Ornithine Transcarbamylase Deficiency

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2021-01-18

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OTC, DMD, RPGR, CPS1, PLXNA2, PART1, SLC25A15, TFEB, BEST1, TSPAN7, AAVS1, CYTB, GPT, GLUL, F7, CYP21A2, PM20D1

Drugs

Adeno-associated viral vector serotype 8 encoding human ornithine transcarbamylase, Adeno-associated viral vector serotype LK03 encoding human ornithine transcarbamylase, Codon -optimised human ornithine transcarbamylase mRNA complexed with lipid -based nanoparticle, Glycerol phenylbutyrate ( RAVICTI ), Heterologous human adult liver derived stem cells ( Promethera HepaStem ), Human heterologous liver cells (for infusion), Modified messenger ribonucleic acid encoding human ornithine transcarbamylase enzyme encapsulated into lipid nanoparticles, Sodium benzoate, Sodium phenylbutyrate ( BUPHENYL, AMMONAPS ), sodium phenylacetate / sodium benzoate ( AMMONUL )

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Summary

Clinical characteristics.

Ornithine transcarbamylase (OTC) deficiency can occur as a severe neonatal-onset disease in males (but rarely in females) and as a post-neonatal-onset (partial deficiency) disease in males and females. Males with severe neonatal-onset OTC deficiency are typically normal at birth but become symptomatic from hyperammonemia 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 by age six months 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 (ADHD), and executive function deficits.

Diagnosis/testing.

The diagnosis of OTC deficiency is established in a male proband with suggestive clinical and laboratory findings and/or at least ONE of the following:

A hemizygous pathogenic variant in OTC by molecular genetic testing
A markedly abnormal increase of orotic acid excretion after an allopurinol challenge test
Decreased OTC enzyme activity in liver

The diagnosis of OTC deficiency is usually established in a female proband with the suggestive clinical and laboratory findings and/or with at least ONE of the following:

A heterozygous pathogenic variant in OTC by molecular genetic testing
A markedly abnormal increase of orotic acid excretion after an allopurinol challenge test

Measurement of OTC enzyme activity in liver is not a reliable means of diagnosis in females.

Management.

Treatment of manifestations: Treatment is best provided by a clinical geneticist and a nutritionist experienced in the treatment of metabolic disease; treatment of hyperammonemic coma should be provided by a team coordinated by a metabolic specialist in a tertiary care center experienced in the management of OTC deficiency. The mainstays of treatment of the acute phase are rapid lowering of the plasma ammonia level to ≤200 μmol/L (if necessary, with renal replacement therapy); use of ammonia scavenger treatment to allow excretion of excess nitrogen via alternative pathways; reversal of catabolism; and reducing the risk of neurologic damage. The goals of long-term treatment are to promote growth and development and to prevent hyperammonemic episodes. In severe, neonatal-onset urea cycle disorders, liver transplantation is typically performed by age six months to prevent further hyperammonemic crises and neurodevelopmental deterioration. In females and males with partial OTC deficiency liver transplant is typically considered in those who have frequent hyperammonemic episodes. Complications of OTC deficiency, including ADHD and learning disability/intellectual disability, are treated according to the standard of care for these conditions while monitoring for signs of liver disease.

Prevention of primary manifestations: If neonatal-onset OTC deficiency is diagnosed prenatally, intravenous (IV) treatment with ammonia scavengers within a few hours of birth (before the ammonia level rises) can prevent a hyperammonemic crisis and coma. For preventive measures after the neonatal period see Treatment of manifestations.

Prevention of secondary complications: Avoid overrestriction of protein/amino acids; use gastrostomy tube feedings as needed to help avoid malnutrition; practice careful hand hygiene among all who have contact with the affected individual to minimize risk of infection; give immunizations on the usual schedule, including annual flu vaccine; provide multivitamin and vitamin D supplementation; and use antipyretics appropriately (e.g., ibuprofen is preferred over acetaminophen because of the potential for liver toxicity).

Surveillance: At the start of therapy, routine measurement of plasma ammonia and plasma amino acids. Assess liver function (depending on symptoms) every three to six months or more often when previously abnormal. Perform neuropsychological testing at the time of expected significant developmental milestones.

Agents/circumstances to avoid: Valproate, haloperidol, systemic corticosteroids, fasting, and physical and psychological stress.

Evaluation of relatives at risk: If the pathogenic variant in the family is known and if prenatal testing has not been performed, it is appropriate to perform biochemical and molecular genetic testing on at-risk newborns (males and females) as soon after birth as possible so that the appropriate treatment or surveillance (for those with the family-specific pathogenic variant) can be promptly established. If the pathogenic variant in the family is NOT known, biochemical analysis (plasma amino acid analysis, ammonia level), an allopurinol challenge test (in older individuals), and/or OTC enzyme activity measurement in liver (males only) can be performed. Preventive measures at birth should be instituted until such a time as the diagnosis can be ruled out.

Pregnancy management: Heterozygous females are at risk of becoming catabolic during pregnancy and especially in the postpartum period. Those who are symptomatic need to be treated throughout pregnancy as necessary; those who are asymptomatic need to avoid catabolism in the peripartum and postpartum periods and should be treated as needed.

Genetic counseling.

OTC deficiency is inherited in an X-linked manner. If an affected male reproduces, none of his sons will be affected and all of his daughters will inherit the pathogenic variant and may or may not develop clinical symptoms related to the disorder. Heterozygous females have a 50% chance of transmitting the pathogenic variant with each pregnancy: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant may or may not develop clinical findings related to the disorder. Carrier testing for females at risk of being heterozygous and prenatal testing for pregnancies at increased risk are possible if the OTC pathogenic variant has been identified in an affected family member.

