Ornithine Transcarbamylase Deficiency

Actionability Pediatric Summary Report

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

• Gene: OTC (HGNC:8512)
• Mode(s) of Inheritance: X-linked
• Literature Search: 11/16/2021
• Curation Status: Released (1.0.1)

Assertions and Scores

Actionability Assertions

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

Actionability Assertion Rationale

• The consensus of the group was that the evidence for males was definitive. There was agreement among the experts of strong actionability for females, but not definitive due to limited evidence. Specifically for females, there were concerns about the possibility of ascertainment bias present in the evidence for likelihood and severity. This topic has been assigned as assertion of definitive. Thus, this topic will not be updated unless it is renominated because of new evidence which could change the assertion.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Morbidity and mortality due to hyperammonemic crises (males) / Referral to a specialist for evaluation to guide dietary management, arginine/citrulline, nitrogen scavengers, and emergency management to mitigate hyperammonemic crises	2	3A	3B	2	10AB
Morbidity and mortality due to hyperammonemic crises (females) / Referral to a specialist for evaluation to guide dietary management, arginine/citrulline, nitrogen scavengers, and emergency management to mitigate hyperammonemic crises	2	2D	3B	2	9DB

Severity of Outcome

Prevalence of the Genetic Condition

Ornithine transcarbamylase deficiency (OTCD) is thought to be the most common urea cycle disorder (UCD). Worldwide estimates of incidence range from 1:14,000 to 1:113,000 live births and may be biased toward the most severe and earliest presentations. A U.S. longitudinal study of UCDs estimated an OTCD prevalence of 1:63,000 at birth.

Clinical Features (Signs / symptoms)

OTCD is due to a deficiency of the urea cycle enzyme ornithine transcarbamylase (OTC). Clinical presentation of OTCD is variable with two common clinical forms:

• Severe neonatal-onset form is characterized by reduced oral intake, loss of appetite, acute neonatal encephalopathy (lethargy) with hyperventilation, and low body temperature.

• Late-onset (partial) form is characterized by encephalopathic or psychotic episodes, recurrent vomiting, migraine headaches, Reye-like syndrome, seizures, protein avoidance, and unexplained “cerebral palsy”.

Both forms present with episodes of hyperammonemia that can lead to death or 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 and may only be detected on EEG, but seizures may also occur independent of hyperammonemia. Subsequent brain damage and cognitive impairment is strongly correlated with the duration and severity of hyperammonemia. Either form of OTCD may present with acute liver dysfunction, acute liver failure, or chronic liver disease, which may be resolved with metabolic management. Typical neurosychological features of all individuals with OTCD, including asymptomatic heterozygous females, include developmental delay, learning disabilities, intellectual disability, attention-deficit/hyperactivity disorder, and executive function deficits.

Natural History (Important subgroups & survival / recovery)

The severe neonatal-onset form presents predominantly in males (it is very rare in females), while the late-onset form presents in males and females. Males with the severe form are typically asymptomatic at birth but become symptomatic on the second to third day, progressing quickly to severe somnolence and coma. Mortality rate of patients with the severe form is up to 60%, with survivors experiencing severe developmental delay; poor cognitive, adaptive, and behavioral function; and recurrent hyperammonemic crises. After successful treatment of hyperammonemia, infants can easily become hyperammonemic again despite appropriate treatment; liver transplant is usually required by age 6 months to improve quality of life.Hemizygous males and heterozygous females with late-onset OTCD can develop symptoms from infancy to later childhood, adolescence, or adulthood. Often, they first become symptomatic in infancy when transition from breast milk to formula or whole milk. No matter how mild the condition, a hyperammonemic crisis can be precipitated by stressors (e.g., a change in diet, a medical problem including illness or injury, medications [mainly valproate], pregnancy through the postpartum period) and become a life-threatening event during a person’s 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 severe hyperammonemia and neurologic compromise depending on favorable vs. non-favorable X-chromosome inactivation. Postpartum coma has been reported as a first manifestation in females with late-onset OTCD. When children, adolescents, or adults with late-onset disease become encephalopathic they may display erratic behavior, and combativeness. The overall mortality rate in patients with a late-onset OTCD has been reported as 13%.

Likelihood of Outcome

Mode of Inheritance

X-linked

Prevalence of Genetic Variants

>1-2 in 100

Population prevalence of OTC pathogenic variants was not available. However, a pathogenic variant in OTC was detected in 80-90% of patients with biochemically confirmed OTCD.

Tier 3

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

>= 40 %

Penetrance for OTC deficiency is complete in hemizygous males.

