Ornithine Transcarbamylase Deficiency

Actionability Pediatric Summary Report

Gene: OTC (HGNC:8512)
Mode(s) of Inheritance:
Literature Search: 01/24/2017
Curation Status: Entered (0.0.0)
Release History
Related Reports
Adult Summary Report: (1.2.2)

Secondary Findings in Pediatric Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

Actionability Assertions

Gene Condition (MONDO ID) OMIM ID Final Assertion
OTC ornithine carbamoyltransferase deficiency (0010703) 311250 Assertion Pending

Actionability Assertion Rationale

  • This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Actionability Scores

Outcome / Intervention Pair Severity Likelihood Effectiveness Nature of Intervention Total Score
No scores were found.

Prevalence of the Genetic Condition

Ornithine transcarbamylase (OTC) deficiency is thought to be the most common urea cycle defect. Estimates of prevalence range from 1 in 14,000 live births to 1 in 77,000 live births and may be biased toward the most severe and earliest presentations. A U.S. longitudinal study of urea cycle disorders estimated an OTC prevalence of 1 in 63,000 at birth.
View Citations

U Lichter-Konecki, et al. (2013) NCBI: NBK154378, Batshaw ML, et al. (2014) PMID: 25135652

Clinical Features (Signs / symptoms)

Urea cycle disorders (UCDs) are inborn errors of ammonia detoxification/arginine synthesis due to defects affecting the catalysts of the Krebs urea cycle, of which OTC is one. The urea cycle, residing primarily in hepatocytes, is an essential biochemical pathway for metabolizing waste nitrogen. OTC deficiency is associated with hyperammonemia, leading to death or to severe neurological handicap in many survivors. The most severe acute consequence of an elevated ammonia level is cerebral edema and coma. Seizures are common during hyperammonemic coma but may also occur independently; they may be overt or detectable only by EEG. The duration and severity of hyperammonemia strongly correlates with subsequent brain damage. However, even asymptomatic carrier females have been shown to have mild cognitive impairments and executive function deficits.
View Citations

U Lichter-Konecki, et al. (2013) NCBI: NBK154378, Online Medelian Inheritance in Man. (2016) OMIM: 311250, Online Medelian Inheritance in Man. (2006) OMIM: 300461, Haberle J, et al. (2012) PMID: 22642880, Summar M, et al. (2001) PMID: 11148544

Natural History (Important subgroups & survival / recovery)

OTC deficiency can occur as a severe neonatal-onset disease in males and as a late-onset (partial) disease in males and females. Neonatal-onset disease in females is very rare. In one U.S. longitudinal study, 26% of participants with OTC presented as newborns whereas 69% presented later in life (5% remained asymptomatic). Males with severe OTC deficiency are typically normal at birth, but become symptomatic on the second to third day progressing quickly to catastrophic somnolence and coma. Neonatal onset is associated with 24% mortality, with survivors experiencing severe developmental delay and recurrent hyperammonemic crises. Following acute treatment, liver transplant is usually required to improve quality of life. Hemizygous males and heterozygous females with partial OTC deficiency can present from infancy to later childhood, adolescence, or adulthood. A hyperammonemic crisis can be precipitated by stressors (e.g. pregnancy, cancer treatment, crush injury) and become a life-threatening event at any age and in any situation in life. In general, the milder the disease, the later the onset and the stronger the stressor required to precipitate symptoms. The phenotype of a heterozygous female can range from asymptomatic to subtle or significant symptoms with recurrent hyperammonemia and neurologic compromise depending on favorable vs. non-favorable X-chromosome inactivation. When adults with late-onset disease become encephalopathic they may display erratic behavior, and combativeness. Liver transplant may be considered in late-onset cases due to disease severity or the fear of a hyperammonemic crisis, even if the disease has been manageable with treatment. The overall mortality rate in late-onset cases has been reported as 11%.
View Citations

U Lichter-Konecki, et al. (2013) NCBI: NBK154378, Batshaw ML, et al. (2014) PMID: 25135652, Online Medelian Inheritance in Man. (2016) OMIM: 311250, Haberle J, et al. (2012) PMID: 22642880, N Ah Mew, et al. (2003) NCBI: NBK1217

Description of sources of evidence:

Tier 1: Evidence from a systematic review or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.