Diagnosis

Diagnostic criteria for ornithine transcarbamylase (OTC) deficiency have been set forth by the Urea Cycle Disorders Consortium of the Rare Disease Clinical Research Network [Tuchman et al 2008].

Suggestive Findings

OTC deficiency should be suspected in an individual with the following clinical features (by sex/age), family history, and supportive laboratory findings:

Clinical Features

Term newborn male

Normal at birth
Development of reduced oral intake with poor latching and suck
Acute neonatal encephalopathy (lethargy, somnolence) with hyperventilation and low body temperature

Child, adolescent, or adult (male or female)

Encephalopathic or psychotic episodes (i.e., episodes of altered mental status), including erratic behavior, clouded consciousness, and delirium
A recent stress that could be regarded as a precipitating event (e.g., significant change in diet, significant medical problem including illness or accident, delivery, systemic use of corticosteroids or valproate)
History of recurrent vomiting
Migraine headaches
Reye-like syndrome
Seizures
History of true protein avoidance (avoidance of not only red meat but also of milk, eggs, other high-protein foods)
Unexplained "cerebral palsy"

Family History

Death of newborn males (related through females in a manner consistent with X-linked inheritance) in the first week of life from "sepsis" or with unexplained somnolence, refusal to feed, tachypnea, and catastrophic illness is suggestive of OTC deficiency.

Note: Absence of a family history of individuals with similar episodes does not preclude the diagnosis.

Supportive Laboratory Findings

Newborn screening (NBS). OTC deficiency is universally screened for in eight states and likely to be detected in three additional states (www.newsteps.org). See Baby's First Test to search by state.

The sensitivity and specificity of a low citrulline level as a marker for OTC deficiency in NBS has been questioned; however, the false positive rate in Minnesota has matched the average performance of primary analytes for conditions detected by tandem mass spectroscopy (MS/MS) on NBS [Hall et al 2014].
The detection of OTC deficiency on NBS may be improved by using the Collaborative Laboratory Integrated Reports (CLIR), an interactive web tool that includes glutamine, glutamate, and amino acid ratios (e.g., citrulline-to-glycine ratio) in the analysis.

Plasma ammonia concentration. During acute encephalopathy, ammonia levels are typically above 200 μmol/L and often above 500-1,000 μmol/L.

Note: The plasma ammonia concentration at which an individual becomes symptomatic varies but is generally above 100 μmol/L; in stage 2 coma [Plum & Posner 1982] the plasma concentration may be between 200 and 400 μmol/L; and in stage 3 to 4 coma, above 500 μmol/L. These levels are approximations and a wider range of elevated ammonia levels may be observed.

Plasma amino acid analysis. A high glutamine concentration (generally >800 μmol/L) and a (very) low citrulline concentration (e.g., single digits, with or without elevated plasma ammonia concentration) is suggestive of a proximal urea cycle defect, such as N-acetylglutamate synthetase (NAGS) deficiency, carbamoyl phosphate synthetase I (CPSI) deficiency, or OTC deficiency.

Urine organic acid (UOA) analysis. Orotic acid concentration is elevated in a random urine sample (e.g., >20 μmol/mmol creatinine if the laboratory provides quantitative values).

Blood gases

Respiratory alkalosis in an encephalopathic individual who is hyperventilating is pathognomonic of urea cycle disorders [Maestri et al 1999].
In a terminally ill individual who has been in a coma for days, acidosis may develop.

Establishing the Diagnosis

Male proband. The diagnosis of OTC deficiency is established in a male proband with the above clinical and laboratory findings and/or with at least ONE of the following:

A hemizygous pathogenic variant in OTC by molecular genetic testing (see Table 1)
A markedly abnormal increase of orotic acid excretion after an allopurinol challenge test (see Allopurinol challenge test below) with or without a family history of OTC deficiency [Tuchman et al 2008]
Decreased OTC enzyme activity in liver (see OTC enzyme activity in liver below)

Female proband. The diagnosis of OTC deficiency is usually established in a female proband with the above clinical features and supportive laboratory findings and/or with at least ONE of the following: a heterozygous pathogenic variant in OTC by molecular genetic testing (see Table 1) or a markedly abnormal increase of orotic acid excretion after an allopurinol challenge test (see Allopurinol challenge test) with or without a family history of OTC deficiency.

Note: Liver biopsy is not recommended to establish the diagnosis in females (see OTC enzyme activity in liver).

Molecular genetic testing approaches can include single-gene testing and use of a multigene panel.

Single-gene testing. Sequence analysis of OTC is performed first.

In a male, lack of amplification by PCR prior to sequence analysis should prompt gene-targeted deletion/duplication analysis.
In a female in whom sequence analysis does not reveal a pathogenic variant, gene-targeted deletion/duplication should be performed next.