Tier 4

>= 40 %

A meta-analysis of observational studies on neonatal mortality and outcome at the end of the first year of life in early onset UCDs, found the following:

In hemizygous males with OTCD:

- 52% presented with neonatal hyperammonemic crises (N=517)

- Mortality in the neonatal period after early onset acute hyperammonemic crisis was 60% (N=303)

- At the end of the first year, 18% were deceased, 67% had developmental delay.

In heterozygous females with OTCD:

- 7% presented with neonatal hyperammonemic crises (N=434)

-Mortality in the neonatal period after early onset acute hyperammonemic crisis was 43%. (N=27).

Tier 1

>= 40 %

In a cohort of 90 individuals with OTCD found the following mortality rates during long-term follow-up:

• 74% mortality among 22 males and 5 females with neonatal presentation

• 13% mortality among 21 males and 31 females with onset between 1 month and 16 years

• 9% mortality among 5 males and 6 females with onset in adulthood.

Tier 5

>= 40 %

A meta-analysis of case reports of outcomes of maternal OTCD, found that among 36 cases of maternal OTCD:

• 15 (42%) presented with either neurological or psychiatric symptoms, and 4 (11%) presented with both

• 6 (17%) had gastrointestinal signs and symptoms, 4 (11%) presented as severe hyperemesis gravidarum

• 2 (6%) had hyperammonemia as their chief complaint

• Past medical history indicated that 3 (8%) had experienced postpartum neuropsychiatric presentations in previous pregnancies and 6 (19%) had previously experienced one or more episodes of hyperammonemia.

• In the 20 patients diagnosed with OTCD prior to pregnancy:

-8 (40%) had either a neurologic or psychiatric presentation

-3 (15%) had severe hyperammonemia

-2 (10%) reported coma, ICU admission, and dialysis postpartum.

• In the 16 patients diagnosed during pregnancy or postpartum

-13 (81%) had neurologic or psychiatric presentation

-4 (25%) presented with hyperemesis gravidarum

-12 (75%) had hyperammonemia

-11 (69%) had ICU admission and coma

-7 (47%) had dialysis

-5 (31%) maternal deaths were reported.

Tier 1

>= 40 %

In one study of 92 pediatric patients with UCDs that included 36 patients with OTCD (81% of which presented with late onset disease), 34% of OTCD patients had intellectual disability, with 6% being severe. Overall, 64% of patients with OTCD had a history of at least one hyperammonemic episode. A separate study of 6 male patients with late-onset OTCD patients and normal IQ reported deficits of motor planning and execution.

Tier 3

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

Unknown

Expressivity

Manifestations of disease and the severity of presentation can vary among individuals in the same family having the same pathogenic variant.

Tier 3

In hemizygous males with the same mild pathogenic variant, only some may develop symptoms while others remain asymptomatic based on differences in environmental stressors.

Tier 4

Intervention Effectiveness

Patient Management

The American College of Medical Genetics and Genomics (ACMG) has developed an ACT sheet to help clinical decision-making in the transition to adult health care for people with OTCD: https://www.acmg.net/PDFLibrary/OTC-Deficiency-Transition.pdf.

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

The mainstay of long-term management is individualized treatment under the expertise of a specialist metabolic dietician. Long-term management aims to maintain stable metabolic control, eliminate chronic complications, achieve normal development and growth, and prevent hyperammonemia. Treatment includes a low protein diet to minimize nitrogen burden; essential amino acid, vitamin, and mineral supplementation; medications to increase waste nitrogen excretion (may include L-arginine, L-citrulline, sodium benzoate, sodium phenylacetate, and/or sodium phenylbutyrate); and an emergency regimen for treatment of intercurrent illness. A detailed management plan should be made available to parents/caregivers and the nursery/school and should include instructions on when and how to contact the metabolic team or local hospital, where a written prescription for emergency treatment should be available. A study of 88 patients with UCDs (including 18 males and 18 females with OTCD) reported that long-term management with protein restriction combined with more extensive management (L-arginine/L-citrulline, essential amino acid supplements, and sodium benzoate) was associated with increased survival in all UCDs compared to protein restriction alone (63.6% versus 38.6%), though this difference was limited to cases that presented neonatally. In another study of 32 symptomatic females with OTCD (age 1 to 17 years at baseline) treated with either sodium benzoate or sodium phenylbutyrate, survival over a mean treatment time of 7 years was 90% compared to a historical calculated average survival rate of 18% among untreated carrier females. The frequency of hyperammonemic episodes decreased with age and was <1 per year in treated older children and young adults. Nineteen of the 23 females in whom intelligence was tested longitudinally had stable test scores.

