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

Diagnosis

Chen X, Yuan L, Sun M, Liu Q, Wu Y
J Clin Lab Anal 2018 Jun;32(5):e22375. Epub 2018 Jan 4 doi: 10.1002/jcla.22375. PMID: 29314318
Zhang G, Chen Y, Ju H, Bei F, Li J, Wang J, Sun J, Bu J
J Clin Lab Anal 2018 Feb;32(2) Epub 2017 Apr 26 doi: 10.1002/jcla.22241. PMID: 28444906
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
Rokicki D, Pajdowska M, Trubicka J, Thong MK, Ciara E, Piekutowska-Abramczuk D, Pronicki M, Sikora R, Haidar R, Ołtarzewski M, Jabłońska E, Muthukumarasamy P, Sthaneswar P, Gan CS, Krajewska-Walasek M, Carrozzo R, Verrigni D, Semeraro M, Rizzo C, Taurisano R, Alhaddad B, Kovacs-Nagy R, Haack TB, Dionisi-Vici C, Pronicka E, Wortmann SB
Clin Chim Acta 2017 Aug;471:95-100. Epub 2017 May 17 doi: 10.1016/j.cca.2017.05.023. PMID: 28526534
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

Therapy

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
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
Shi D, Zhao G, Ah Mew N, Tuchman M
Mol Genet Metab 2017 Mar;120(3):198-206. Epub 2016 Dec 8 doi: 10.1016/j.ymgme.2016.12.002. PMID: 28007335Free PMC Article
Ah Mew N, McCarter R, Daikhin Y, Lichter-Konecki U, Nissim I, Yudkoff M, Tuchman M
J Pediatr 2014 Aug;165(2):401-403.e3. Epub 2014 May 29 doi: 10.1016/j.jpeds.2014.04.012. PMID: 24880889Free PMC Article
Bates TR, Lewis BD, Burnett JR, So K, Mitchell A, Delriviere L, Jeffrey GP
Liver Transpl 2011 Dec;17(12):1481-4. doi: 10.1002/lt.22407. PMID: 21837743

Prognosis

Chen X, Yuan L, Sun M, Liu Q, Wu Y
J Clin Lab Anal 2018 Jun;32(5):e22375. Epub 2018 Jan 4 doi: 10.1002/jcla.22375. PMID: 29314318
Zhang G, Chen Y, Ju H, Bei F, Li J, Wang J, Sun J, Bu J
J Clin Lab Anal 2018 Feb;32(2) Epub 2017 Apr 26 doi: 10.1002/jcla.22241. PMID: 28444906
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
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

Clinical prediction guides

Chen X, Yuan L, Sun M, Liu Q, Wu Y
J Clin Lab Anal 2018 Jun;32(5):e22375. Epub 2018 Jan 4 doi: 10.1002/jcla.22375. PMID: 29314318
Zhang G, Chen Y, Ju H, Bei F, Li J, Wang J, Sun J, Bu J
J Clin Lab Anal 2018 Feb;32(2) Epub 2017 Apr 26 doi: 10.1002/jcla.22241. PMID: 28444906
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
Díez-Fernández C, Gallego J, Häberle J, Cervera J, Rubio V
J Genet Genomics 2015 May 20;42(5):249-60. Epub 2015 Apr 1 doi: 10.1016/j.jgg.2015.03.009. PMID: 26059772

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