A multigene panel that includes OTC and other genes of interest (see Differential Diagnosis) may also be considered. Note: The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in Ornithine Transcarbamylase (OTC) Deficiency

Gene ¹	Method	Proportion of Probands with a Pathogenic Variant ² Detectable by Method
OTC	Sequence analysis ^3, 4, 5	60%-80% ^6, 7
OTC	Gene-targeted deletion/duplication analysis & complex rearrangements ⁸	5%-10% ^9, 10, 11
Unknown ¹²	NA

1.: See Table A. Genes and Databases for chromosome locus and protein.
2.: See Molecular Genetics for information on allelic variants detected in this gene.
3.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4.: Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.
5.: Sequencing of OTC regulatory regions can be used to screen for pathogenic variants in the OTC promoter and enhancer [Luksan et al 2010]. See Molecular Genetics.
6.: In individuals with biochemically confirmed OTC deficiency (i.e., elevated urinary orotate, a positive allopurinol test, reduced OTC enzyme activity in liver biopsy, or a combination of these findings) [Caldovic et al 2015]
7.: Bailly et al [2015], Choi et al [2015], Mohamed et al [2015], Prasun et al [2015]
8.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
9.: When sequence analysis was followed by deletion/duplication analysis a molecular defect was detected in 80%-90% of affected individuals with biochemically confirmed OTC deficiency [Tuchman et al 1998, Shchelochkov et al 2009, Caldovic et al 2015].
10.: Large deletions, duplications, and chromosomal rearrangements that encompass parts or all of OTC as well as neighboring genes have been detected using cytogenetic and molecular genetic techniques (see Genetically Related Disorders and Molecular Genetics) [Caldovic et al 2015, Choi et al 2015, Di Stefano et al 2015, Gallant et al 2015].
11.: Synthesis and sequencing of OTC cDNA from illegitimate transcripts isolated from fibroblasts or from transcripts isolated from liver biopsy specimens has been used to detect pathogenic variants that create novel splice sites leading to aberrant OTC transcripts [Häberle & Koch 2003, Engel et al 2008].
12.: Because an estimated 10%-20% of affected individuals have no detectable pathogenic variant, locus heterogeneity cannot be excluded.

Allopurinol challenge test. In males and females suspected of having partial OTC deficiency who have normal molecular genetic testing and normal or borderline urinary orotic acid concentration under normal conditions, an allopurinol challenge test should be performed. A markedly abnormal increase of orotic acid excretion after administering allopurinol is diagnostic [Burlina et al 1992, Oexle 2006a, Oexle 2006b, Grünewald et al 2004]. The test consists of taking a single dose of allopurinol and immediately thereafter starting to collect urine during four six-hour periods for a total of 24 hours. Aliquots from each six-hour period are analyzed for orotic acid concentration.

OTC enzyme activity in liver. Previously the gold standard for diagnosing OTC deficiency [Tuchman et al 1989], analysis of OTC enzyme activity in liver requires a liver biopsy, and thus is currently used only when an OTC pathogenic variant is not found in a male with a high clinical suspicion of OTC deficiency or if an allopurinol challenge is inconclusive.

Males. In severely affected males, OTC enzyme activity is typically less than 20% of the control value. In milder OTC deficiency, enzymatic activity may be as high as 30% of the control value.
Females. Results of enzyme activity analysis in a liver biopsy may not represent the true total OTC activity in a heterozygous female because of the X-chromosome inactivation pattern (previously known as lyonization) in the biopsy specimen (see Clinical Description, Heterozygous Females).

Clinical Characteristics

Clinical Description

Ornithine transcarbamylase (OTC) deficiency can occur as a severe neonatal-onset disease in males and as a post-neonatal-onset (partial deficiency) disease in males and females. Neonatal-onset disease in females is very rare.

Although neonatal-onset ornithine transcarbamylase (OTC) deficiency accounted for approximately 60% of all OTC deficiency in the older literature [Matsuda et al 1991], the longitudinal study of the Urea Cycle Disorders Consortium (UCDC) of the NICHD-supported Rare Disease Clinical Research Network (RDCRN) has enrolled to date a substantially smaller proportion of individuals with neonatal-onset OTC deficiency than with post-neonatal-onset OTC deficiency. Of 260 individuals who had symptomatic OTC deficiency, 47 (18%) had neonatal-onset disease (42 males and 5 females) and 213 (82%) had post-neonatal onset disease (154 females and 59 males) [Batshaw et al 2014].

Neonatal-Onset OTC Deficiency

Males with severe OTC deficiency are typically normal at birth, but become symptomatic on the second to third day of life with poor suck, reduced intake, and hypotonia, followed by lethargy progressing to somnolence and coma. They hyperventilate, and may have seizures. By the time neonates with OTC deficiency come to medical attention they typically are catastrophically ill with low body temperature (hypothermia), severe encephalopathy, and respiratory alkalosis.

When clinical and laboratory findings support the diagnosis of a urea cycle disorder, rescue therapy is begun immediately (see Management, Treatment of Manifestations).

The prognosis of a newborn in hyperammonemic coma depends on the duration of elevated ammonia level, not the height of the ammonia level or the presence or absence of seizures [Msall et al 1984].

After successful rescue from neonatal hyperammonemic coma, infants with severe neonatal-onset OTC deficiency can easily become hyperammonemic again despite a low-protein diet and treatment with an oral ammonia scavenger. Even on maximum ammonia scavenger therapy a neonate with severe OTC deficiency may only tolerate 1.5 g/kg/day of protein (the minimum amount needed to grow), and growth may be along the third percentile for length.

After neonatal rescue therapy, a child with severe neonatal-onset disease can also experience a "honeymoon" period in which the protein tolerance is so high, due to rapid growth, that the child is metabolically stable for some months before experiencing frequent hyperammonemic episodes.

Typically by age six months (if not sooner) a liver transplant is needed because of the effect of recurrent hyperammonemia on the brain and of prolonged hospitalizations on quality of life.