Mode of Inheritance

Prevalence of Genetic Variants

>1-2 in 100
Population prevalence of OTC genetic mutations was not available. However, a molecular defect in OTC was detected in 80-90% of patients with biochemically confirmed OTC deficiency.
Tier 3 View Citations

U Lichter-Konecki, et al. (2013) NCBI: NBK154378

Penetrance (Includes any high-risk racial or ethnic subgroups)

>= 40 %
Penetrance for OTC deficiency is complete in hemizygous males.
Tier 4 View Citations

U Lichter-Konecki, et al. (2013) NCBI: NBK154378

>= 40 %
Approximately 15% of heterozygous females are thought to become symptomatic during their lifetime.
Tier 3 View Citations

U Lichter-Konecki, et al. (2013) NCBI: NBK154378

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Unknown

Expressivity

The same genetic defect can yield both mild and severe presentations even in different members of the same family.
Tier 3 View Citations

Haberle J, et al. (2012) PMID: 22642880

Description of sources of evidence:

Tier 1: Evidence from a systematic review or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.

Patient Management

To establish the extent of disease and needs in an individual diagnosed with OTC deficiency, the following evaluations are recommended:

-Plasma ammonia concentration

-Plasma amino acid analysis

-Nutrition labs (e.g., vitamin D level, ferritin, pre-albumin)

-Liver function tests (liver enzymes, bilirubin, albumin)

-Prothrombin time/Partial thromboplastin time and fibrinogen

-Neuropsychological/psychological evaluation
Tier 4 View Citations

U Lichter-Konecki, et al. (2013) NCBI: NBK154378

In an asymptomatic female known to be heterozygous, precautions should be taken in the peripartum and postpartum period to prevent catabolism; in addition, measurement of ammonia levels and administration of dextrose should be considered as heterozygous females have become symptomatic for the first time in the peripartum period.
Tier 4 View Citations

U Lichter-Konecki, et al. (2013) NCBI: NBK154378

Elective surgery should be performed in centers with a metabolic department, including emergency treatment options for hyperammonemia.
Tier 2 View Citations

Haberle J, et al. (2012) PMID: 22642880

In the absence of an acute event or clear symptoms, the following interventions may apply depending on individual evaluation. While all recommendations apply to patients of all ages, NOTE that the only evidence available was collected in patients who were diagnosed as infants or children (although not with severe newborn disease) and therefore may be less applicable to adults. Dietary treatment with a reduced protein intake is an important part of therapy and is based on minimizing the nitrogen load on the urea cycle. This warrants the expertise of a specialist dietitian to balance nutritional requirements with metabolic stability. Patients should be trained on food protein calculation and provision of adequate energy and nutrient intake. They need to be aware of the [potential] need for life-long dietary treatment and regular dietary assessments. Restricted diets should be supplemented with essential amino acids, minerals, vitamins, and trace elements, as needed.
Tier 2 View Citations

Haberle J, et al. (2012) PMID: 22642880, Urea Cycle Disorders Conference group., et al. (2001) PMID: 11148543

In a study of 17 patients (age 0.2 to 39 months) with a UCD (6 with OTC deficiency) prescribed a restricted protein diet and a medical food containing essential amino acids, energy, minerals, and vitamins, length (p=0.04) and weight (p=0.01) z-scores increased significantly over 6 months. At 10 months of age, weight gains were significantly and positively correlated with daily energy intakes. In another study, 26 infants with UCDs including 7 with OTC deficiency were treated for 7 to 62 months with reduced protein, essential amino acids, a nitrogen scavenger, and arginine. Overall, 22 survived, 19 with normal height, weight, and head circumference; 13 had normal intellectual development. Of 7 OTC deficiency patients, 4 survived.
Tier 5 View Citations

Acosta PB, et al. (2005) PMID: 16260164, Batshaw ML, et al. (1982) PMID: 7078580

Most UCD patients need supplementation with L-arginine or its precursor, L-citrulline.
Tier 2 View Citations

