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Ornithine carbamoyltransferase deficiency(OTCD)

MedGen UID:
75692
Concept ID:
C0268542
Disease or Syndrome
Synonyms: Ornithine Carbamoyltransferase Deficiency Disease; Ornithine transcarbamylase deficiency; ORNITHINE TRANSCARBAMYLASE DEFICIENCY, HYPERAMMONEMIA DUE TO; OTC deficiency; OTCD
SNOMED CT: Ornithine carbamoyltransferase deficiency (80908008); Ornithine transcarbamylase deficiency (80908008); Deficiency of citrulline phosphorylase (80908008); Ornithine transcarbamoylase deficiency (80908008); Deficiency of ornithine carbamoyltransferase (80908008); Deficiency of ornithine transcarbamylase (80908008); OCT (ornithine carbamoyltransferase) deficiency (80908008); OTC (ornithine transcarbamylase) deficiency (80908008); OTC-gene related ornithine carbamoyltransferase deficiency (80908008)
Modes of inheritance:
X-linked recessive inheritance
MedGen UID:
375779
Concept ID:
C1845977
Finding
Source: Orphanet
A mode of inheritance that is observed for recessive traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked recessive disorders manifest in males (who have one copy of the X chromosome and are thus hemizygotes), but generally not in female heterozygotes who have one mutant and one normal allele.
 
Gene (location): OTC (Xp11.4)
 
Monarch Initiative: MONDO:0010703
OMIM®: 311250
Orphanet: ORPHA664

Definition

Ornithine transcarbamylase (OTC) deficiency can occur as a severe neonatal-onset disease in males (but rarely in females) and as a post-neonatal-onset (also known as "late-onset" or partial deficiency) disease in males and females. Males with severe neonatal-onset OTC deficiency are asymptomatic at birth but become symptomatic from hyperammonemia in the first week of life, most often on day two to three of life, and are usually catastrophically ill by the time they come to medical attention. After successful treatment of neonatal hyperammonemic coma these infants can easily become hyperammonemic again despite appropriate treatment; they typically require liver transplant to improve quality of life. Males and heterozygous females with post-neonatal-onset (partial) OTC deficiency can present from infancy to later childhood, adolescence, or adulthood. No matter how mild the disease, a hyperammonemic crisis can be precipitated by stressors and become a life-threatening event at any age and in any situation in life. For all individuals with OTC deficiency, typical neuropsychological complications include developmental delay, learning disabilities, intellectual disability, attention-deficit/hyperactivity disorder, and executive function deficits. [from GeneReviews]

Additional descriptions

From OMIM
Ornithine transcarbamylase deficiency is an X-linked inborn error of metabolism of the urea cycle, which causes hyperammonemia. The disorder is treatable with supplemental dietary arginine and low protein diet. 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: OTC deficiency, carbamyl phosphate synthetase deficiency (237300), argininosuccinate synthetase deficiency, or citrullinemia (215700), argininosuccinate lyase deficiency (207900), and arginase deficiency (207800).  http://www.omim.org/entry/311250
From MedlinePlus Genetics
Ornithine transcarbamylase deficiency is an inherited disorder that causes 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 nervous system is especially sensitive to the effects of excess ammonia.

Ornithine transcarbamylase deficiency can become evident at any age. The most severe form occurs in the first few days of life. This neonatal-onset form of the disorder usually affects males; it is very rare in females. An infant with the neonatal-onset form of ornithine transcarbamylase deficiency may be lacking in energy (lethargic) or unwilling to eat, and have a poorly-controlled breathing rate or body temperature. Infants with this disorder may be described as "floppy" and can experience seizures or coma. Complications from ornithine transcarbamylase deficiency may include developmental delay and intellectual disability. Progressive liver damage may also occur.

In some affected individuals, signs and symptoms of ornithine transcarbamylase deficiency may be less severe, and may not appear until later in life. The late-onset form of the disorder occurs in both males and females. People with late-onset ornithine transcarbamylase deficiency may experience episodes of altered mental status, such as delirium, erratic behavior, or a reduced level of consciousness. Headaches, vomiting, aversion to protein foods, and seizures can also occur in this form of the disorder.  https://medlineplus.gov/genetics/condition/ornithine-transcarbamylase-deficiency