The overall outcome depends on the severity of brain damage during the initial hyperammonemic crisis and during subsequent hyperammonemic crises, as well as on the success of long-term treatment in maintaining metabolic balance and treating complications of the disease.

Post-Neonatal-Onset (Partial) OTC Deficiency

Hemizygous males and heterozygous females with partial OTC deficiency can present from infancy to later childhood, adolescence, or adulthood [Ahrens et al 1996, Ausems et al 1997, McCullough et al 2000]. Often they first become symptomatic in infancy when switched from breast milk to formula or whole milk (breast milk contains less protein than infant formulas manufactured in the US). Infants may show episodic vomiting, lethargy, irritability, failure to thrive, and developmental delay. They show true protein avoidance, which can be documented by a detailed assessment of their dietary intake. When forced to eat high-protein-content food, they may become symptomatic.

A stressor can cause an individual with partial OTC deficiency to become symptomatic at any age. In general the milder the disease, the later the onset and the stronger the stressor required to precipitate symptoms.

Adults with very mild disease have become symptomatic after crush injury, post-operatively [Chiong et al 2007, Hu et al 2007], when on a high-protein diet (e.g., Atkins diet [Ben-Ari et al 2010]), during the postpartum period (see Pregnancy Management), during cancer therapy, after prolonged fasting [Marcus et al 2008], when treated with high-dose systemic corticosteroids [Lipskind et al 2011], or after a febrile illness [Panlaqui et al 2008]. Treatment with valproate [Morgan et al 1987, Arn et al 1990, Honeycutt et al 1992] or haloperidol has been associated with hyperammonemic crises in persons with OTC deficiency [Rubenstein et al 1990, Leão 1995, Oechsner et al 1998, Thakur et al 2006].

When children, adolescents, or adults with post-neonatal-onset disease become encephalopathic they may reach stage 2 coma [Plum & Posner 1982] with erratic behavior, combativeness, and delirium (e.g., not recognizing family members around them, unintelligible speech). They may come to medical attention if these behavioral abnormalities lead to an emergency medical or psychiatric evaluation.

Heterozygous Females

The phenotype of a heterozygous female can range from asymptomatic to significant symptoms with recurrent hyperammonemia and neurologic compromise depending on favorable vs non-favorable X-chromosome inactivation. The amount of OTC enzyme activity in the liver of a heterozygous female depends on the pattern of X-chromosome inactivation in her liver [Yorifuji et al 1998]. Thus, a heterozygous female can manifest symptoms of OTC deficiency if X-chromosome inactivation in her liver cells is skewed such that the X chromosome with the pathogenic OTC allele is active in more hepatocytes than the X chromosome with the wild type OTC allele [Ricciuti et al 1976, McCullough et al 2000, Yamaguchi et al 2006].

Previously, approximately 15% of heterozygous females were thought to become symptomatic during their lifetime [Batshaw et al 1986]. Many heterozygous females exhibit mild symptoms, self-restrict protein intake, and are never diagnosed as being symptomatic. The diagnosis may only be revealed when a more severely affected child is born, prompting molecular genetic testing in the mother. Thus, the percent of symptomatic females may be higher than previously thought. When a male has post-neonatal-onset disease, the risk for symptoms in heterozygous females in his family is much lower than in families in which a male has neonatal-onset severe disease [McCullough et al 2000].

Complications of Neonatal-Onset and Post-Neonatal-Onset Disease

Neuropsychological. Typical neuropsychological complications include developmental delay, learning disabilities, intellectual disability [Rowe et al 1986], attention deficit hyperactivity disorder (ADHD), and executive function deficits [Gyato et al 2004, Krivitzky et al 2009].

Attention deficit hyperactivity disorder and executive function deficits can greatly affect (school) performance even when intellectual ability is in the normal range [Gyato et al 2004, Krivitzky et al 2009].
Impulsivity and immaturity can lead to inappropriate behavior and problems in peer relationships especially for preteens and adolescents.
In adulthood, problems with private and professional relationships may persist, leading to problems in interpersonal relationships and frequent job changes.

Even asymptomatic heterozygous females were shown to have mild cognitive impairments and executive function deficits on neuropsychological testing [Nagata et al 1991, Gyato et al 2004].

Neurologic. During hyperammonemic coma electroencephalogram (EEG) shows low voltage with slow waves and may include a burst suppression pattern in which the duration of the interburst interval correlates with the height of the ammonia levels [Clancy & Chung 1991].

Seizures are common during hyperammonemic coma and may only be detected on EEG. They do not indicate a poor prognosis. However, persons with urea cycle disorders may also be prone to having seizures independent of hyperammonemic episodes [Zecavati et al 2008].

Neuroimaging studies reveal, during a crisis, cerebral edema with small ventricles, flattening of cerebral gyri, and low density of white matter [Kendall et al 1983].

Neonates who survived after prolonged coma may have ventriculomegaly, diffuse brain atrophy (not affecting the cerebellum), low-density white matter defects, and injury to the bilateral lentiform nuclei and the deep sulci of the insular and perirolandic regions [Kendall et al 1983, Yamanouchi et al 2002, Takanashi et al 2003, Majoie et al 2004].

Although metabolic strokes (involving the caudate and putamen and resulting in extrapyramidal syndromes) have been described in OTC deficiency and CPS1 deficiency (see Urea Cycle Disorders Overview) [Keegan et al 2003, Takanashi et al 2003], they are not typical for urea cycle disorders.

Note: For more information regarding MR spectroscopy research results in OTC deficiency see Pathophysiology (pdf).