Tier 2

Early clinical suspicion and prompt diagnosis of hyperammonemia episodes are crucial for favorable outcomes. If a patient is unwell or is at risk of illness, the emergency regimen should be started at home. Patients should have a written treatment protocol with them to outline acute management and define specific medication dosages to hasten accurate treatment. The protocol should include contact information for the metabolic team and should be updated as the child grows. The start of ammonia detoxification and measures to reverse catabolism must not be delayed. Treatment of patients in hyperammonemic crisis depends in the severity of the hyperammonemia and clinical status and includes stopping protein intake, intravenous (IV) 10% glucose (with appropriate electrolytes and possibly lipids) to prevent catabolism, L-arginine, L-citrulline, vitamins, maintaining hydration, ammonia scavengers (sodium benzoate with or without sodium phenylbutyrate (PBA)/phenylacetate), and hemo(dia)filtration. Regular monitoring of blood gases, electrolytes, glucose, and ammonia levels should be done. Any underlying trigger for the episode should be treated promptly. Patients should be transferred without delay to a specialist care center.

Tier 2

A 25-year open-label, uncontrolled clinical trial of IV sodium phenylacetate and sodium benzoate as an emergency treatment of acute hyperammonemia, including 164 pediatric and adult patients with OTCD (86 male and 78 female patients), reported that OTCD patients experienced a total of 654 episodes of hyperammonemia and that 71% of males and 88% of females survived all known hyperammonemic episodes over the 25-year period.

Tier 5

During intercurrent illness or other events with the risk of hyperammonemia, a “sick day” regimen should be established at home. This may involve decreasing protein intake, increasing non-protein calories, and adjusting medication dosage.

Tier 2

Given the risk of acute metabolic decompensation during surgery and general anesthesia, elective surgery should be performed in centers with a metabolic department, including available emergency treatment for hyperammonemia. The patient should have normal preoperative ammonia and amino acid concentrations and be without intercurrent illness. Close postsurgical monitoring of clinical status and ammonia is required.

Tier 2

Maintenance therapy during pregnancy includes referral to metabolic dietician to ensure maintaining adequate oral intake to avoid maternal hyperammonemia. Maintenance therapy is based on a restricted protein diet, oral nitrogen scavengers, and essential amino acids. Elective delivery at 39 weeks is highly recommended if diagnosis has been established antepartum to ensure management by the maternal fetal medicine specialist, metabolic dietitian, geneticist, and neonatologist. During labor and delivery, it is essential to monitor blood ammonia every 6 hours and maintain IV fluids with dextrose to compensate catabolism. Monitoring blood ammonia during the postpartum period is critical at least for 72 hours. Patients should receive discharge instructions about symptoms of hyperammonemia in the postpartum period and be instructed to report any symptoms to their obstetrician. Ammonia level should be checked in the presence of any clinical suspicion during the postpartum period. Dietitian consult postpartum to prevent any superimposed catabolic state or excess protein load should be done. A systematic review of 36 cases in the literature compared outcomes of maternal OTCD when diagnosis was known prior to pregnancy (n=20) or when diagnosis was made during pregnancy or postpartum (n=16). Neurologic or psychiatric presentation occurred during pregnancy or postpartum in 8 cases (40%) diagnosed prior to pregnancy and 13 cases (81%) diagnosed later. Three cases diagnosed prior to pregnancy (15%) had hyperammonemia; two (10%) had ICU admission, dialysis, and coma with no deaths. All had a favorable outcome. In cases diagnosed during pregnancy or postpartum, 4 (25%) presented with hyperemesis gravidarum. Twelve (75%) had hyperammonemia; 11 (69%) had ICU admission and coma and 7 (47%) had dialysis. There were 5 (31%) maternal deaths. Three (19%) had prolonged hospitalization course.

Tier 1

Liver transplant is the only curative treatment for OTCD, allowing return to a regular diet and stopping treatment with nitrogen scavengers. Although transplant cures hyperammonemia, it does not revert preexisting neurological damage and does not correct the arginine deficiency. Arginine supplementation may still be needed. A transplant may be considered in severely affected patients without sufficient response to standard treatment and with poor quality of life, without severe neurological damage, and ideally, in a stable metabolic condition. The same overall post-transplant survival has been found in OTCD and in non-UCD patients. Survival rates in large pediatric programs attain now ~95% at 1 year and ~90% at 5 years, with self-reported “good” or “excellent” quality of life at 6–121 months post-transplant. In a study of 186 children with UCDs the 5-year patient survival rate was 88% for children <2 years old at transplant and 99% for children who were ≥2 years old at transplant.