Clinical features

From HPO
Abdominal pain
MedGen UID:
7803
Concept ID:
C0000737
Sign or Symptom
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) and perceived to originate in the abdomen.
Oroticaciduria
MedGen UID:
78642
Concept ID:
C0268128
Finding
An increased concentration of orotic acid in the urine.
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 characterized 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.
Hereditary episodic ataxia
MedGen UID:
314033
Concept ID:
C1720189
Disease or Syndrome
Periodic spells of incoordination and imbalance, that is, episodes of ataxia typically lasting from 10 minutes to several hours or days.
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.
Prolonged prothrombin time
MedGen UID:
208879
Concept ID:
C0853225
Finding
Increased time to coagulation in the prothrombin time test, which is a measure of the extrinsic pathway of coagulation. The results of the prothrombin time test are often expressed in terms of the International normalized ratio (INR), which is calculated as a ratio of the patient's prothrombin time (PT) to a control PT standardized for the potency of the thromboplastin reagent developed by the World Health Organization (WHO) using the formula
Respiratory alkalosis
MedGen UID:
1411
Concept ID:
C0002064
Pathologic Function
Alkalosis due to excess loss of carbon dioxide from the body.
Elevated circulating aspartate aminotransferase concentration
MedGen UID:
57497
Concept ID:
C0151904
Finding
The concentration of aspartate aminotransferase (AST) in the blood circulation is above the upper limit of normal.
Elevated circulating alanine aminotransferase concentration
MedGen UID:
57740
Concept ID:
C0151905
Finding
An abnormally high concentration in the circulation of alanine aminotransferase (ALT).
Low plasma citrulline
MedGen UID:
326522
Concept ID:
C1839532
Finding
A decreased concentration of citrulline in the blood.
Hyperglutaminemia
MedGen UID:
326901
Concept ID:
C1839533
Finding
An increased concentration of glutamine in the blood.
Episodic ammonia intoxication
MedGen UID:
333343
Concept ID:
C1839541
Finding
Elevated circulating uracil concentration
MedGen UID:
1762024
Concept ID:
C5421635
Finding
Concentration of uracil in the blood circulation is above the normal range.
Hyperammonemia
MedGen UID:
1802066
Concept ID:
C5574662
Laboratory or Test Result
An increased concentration of ammonia in the blood.
Reduced hepatic ornithine transcarbamylase activity
MedGen UID:
1053151
Concept ID:
CN377143
Finding
Activity or concentration of ornithine transcarbamylase in the liver below the lower limit of normal.

Recent clinical studies

Etiology

Scharre S, Posset R, Garbade SF, Gleich F, Seidl MJ, Druck AC, Okun JG, Gropman AL, Nagamani SCS, Hoffmann GF, Kölker S, Zielonka M; Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD) Consortia Study Group
Ann Clin Transl Neurol 2022 Nov;9(11):1715-1726. Epub 2022 Oct 10 doi: 10.1002/acn3.51668. PMID: 36217298Free PMC Article
Peng MZ, Li XZ, Mei HF, Sheng HY, Yin X, Jiang MY, Cai YN, Su L, Lin YT, Shao YX, Liu L
Clin Biochem 2020 Oct;84:63-72. Epub 2020 Jun 19 doi: 10.1016/j.clinbiochem.2020.06.011. PMID: 32569589
Bryson TE, Anglin CM, Bridges PH, Cottle RN
Yale J Biol Med 2017 Dec;90(4):553-566. Epub 2017 Dec 19 PMID: 29259521Free PMC Article
Stern W
J Inherit Metab Dis 2016 Mar;39(2):321-4. doi: 10.1007/s10545-015-9908-7. PMID: 26743057
Helman G, Pacheco-Colón I, Gropman AL
Semin Neurol 2014 Jul;34(3):341-9. Epub 2014 Sep 5 doi: 10.1055/s-0034-1386771. PMID: 25192511

Diagnosis

Scharre S, Posset R, Garbade SF, Gleich F, Seidl MJ, Druck AC, Okun JG, Gropman AL, Nagamani SCS, Hoffmann GF, Kölker S, Zielonka M; Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD) Consortia Study Group
Ann Clin Transl Neurol 2022 Nov;9(11):1715-1726. Epub 2022 Oct 10 doi: 10.1002/acn3.51668. PMID: 36217298Free PMC Article
Stepien KM, Geberhiwot T, Hendriksz CJ, Treacy EP
J Inherit Metab Dis 2019 Nov;42(6):1136-1146. Epub 2019 May 8 doi: 10.1002/jimd.12096. PMID: 30932189
Stern W
J Inherit Metab Dis 2016 Mar;39(2):321-4. doi: 10.1007/s10545-015-9908-7. PMID: 26743057
Helman G, Pacheco-Colón I, Gropman AL
Semin Neurol 2014 Jul;34(3):341-9. Epub 2014 Sep 5 doi: 10.1055/s-0034-1386771. PMID: 25192511
Segura-Bruna N, Rodriguez-Campello A, Puente V, Roquer J
Acta Neurol Scand 2006 Jul;114(1):1-7. doi: 10.1111/j.1600-0404.2006.00655.x. PMID: 16774619