Neuropathology in those children who died after prolonged coma included cortical atrophy with ventriculomegaly, prominent cortical neuronal loss, and spongiform changes at the gray-white interface and in the basal ganglia and thalamus [Dolman et al 1988].

Better neurologic outcomes are seen in infants with neonatal-onset disease who were treated soon after the onset of coma.

Gastrointestinal

During a hyperammonemic crisis liver enzymes are typically moderately elevated and PT and PTT may be prolonged.
Severe elevations of liver enzyme and coagulopathy consistent with acute liver failure are more typically seen in individuals with OTC deficiency after the neonatal period [Mustafa & Clarke 2006].
Prolonged PT and PTT as well as mildly increased direct bilirubin are also observed in persons with a urea cycle disorder during long-term follow up when ammonia levels are normal and the individual is asymptomatic.

Liver cell carcinoma has recently been described in a few older individuals (e.g., in a symptomatic heterozygous female age 66 years [Wilson et al 2012]), suggesting that OTC deficiency may be associated with an increased risk for liver cancer. However, data are currently insufficient to support such a conclusion.

Pathophysiology

For more information about the pathophysiology of OTC, click here.

Genotype-Phenotype Correlations

While the following genotype-phenotype correlations do in general exist, it is well established that significant medical problems (e.g., neonatal sepsis or other causes of newborn catabolism) can cause a severe, early presentation in an individual with an OTC pathogenic variant typically associated with mild disease, making it appear that the pathogenic variant is associated with severe neonatal-onset disease. Likewise, individuals with pathogenic variants associated with mild, late-onset disease (including females heterozygous for a milder pathogenic variant and skewed X-chromosome inactivation) may experience severe life-threatening hyperammonemia at any time in their life when they are exposed to strong environmental stressors.

In general:

Pathogenic missense variants that affect residues essential for catalysis, substrate binding, and folding severely impair or completely abolish OTC enzyme activity and result in neonatal-onset disease in hemizygous males [Caldovic et al 2015].
Pathogenic nonsense variants, insertions, and deletions that cause frameshift of the open reading frame and single-nucleotide variants in canonical intronic splice sites result in complete absence of functional OTC and neonatal-onset disease in hemizygous males [Caldovic et al 2015].
Females heterozygous for a pathogenic variant can develop symptoms of OTC deficiency later in life if X-chromosome inactivation in their hepatocytes is skewed in favor of the X chromosome with the pathogenic allele [McCullough et al 2000, Caldovic et al 2015].
Amino acid substitutions that decrease OTC enzyme activity or stability may result in a post-neonatal-onset phenotype in hemizygous males [Caldovic et al 2015] and heterozygous females [Pinner et al 2010].
Although one would only expect pathogenic variants that cause severe neonatal-onset disease in hemizygous males to be associated with disease manifestation in heterozygous females, symptoms of OTC deficency in two females heterozygous for a hypomorphic OTC pathogenic variant were reported [Pinner et al 2010].

Penetrance

Penetrance for OTC deficiency is complete in hemizygous males.

The following observations, which may erroneously be interpreted as evidence of incomplete penetrance, are in fact explained by X-chromosome inactivation and environmental factors:

Heterozygous females who become symptomatic (the result of skewed X-chromosome inactivation)
Hemizygous males with the same mild pathogenic variant, only some of whom develop symptoms (the result of differences in environmental stressors)

Prevalence

OTC deficiency is thought to be the most common urea cycle defect (see Urea Cycle Disorders Overview).

Estimated prevalence of OTC deficiency was one in 14,000 live births [Brusilow & Maestri 1996]. However, other surveys of incidence of OTC deficiency in Italy, Finland, and New South Wales, Australia, revealed a lower prevalence of one in 70,000, one in 62,000, and one in 77,000 live births, respectively [Dionisi-Vici et al 2002, Keskinen et al 2008, Balasubramaniam et al 2010].

Given that males and females with partial OTC deficiency may manifest symptoms at any age, prevalence numbers are biased toward the earliest and most severe presentations.

Differential Diagnosis

Neonatal-onset urea cycle disorders (UCDs) – N-acetylglutamate synthase (NAGS) deficiency, severe carbamyl phosphate synthetase I (CPSI) deficiency, argininosuccinate synthetase (ASS) deficiency (citrullinemia type I), and argininosuccinate lyase (ASL) deficiency (argininosuccinic aciduria [ASA]) – show the same clinical symptoms at presentation as severe OTC deficiency. See Urea Cycle Disorders Overview.

Respiratory alkalosis is a typical finding in UCD [Maestri et al 1999] and its presence clearly distinguishes a UCD from an organic acidemia presenting with hyperammonemia and ketoacidosis. However, when a child who has been in a coma for days becomes terminally ill, acidosis rather than respiratory alkalosis may be present.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ornithine transcarbamylase (OTC) deficiency, the following evaluations are recommended if they have not already been completed:

Plasma ammonia concentration
Plasma amino acid analysis
Laboratory values that reflect nutritional status (e.g., vitamin D level, ferritin, pre-albumin)
Liver function tests (liver enzymes, bilirubin, albumin)
PT/PTT and fibrinogen
Developmental/neuropsychological/psychological evaluation
Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Treatment is best provided by a clinical geneticist and a nutritionist experienced in the treatment of metabolic disease.

Care of Hyperammonemic Coma

Care should be provided by a team coordinated by a metabolic specialist in a tertiary care center experienced in the management of individuals with OTC deficiency. In the acute phase, the mainstays of treatment are the following.