Tier 2

Surveillance

Regular clinical, biochemical, and nutritional monitoring by a multidisciplinary metabolic team is essential, depends on age and metabolic stability of the patient, and should follow an individualized plan:

• Blood assays include:

- Plasma ammonia and amino acid profile every 6 months

- Plasma carnitine to detect secondary carnitine deficiency

- Hemoglobin, albumin, pre-albumin, and transferrin to assess the nutritional status

- Determination of vitamins, minerals, trace elements, ferritin, cholesterol, triglycerides, alpha-fetoprotein, essential fatty acid, and creatine

• Dietary assessments are essential, including monitoring of protein intake

• Clinical monitoring should include recording of growth and head circumference, inspection for hair loss, skin rash, and other signs of protein/vitamin deficiency

• To help predict clinical and neurocognitive outcome, it is desirable to perform MRI early during an acute episode and within 1-4 days after

• For long-term neurological monitoring, brain MRI and possibly spectroscopy, even in the absence of neurological and/or cognitive impairment, with timing on a case-by-case basis. Spectroscopy is helpful to detect subtle changes in females.

• Neurological and neurocognitive assessments for intellectual development and specific abilities/weaknesses should be performed regularly. This includes patients with milder disease or heterozygous females since they may develop specific weaknesses in executive functions even if the intellectual development is not affected

• Liver size and structure should be assessed by ultrasound scan

• History of intercurrent illnesses and use of the emergency regimen.

Tier 2

Infants need more frequent monitoring and adjustment of their diet and treatment than older stable patients. Young and severely affected patients should be seen at least every 3 months while older or less severely affected patients may only need annual appointments.

Tier 2

Circumstances to Avoid

Ibuprofen for fever relief is preferred over acetaminophen, as acetaminophen in high doses is potentially toxic to the liver.

Tier 2

Antiemetics should be used with extreme caution as they may mask signs of hyperammonemia.

Tier 2

Steroids should be avoided as they increase the amount of protein turnover and hence increase the nitrogen load. Valproic acid should be avoided as it is known to decrease urea cycle function.

Tier 2

Over-restriction of protein should be avoided in pregnant and lactating patients. In addition, generally excessive protein restriction may compromise growth and well-being and can cause metabolic instability.

Tier 2

Avoid the use of haloperidol in patients with OTCD as it may trigger hyperammonemic episodes.

Tier 3

Avoid over-restriction of protein/amino acids or fasting.

Tier 4

Minimize risk of respiratory and gastrointestinal illnesses.

Tier 4

Avoid physical and psychological stress.

Tier 4

Nature of Intervention

Nature of Intervention

Management of OTCD requires lifelong monitoring by the multidisciplinary metabolic team. Long-term treatment is challenging for patients and families because of poor palatability (particularly of EAA supplements), the volume and frequency of drugs, and the dietary/lifestyle discipline required; all of which are serious barriers to adherence. Despite treatment, there remains a permanent impending risk of hyperammonemia and a largely uncertain prognosis. A protein-restrictive diet may be burdensome. Nitrogen scavengers are typically administered orally via granules, tablets, or liquid preparations but must be given several times a day with meals to avoid mucositis or gastritis. At recommended doses, nitrogen scavengers are well tolerated. However, repeated boluses of scavengers and long-term treatment can lead to hypokalemia. Sodium PBA causes menstrual dysfunction/amenorrhea in ~25% of post-pubertal females; can decrease appetite, disturb taste, and cause disagreeable body odor; may increase the risk of endogenous protein catabolism; and decrease albumin levels in some patients. Both nitrogen scavengers (at high doses) and L-arginine may lead to hypotension, metabolic alkalosis, hypokalemia, and gastrointestinal symptoms. Some types of hemo(dia)filtration require vascular access, are technically challenging, and have a high risk of complications, especially in neonates. Liver transplant requires immunological therapy and long-term follow-up.

Context: Adult Pediatric

Chance to Escape Clinical Detection

UCDs may present with acute or chronic symptoms at any age and in many cases a precipitating factor cannot be identified. Clinical signs and symptoms may be subtle and nonspecific and commonly neurological, gastrointestinal, or psychiatric.

Context: Adult Pediatric

Tier 4

Heterozygous females who exhibit mild symptoms may self-restrict protein and never be diagnosed as being symptomatic. The diagnosis may only be revealed when a more severely affected child is born.

Context: Adult Pediatric

Tier 4

Under recognition and delayed diagnosis of UCDs is widespread.

Context: Adult Pediatric

Tier 4

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			OTC			311250	0010703

References List

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