Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Passed (Consensus scoring is Complete)
• Curation Status (Adult): Released - Under Revision 1.0.0
• GENE/GENE PANEL: OTC
• Condition: Ornithine Transcarbamylase Deficiency
• Mode(s) of Inheritance: X-linked

Actionability Assertion

• OTC ⇔ 311250: Assertion Pending

Actionability 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.

Final Consensus Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Hyperammonemic encephalopathy / Dietary modification (women)	2	2C	2E	2	8CE
Hyperammonemic encephalopathy / Dietary modification (men)	2	2C	2E	2	9CE
Hyperammonemic encephalopathy / Use of nitrogen scavengers (women)	2	2C	2E	3	9CE
Hyperammonemic encephalopathy / Use of nitrogen scavengers (men)	2	2C	2E	3	10CE

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

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. [1, 2]

Clinical Features

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. [1, 3, 4, 5, 6]

Natural History

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%. [1, 2, 3, 5, 7]

2. How effective are interventions for preventing harm?

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) [1]

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) [1]

Elective surgery should be performed in centers with a metabolic department, including emergency treatment options for hyperammonemia. (Tier 2) [5]

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) [5, 8]

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) [9, 10]

Most UCD patients need supplementation with L-arginine or its precursor, L-citrulline. (Tier 2) [5]

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) [11]

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) [5]

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) [12]

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) [5, 8]

Monitoring for hyperammonemia is appropriate following a large fracture or other trauma in which significant internal bleeding occurs. (Tier 4) [7]

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) [1, 3]

Avoid over-restriction of protein/amino acids or fasting. (Tier 4) [1]

Minimize risk of respiratory and gastrointestinal illnesses. (Tier 4) [1]

Avoid physical and psychological stress. (Tier 4) [1]

The use of ibuprofen for fever relief is preferred over acetaminophen, as acetaminophen in high doses is potentially toxic to the liver. (Tier 2) [8]

Extreme caution should be exercised in the use of antiemetics, as they may mask signs of hyperammonemia. (Tier 2) [8]

3. What is the chance that this threat will materialize?

Mode of Inheritance

X-linked [1, 7]

Prevalence of Genetic Variants

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) [1]

Penetrance

Penetrance for OTC deficiency is complete in hemizygous males. (Tier 4) [1]

Approximately 15% of heterozygous females are thought to become symptomatic during their lifetime. (Tier 3) [1]

Relative Risk

Information on relative risk was not available for the Adult context.

Expressivity

The same genetic defect can yield both mild and severe presentations even in different members of the same family. (Tier 3) [5]

4. What is the Nature of the Intervention?

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.

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

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. (Tier 4) [5]

Date of Search: 01.24.2017

Reference List

1. U Lichter-Konecki, L Caldovic, H Morizono, K Simpson. Ornithine Transcarbamylase Deficiency. 2013 Aug 29 [Updated 2016 Apr 14]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK154378

2. Batshaw ML, Tuchman M, Summar M, Seminara J. A longitudinal study of urea cycle disorders. Mol Genet Metab. (2014) 113(1-2):127-30.

3. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. ORNITHINE TRANSCARBAMYLASE DEFICIENCY, HYPERAMMONEMIA DUE TO. MIM: 311250: 2016 Sep 23. World Wide Web URL: http://omim.org.

4. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. ORNITHINE CARBAMOYLTRANSFERASE; OTC. MIM: 300461: 2006 Oct 13. World Wide Web URL: http://omim.org.

5. 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. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis. (2012) 7:32.

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

7. N Ah Mew, BC Lanpher, A Gropman, KA Chapman, KL Simpson, , ML Summar. Urea Cycle Disorders Overview. 2003 Apr 29 [Updated 2015 Apr 09]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1217

8. Consensus statement from a conference for the management of patients with urea cycle disorders. J Pediatr. The Journal of pediatrics. (2001) 138(1 Suppl):S1-5.

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

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

11. 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. Effects of arginine treatment on nutrition, growth and urea cycle function in seven Japanese boys with late-onset ornithine transcarbamylase deficiency. Eur J Pediatr. (2006) 165(9):618-24.

12. Maestri NE, Brusilow SW, Clissold DB, Bassett SS. Long-term treatment of girls with ornithine transcarbamylase deficiency. N Engl J Med. (1996) 335(12):855-9.