Rapid lowering of the plasma ammonia

Level should be 200 μmol/L or lower even if a diagnosis has not yet been established because of the severely toxic effect of an elevated ammonia level on the brain.
The fastest method for lowering the ammonia level is hemodialysis [Tuchman 1992, McBryde et al 2004]:
- A neonate should not be hemodialysed longer than four hours and should then be switched to hemofiltration for stabilization to prevent a rebound of the ammonia level.
- An older individual can be dialysed longer and should also be switched to hemofiltration for stabilization.
Depending on the height of the ammonia level (≤1500 μmol/L), one can also start with high flow hemofiltration methods to achieve a similarly speedy reduction of the ammonia level and then switch to regular hemofiltration for stabilization to prevent a rebound of the ammonia level.
Note: Peritoneal dialysis is ineffective for management of acute hyperammonemia and is not recommended.

Ammonia scavenger therapy

Treatment allows an alternative pathway for the excretion of excess nitrogen (see Table 2).
Nitrogen scavenger therapy is available as an intravenous infusion of a mixture of sodium phenylacetate and sodium benzoate for acute management and as an oral preparation of phenylbutyrate or sodium benzoate for long-term maintenance therapy.
Citrulline is supplemented at 170 mg/kg/day or 3.8g/m2/day (enterally).

Table 2.

Intravenous (IV) Ammonia Scavenger Therapy Protocol Used in OTC Deficiency and Carbamyl Phosphate Synthetase I (CPSI) Deficiency

Patient Weight	Components of Infusion Solution		Loading ¹ and Maintenance Dose ^2, 3
Patient Weight	Sodium phenylacetate & sodium benzoate ⁴	Arginine HCl injection, 10%	Sodium phenylacetate	Sodium benzoate	Arginine HCl ⁵
<25 kg	Undiluted: 2.5 mL (contains 250 mg of each) Dilute 1:10 ⁴	2.0 mL at 100 mg/mL	250 mg/kg	250 mg/kg	200 mg/kg
≥25 kg	Undiluted: 55 mL (contains 5,500 mg of each) Dilute 1:10 ⁴	40 mL at 100 mg/mL	5,500 mg/m²	5,500 mg/m²	4,000 mg/m²

: Batshaw et al [2001]
1.: Loading dose given over 90 to 120 minutes
2.: Maintenance dose given over 24 hours
3.: If an affected individual has symptomatic hyperammonemia and has not received a full dose of ammonia scavenger in the previous 12 hours, the affected person should first receive an IV bolus directly followed by maintenance infusion.
4.: Sodium phenylacetate/sodium benzoate must be diluted with sterile 10% dextrose before administration. The typical dilution is 1:10.
5.: Arginine infusion not to exceed 150mg/kg/h

Reversal of catabolism

Provide calories from glucose and fat, and resume protein intake (in the form of natural protein and an essential amino acid mix) no later than 24 hours after protein intake was discontinued
Note: Persons on hemodialysis or hemofiltration in particular need adequate nutrition to overcome catabolism because nutrients are removed by these procedures. Discontinuation of protein intake should not exceed 24 hours because deficiency of essential amino acids results in muscle breakdown and uncontrolled nitrogen release. Daily quantitative plasma amino acid analysis should guide nutritional therapy, the goal of which is to keep essential amino acid levels in the normal range.
Use of a high glucose infusion rate supported by continuous insulin infusion to maintain high set point normoglycemia (140 mg/dL) as needed. For a newborn in crisis the goal is to deliver at least 100 kcal/kg/day, mostly from glucose and fat.

Reducing the risk of neurologic damage

Affected individuals who are intubated and sedated may not show clinical signs of seizures, which are prevalent in acute hyperammonemia. EEG surveillance is thus highly recommended to allow electroencephalographic detection and subsequent treatment of seizures.
Note: Phenobarbital is removed by dialysis and valproic acid is contraindicated in urea cycle disorders.
The use of hypothermia for neuroprotection in hyperammonemia has long been proposed [Vaquero & Butterworth 2007] but has yet to be proven efficacious. A pilot study showed feasibility and safety (see Therapies Under Investigation).
No other interventions (besides lowering the ammonia level) have proven efficacy for neuroprotection in hyperammonemic coma due to a urea cycle disorder or other conditions.

Long-Term Treatment

Long-term treatment (including restriction of protein intake, use of nitrogen scavengers, and in some cases liver transplantation) is aimed at promoting growth and development and preventing hyperammonemic episodes.

Protein intake should be restricted to the required dietary allowance (RDA) for protein or the minimum amount necessary to allow growth and prevent catabolism depending on the severity of the disease. Use of an essential amino acid mixture is generally necessary to maintain normal essential amino acid levels in those on significant protein restriction, even persons with partial OTC deficiency. The diet should also provide vitamins, minerals, and trace elements, either in a calorie-rich, protein-free formula or in the form of supplements.

Although protein restriction is the mainstay of therapy, when protein intake is too low, catabolism can cause chronic hyperammonemia just as high protein intake does. Careful monitoring of plasma amino acid concentrations is necessary to detect essential amino acid deficiencies. High glutamine concentrations are interpreted as evidence of poor metabolic control and chronic hyperammonemia.

Nitrogen scavengers provide alternative routes for nitrogen disposal and allow more protein intake [Batshaw et al 2001, Berry & Steiner 2001].

Although it removes only half as much nitrogen as phenylbutyrate, oral sodium benzoate is the ammonia scavenger of choice in European countries and Australia rather than phenylbutyrate because it is felt to have fewer side effects.