Therapy

Peng MZ, Li XZ, Mei HF, Sheng HY, Yin X, Jiang MY, Cai YN, Su L, Lin YT, Shao YX, Liu L
Clin Biochem 2020 Oct;84:63-72. Epub 2020 Jun 19 doi: 10.1016/j.clinbiochem.2020.06.011. PMID: 32569589
Berraondo P, Martini PGV, Avila MA, Fontanellas A
Gut 2019 Jul;68(7):1323-1330. Epub 2019 Feb 22 doi: 10.1136/gutjnl-2019-318269. PMID: 30796097
Nature 2016 Jun 30;534(7609):590. doi: 10.1038/534590a. PMID: 27357758
Walker V
Diabetes Obes Metab 2009 Sep;11(9):823-35. Epub 2009 Jun 16 doi: 10.1111/j.1463-1326.2009.01054.x. PMID: 19531057
Segura-Bruna N, Rodriguez-Campello A, Puente V, Roquer J
Acta Neurol Scand 2006 Jul;114(1):1-7. doi: 10.1111/j.1600-0404.2006.00655.x. PMID: 16774619

Prognosis

Scharre S, Posset R, Garbade SF, Gleich F, Seidl MJ, Druck AC, Okun JG, Gropman AL, Nagamani SCS, Hoffmann GF, Kölker S, Zielonka M; Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD) Consortia Study Group
Ann Clin Transl Neurol 2022 Nov;9(11):1715-1726. Epub 2022 Oct 10 doi: 10.1002/acn3.51668. PMID: 36217298Free PMC Article
Peng MZ, Li XZ, Mei HF, Sheng HY, Yin X, Jiang MY, Cai YN, Su L, Lin YT, Shao YX, Liu L
Clin Biochem 2020 Oct;84:63-72. Epub 2020 Jun 19 doi: 10.1016/j.clinbiochem.2020.06.011. PMID: 32569589
Wilnai Y, Blumenfeld YJ, Cusmano K, Hintz SR, Alcorn D, Benitz WE, Berquist WE, Bernstein JA, Castillo RO, Concepcion W, Cowan TM, Cox KL, Lyell DJ, Esquivel CO, Homeyer M, Hudgins L, Hurwitz M, Palma JP, Schelley S, Akula VP, Summar ML, Enns GM
Mol Genet Metab 2018 Mar;123(3):297-300. Epub 2018 Jan 16 doi: 10.1016/j.ymgme.2018.01.004. PMID: 29396029
Gelsinger P
Bull Med Ethics 2002 Jun-Jul;(179):13-20. PMID: 12739533
Brusilow SW
Medicine (Baltimore) 2002 May;81(3):240-9. doi: 10.1097/00005792-200205000-00007. PMID: 11997720

Clinical prediction guides

Lo RS, Cromie GA, Tang M, Teng K, Owens K, Sirr A, Kutz JN, Morizono H, Caldovic L, Ah Mew N, Gropman A, Dudley AM
Am J Hum Genet 2023 May 4;110(5):863-879. doi: 10.1016/j.ajhg.2023.03.019. PMID: 37146589Free PMC Article
Buerger C, Garbade SF, Dietrich Alber F, Waisbren SE, McCarter R, Kölker S, Burgard P; Urea Cycle Disorders Consortium
J Inherit Metab Dis 2019 Mar;42(2):243-253. Epub 2019 Jan 22 doi: 10.1002/jimd.12013. PMID: 30671983Free PMC Article
Pacheco-Colón I, Fricke S, VanMeter J, Gropman AL
Mol Genet Metab 2014 Sep-Oct;113(1-2):118-26. Epub 2014 May 20 doi: 10.1016/j.ymgme.2014.05.005. PMID: 25066103Free PMC Article
Sprouse C, King J, Helman G, Pacheco-Colón I, Shattuck K, Breeden A, Seltzer R, VanMeter JW, Gropman AL
Mol Genet Metab 2014 Sep-Oct;113(1-2):136-41. Epub 2014 May 20 doi: 10.1016/j.ymgme.2014.05.007. PMID: 24881970Free PMC Article
Gyato K, Wray J, Huang ZJ, Yudkoff M, Batshaw ML
Ann Neurol 2004 Jan;55(1):80-6. doi: 10.1002/ana.10794. PMID: 14705115

Recent systematic reviews

Torkzaban M, Haddad A, Baxter JK, Berghella V, Gahl WA, Al-Kouatly HB
Am J Med Genet A 2019 Oct;179(10):2091-2100. Epub 2019 Aug 22 doi: 10.1002/ajmg.a.61329. PMID: 31441224

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, Ornithine Transcarbamylase (OTC) deficiency, 2012

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