Haberle J, et al. (2012) PMID: 22642880

In one study of 7 Japanese boys (age 3 to 5 years) with late onset OTC deficiency who had ceased arginine treatment a few years prior to the study, resumption of treatment reduced the frequency of hyperammonemic attacks to one-third the rate before re-starting therapy at a followup of 18 months. Arginine levels returned to slightly higher than normal age-matched controls.
Tier 5 View Citations

Nagasaka H, et al. (2006) PMID: 16703326

Nitrogen scavengers (sodium benzoate, sodium phenyl butyrate) should be taken at recommended doses 4 times daily during meals with abundant fluids to safely avoid mucositis or gastritis. However, information on nitrogen scavenger therapy during pregnancy is scarce.
Tier 2 View Citations

Haberle J, et al. (2012) PMID: 22642880

In one study of 32 symptomatic girls (age 1 to 17 years at baseline) with OTC deficiency treated with either sodium benzoate or sodium phenyl butyrate, survival over a mean treatment time of 7 years was 90% compared to a historical calculated average of 18% among untreated carrier females. The frequency of hyperammonemic episodes per year was less than 1 in treated older children and young adults.
Tier 5 View Citations

Maestri NE, et al. (1996) PMID: 8778603

Surveillance

Clinical, biochemical and nutritional monitoring are essential and should follow an individualized plan

-Laboratory monitoring must include at a minimum plasma ammonia and amino acid profile. Monitoring of glutamine, hemoglobin, albumin, pre-albumin, and transferrin may also provide useful criteria to assess the nutritional status.

-Regular dietary assessments are essential.

-Clinical monitoring should include inspection for hair loss, skin rash, and other signs of protein/vitamin deficiency.

-To help predict clinical and neurocognitive outcome, it appears desirable to perform MRI early during an acute episode and at 2-year intervals. Regular neurocognitive testing for IQ and specific abilities/weaknesses is recommended.
Tier 2 View Citations

Haberle J, et al. (2012) PMID: 22642880, Urea Cycle Disorders Conference group., et al. (2001) PMID: 11148543

Monitoring for hyperammonemia is appropriate following a large fracture or other trauma in which significant internal bleeding occurs.
Tier 4 View Citations

N Ah Mew, et al. (2003) NCBI: NBK1217

Circumstances to Avoid

Avoid the use of sodium valproate, haloperidol, and systemic corticosteroids in patients with OTC deficiency as these may trigger hyperammonemic episodes and/or liver failure.
Tier 3 View Citations

U Lichter-Konecki, et al. (2013) NCBI: NBK154378, Online Medelian Inheritance in Man. (2016) OMIM: 311250

Avoid over-restriction of protein/amino acids or fasting.
Tier 4 View Citations

U Lichter-Konecki, et al. (2013) NCBI: NBK154378

Minimize risk of respiratory and gastrointestinal illnesses.
Tier 4 View Citations

U Lichter-Konecki, et al. (2013) NCBI: NBK154378

Avoid physical and psychological stress.
Tier 4 View Citations

U Lichter-Konecki, et al. (2013) NCBI: NBK154378

The use of ibuprofen for fever relief is preferred over acetaminophen, as acetaminophen in high doses is potentially toxic to the liver.
Tier 2 View Citations

Urea Cycle Disorders Conference group., et al. (2001) PMID: 11148543

Extreme caution should be exercised in the use of antiemetics, as they may mask signs of hyperammonemia.
Tier 2 View Citations

Urea Cycle Disorders Conference group., et al. (2001) PMID: 11148543

Description of sources of evidence:

Tier 1: Evidence from a systematic review or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.