Phenylbutyrate causes menstrual dysfunction and body odor, and appears to deplete branched chain amino acids; sodium benzoate causes hypokalemia due to increased renal losses of potassium [Scaglia et al 2004, Häberle et al 2012].

Recommendations for ammonia scavenger therapy:

Long-term ammonia scavenger treatment may consist of 450-600 mg/kg/day of sodium phenylbutyrate and 170 mg/kg/day of L-citrulline in children <25 kg, and 9.9-13.0 g/m²/day of sodium phenylbutyrate and 3.8 g/m²/day of L-citrulline in individuals weighing ≥25 kg. Treatment should be accompanied by an appropriate low-protein diet [Batshaw et al 2001].
Note: (1) Citrulline offers the advantage over arginine of incorporating aspartate into the pathway thus pulling one additional nitrogen molecule into the urea cycle. (2) Sodium benzoate is being used instead of sodium phenylbutyrate in conjunction with L-citrulline. The recommended dose is ≤250 mg/kg/d in children <25 kg and a maximum of 12 g/d [Häberle et al 2012].
Glycerol phenylbutyrate, which is significantly more palatable than sodium phenylbutyrate, is another treatment option. It has the same mechanism of action as sodium phenylbutyrate.

Liver transplantation. No matter how mild OTC deficiency appears to be, stressors can at any age precipitate a hyperammonemic crisis that becomes life threatening. The fear of such an event, along with the restrictions on daily living imposed by the dietary therapy, prompt many families to consider liver transplantation even if the disease has been manageable up to that point with diet and medication.

In severe, neonatal-onset urea cycle disorders, liver transplantation remains the most effective means of preventing further hyperammonemic crises and neurodevelopmental deterioration [Leonard & McKiernan 2004]. It is typically performed by age six months.
Females and males with partial OTC deficiency can, after diagnosis, be maintained on a low-protein diet and oral ammonia scavenger treatment for life; the need for liver transplant depends on the individual and is typically considered when an affected individual is unstable and has frequent hyperammonemic episodes.
Living related donor livers are often considered for partial liver transplantation (LT) in individuals with a urea cycle disorder. The suitability of a heterozygous mother as a donor has been discussed [Wong 2012]. According to Wakiya et al [2012], enzyme activity measurement in a liver biopsy sample is useful in determining the suitability of a heterozygous mother as a donor. However, this approach is problematic for several reasons:
- A liver biopsy sample may not adequately represent the enzyme activity in the liver of a heterozygous female. It can thus not be known whether a transplanted lobe contains enough enzyme activity to prevent symptoms in the recipient.
- After partial hepatectomy the liver of the donor mother will regenerate. Since the X-chromosome inactivation pattern in the regenerated liver in the donor cannot be predicted, it is also impossible to predict whether the overall enzyme activity in the donor mother will remain adequate to prevent symptoms in her.
- Likewise, the lobe that is transplanted into the recipient child will undergo changes after transplantation; thus, the enzyme activity in the donated lobe cannot be accurately determined at the time of transplantation, since additional post-transplantation changes could make the final enzyme activity in the recipient even more unpredictable.

Note: The efficacy of hepatocyte transfer for providing sufficient enzyme activity to bridge the time to liver transplantation in unstable individuals with neonatal-onset disease is currently under investigation (see Therapies Under Investigation).

Attention deficit/hyperactivity disorder (ADHD). Instruction in small classroom settings to minimize distraction and extra support to manage executive function deficits are often required and necessary to maximize success in school.

Monotherapy or combination therapy with non-stimulant or stimulant medication is often necessary for the treatment of ADHD (at least during times of learning) [Gyato et al 2004, Krivitzky et al 2009]. However, these medications negatively affect appetite and their use warrants even closer monitoring of intake and body weight to avoid a catabolic state that could lead to hyperammonemia.

Seizure disorders. Valproic acid is contraindicated for treatment of seizures in urea cycle disorders because it can cause a hyperammonemic crisis.

Learning disability/intellectual disability. Brain damage from an initial hyperammonemic coma, frequent hyperammonemic episodes with moderate to severe hyperammonemia, and chronic hyperammonemia can lead to learning disabilities and intellectual disability. Appropriate support services are necessary to optimize intellectual outcome in these individuals.

Also see Urea Cycle Disorders Overview.

Prevention of Primary Manifestations

In neonatal-onset OTC deficiency diagnosed prenatally, prospective intravenous (IV) treatment with ammonia scavengers within a few hours of birth (before the ammonia level rises) can prevent a hyperammonemic crisis and coma.

Later on, prevention of hyperammonemic episodes is focused on restriction of dietary protein through low-protein diet and administration of oral nitrogen scavenging drugs balanced with supplementation of essential amino acids (see Treatment of Manifestations).

Prevention of Secondary Complications

The following are recommended:

Avoid overrestriction of protein/amino acids, a common cause of hyperammonemia and poor growth. Gastrostomy tube feedings help avoid malnutrition in affected individuals who self-restrict protein intake and object to the taste of the essential amino acid formulas used for the treatment of urea cycle disorders.
Minimize risk of respiratory and gastrointestinal illnesses through hand hygiene.
Give immunizations on the usual schedule, including annual flu vaccine.
Provide multivitamin and vitamin D supplementation.
Use antipyretics appropriately. Note: Ibuprofen is preferred in the home setting over acetaminophen because of the potential liver toxicity of acetaminophen.