Nature of Intervention

The interventions are primarily non-invasive surveillance, a strict metabolic diet with any necessary oral supplementation, and oral nitrogen scavenger therapy (e.g. sodium benzoate), if required.
Context: Adult

Chance to Escape Clinical Detection

UCDs may present with acute or chronic symptoms at any age and are often triggered by catabolic events, protein load or by some drugs. In many cases a precipitating factor cannot be identified. Clinical signs and symptoms are nonspecific and commonly neurological, gastrointestinal or psychiatric.
Context: Adult
Tier 4 View Citations

Haberle J, et al. (2012) PMID: 22642880

Description of sources of evidence:

Tier 1: Evidence from a systematic review or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Gene Condition Associations
OMIM Identifier Primary MONDO Identifier Additional MONDO Identifiers
OTC 311250 0010703

References List

Acosta PB, Yannicelli S, Ryan AS, Arnold G, Marriage BJ, Plewinska M, Bernstein L, Fox J, Lewis V, Miller M, Velazquez A. (2005) Nutritional therapy improves growth and protein status of children with a urea cycle enzyme defect. Molecular genetics and metabolism. 86(4):448-55.

Batshaw ML, Brusilow S, Waber L, Blom W, Brubakk AM, Burton BK, Cann HM, Kerr D, Mamunes P, Matalon R, Myerberg D, Schafer IA. (1982) Treatment of inborn errors of urea synthesis: activation of alternative pathways of waste nitrogen synthesis and excretion. The New England journal of medicine. 306(23):1387-92.

Batshaw ML, Tuchman M, Summar M, Seminara J. (2014) A longitudinal study of urea cycle disorders. Molecular genetics and metabolism. 113(1-2):127-30.

Haberle J, Boddaert N, Burlina A, Chakrapani A, Dixon M, Huemer M, Karall D, Martinelli D, Crespo PS, Santer R, Servais A, Valayannopoulos V, Lindner M, Rubio V, Dionisi-Vici C. (2012) Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet journal of rare diseases. 7(1750-1172):32.

Maestri NE, Brusilow SW, Clissold DB, Bassett SS. (1996) Long-term treatment of girls with ornithine transcarbamylase deficiency. The New England journal of medicine. 335(12):855-9.

N Ah Mew, BC Lanpher, A Gropman, KA Chapman, KL Simpson, , ML Summar. Urea Cycle Disorders Overview. (2003) [Updated Apr 09 2015]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1217/

Nagasaka H, Yorifuji T, Murayama K, Kubota M, Kurokawa K, Murakami T, Kanazawa M, Takatani T, Ogawa A, Ogawa E, Yamamoto S, Adachi M, Kobayashi K, Takayanagi M. (2006) Effects of arginine treatment on nutrition, growth and urea cycle function in seven Japanese boys with late-onset ornithine transcarbamylase deficiency. European journal of pediatrics. 165(9):618-24.

ORNITHINE CARBAMOYLTRANSFERASE; OTC. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 300461, (2006) World Wide Web URL: http://omim.org/

ORNITHINE TRANSCARBAMYLASE DEFICIENCY, HYPERAMMONEMIA DUE TO. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 311250, (2016) World Wide Web URL: http://omim.org/

Summar M, Tuchman M. (2001) Proceedings of a consensus conference for the management of patients with urea cycle disorders. The Journal of pediatrics. 138(1 Suppl):S6-10.

U Lichter-Konecki, L Caldovic, H Morizono, K Simpson. Ornithine Transcarbamylase Deficiency. (2013) [Updated Apr 14 2016]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK154378/

Urea Cycle Disorders Conference group.. (2001) Consensus statement from a conference for the management of patients with urea cycle disorders. The Journal of pediatrics. 138(1 Suppl):S1-5.

Early Rule-Out Summary

This topic passed the early rule out stage

Findings of Early Rule-Out Assessment

  1. Is there a qualifying resource, such as a practice guideline or systematic review, for the genetic condition?
  2. Does the practice guideline or systematic review indicate that the result is actionable in one or more of the following ways?

    3. a. Patient Management

    b. Surveillance or Screening

    c. Circumstances to Avoid

  3. Is there an intervention that is initiated during childhood (<18 years of age) in an undiagnosed child with the genetic condition?
  4. Does the disease present outside of the neonatal period?
  5. Is this condition an important health problem?
  6. Is there at least on known pathogenic variant with at least moderate penetrance (≥40%) or moderate relative risk (≥2) in any population?