See also Therapies Under Investigation regarding the use of hypothermia as neuroprotective therapy to prevent intellectual disability, a complication of hyperammonemia.

Surveillance

The following are appropriate:

At the start of therapy, measure plasma ammonia concentration at least every two weeks (or more often depending on the stability of the affected individual), then slowly extend to every month, every two months, every three months, and every four months, as possible.
At the start of therapy, perform plasma amino acid (PAA) analysis at least every two weeks (or more often depending on the stability of the affected individual), then slowly extend to every month, every two months, every three months, and every four months.
Perform liver function tests depending on symptoms every three to six months or more often if they have been previously elevated.
Perform neuropsychological testing at the time that significant developmental milestones are expected to be achieved (e.g., at 6-9 months, 18 months, 3 years)

Agents/Circumstances to Avoid

Avoid the following:

Valproate
Haloperidol
Fasting
Stress, especially physical stress; potentially also psychological stress
Systemic corticosteroids because they cause catabolism, which can trigger a hyperammonemic crisis
Note: If systemic corticosteroids need to be administered as a life-saving therapy (e.g., during a severe asthma attack or an anaphylactic reaction), a metabolic specialist should be consulted; at the same time, preemptive measures (e.g., increased calorie intake) should be instituted to prevent catabolism.

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives (both male and female) of an affected individual in order to identify as early as possible those who would benefit from initiation of treatment and/or preventive measures.

Evaluations can include:

Molecular genetic testing if the OTC pathogenic variant in the family is known;
- If prenatal testing has not been performed, it is appropriate to perform biochemical (plasma amino acid analysis, ammonia level) and molecular genetic testing on at-risk newborns (males and females) as soon after birth as possible to clarify their disease status so that the appropriate treatment or surveillance of those with the family-specific pathogenic variant can be promptly established before the child experiences a metabolic crisis.
Biochemical analysis (plasma amino acid analysis, ammonia level), an allopurinol challenge test (in older individuals), and/or OTC enzyme activity measurement in liver (males only) if the OTC pathogenic variant in the family is not known.

In general for children with neonatal-onset disease, such testing cannot be performed rapidly enough to prevent a metabolic crisis. Therefore, preventive measures at birth should be instituted until such a time as the diagnosis can be ruled out (see the description of prospective treatment in Prevention of Primary Manifestations).

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Heterozygous females are at risk of becoming catabolic during pregnancy and (especially) post partum [Redonnet-Vernhet et al 2000, Mendez-Figueroa et al 2010, Celik et al 2011, Lipskind et al 2011, Ituk et al 2012].

A symptomatic heterozygous female needs to be treated throughout pregnancy according to her pre-pregnancy protocol with adaptation for her needs during pregnancy. In the peripartum and immediate postpartum periods proactive measures to prevent catabolism include, for example, administration of a 10% dextrose solution with appropriate electrolytes at 1.5 times maintenance and addition of intralipids as needed to meet caloric requirements during these periods.
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.

Therapies Under Investigation

The use of hypothermia for neuroprotection in hyperammonemia has long been proposed [Vaquero & Butterworth 2007]. Two case reports were published about its use in UCD [Whitelaw et al 2001, Vargha et al 2012].

Whole-body therapeutic hypothermia (TH) may decrease ammonia production through an overall slowing of metabolism. Decreased ammonia production was indicated in acute liver failure studies by lower arterial ammonia levels with cooling. The success of hemodialysis in lowering the ammonia level depends on whether the amount of ammonia removed by dialysis exceeds the amount of ammonia produced. If TH reduces ammonia production, dialysis will be more effective. In addition to its direct effect on ammonia metabolism TH may have a neuroprotective effect, at least in part due to reduced brain uptake of ammonia, reduced brain glutamine production, normal osmolyte levels, reduced intracranial pressure and cerebral blood flow, and improved cerebral perfusion [Jalan et al 1999, Jalan et al 2004].

Results of a pilot study assessing the feasibility and safety of whole-body therapeutic hypothermia during neonatal hyperammonemic coma have been published [ClinicalTrials.gov, Lichter-Konecki et al 2013]. While the study was not able to determine if the treatment was efficacious, the authors concluded that it was feasible and could be conducted safely.

The efficacy of hepatocyte transfer for providing sufficient enzyme activity is under investigation (see ClinicalTrials.gov).

In September 2009 a meeting in London assessed the "state of the art" of hepatocyte transplantation and limits to its success; according to Puppi et al [2012] the participating experts agreed that, "to obtain sufficient levels of repopulation of the liver with donor cells in patients with metabolic liver disease, some form of liver preconditioning would likely be required to enhance the engraftment and/or proliferation of donor cells. It was reported that clinical protocols for preconditioning by hepatic irradiation, portal vein embolization, and surgical resection had been developed."

Use of human induced pluripotent stem (iPS) cells is under consideration. The principal concept is the use of an affected individual's somatic cells to generate pluripotent stem cells that are then induced to become hepatocytes. Gene therapy could be performed on those hepatocytes in vitro, and the ‘corrected' hepatocytes could then be used for liver regeneration in the same person without the need for immune suppression [Soto-Gutierrez et al 2011].

Current gene therapy approach. An adeno-associated virus (AAV) vector construct harboring the OTC cDNA has been developed; its efficient delivery to the liver of animal models has been accomplished [Wang et al 2010, Wang et al 2012a, Wang et al 2012b]. However, most recent efforts have focused on AAV-mediated gene correction using the CRISPR-Cas9 system [Yang et al 2016].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.