Ornithine Transcarbamylase Deficiency

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 (also known as "late-onset" or partial deficiency) disease in males and females.

• Males with severe neonatal-onset OTC deficiency are asymptomatic at birth but become symptomatic from hyperammonemia in the first week of life, most often on day two to three of life, and are usually catastrophically ill by the time they come to medical attention. After successful treatment of neonatal hyperammonemic coma these infants can easily become hyperammonemic again despite appropriate treatment; they typically require liver transplant to improve quality of life.
• Males and heterozygous females with post-neonatal-onset (partial) OTC deficiency can present from infancy to later childhood, adolescence, or adulthood.

No matter how mild the disease, a hyperammonemic crisis can be precipitated by stressors and become a life-threatening event at any age and in any situation in life. For all individuals with OTC deficiency, typical neuropsychological complications include developmental delay, learning disabilities, intellectual disability, attention-deficit/hyperactivity disorder, and executive function deficits.

Diagnosis/testing.

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

• A hemizygous pathogenic variant in OTC by molecular genetic testing
• A markedly abnormal increase of orotic acid excretion (≥20 umol/mmol creatinine) in a random urine collection or after an allopurinol challenge test, along with a past medical history of biochemical features consistent with OTC deficiency (e.g., elevated ammonia, elevated glutamine and low-to-normal citrulline), as well as absence of biochemical or DNA evidence suggestive of another inborn error of metabolism
• 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 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 (≥20 umol/mmol creatinine) in a random urine collection or after an allopurinol challenge test, along with a past medical history of biochemical features consistent with OTC deficiency (e.g., elevated ammonia, elevated glutamine and low-to-normal citrulline), as well as absence of biochemical or DNA evidence suggestive of another inborn error of metabolism

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 metabolic physician / biochemical geneticist and specialist metabolic dietitian; 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 developmental delay and intellectual disability, are treated according to the standard of care for these conditions while monitoring for signs of liver disease.

Surveillance: At the start of therapy, routine measurement of plasma ammonia and plasma amino acids every two weeks with gradual extension of the intervals between testing. Laboratory analysis for vitamin and mineral deficiencies annually or as indicated by the metabolic dietician. 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, fasting, systemic corticosteroids, 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 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 should be instituted at birth and maintained until the diagnosis has been 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 according to pre-pregnancy protocols adapted for needs during pregnancy; those who are asymptomatic need to avoid catabolism in the peripartum and postpartum periods and should be treated accordingly.

Genetic counseling.

OTC deficiency is inherited in an X-linked manner. If the mother of a proband has an OTC pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and may or may not develop clinical findings related to the disorder. Males with OTC deficiency transmit the pathogenic variant to all of their daughters and none of their sons. Molecular genetic heterozygote testing for at-risk female relatives and prenatal and preimplantation genetic testing for OTC deficiency are possible if the OTC pathogenic variant has been identified in the family.

Scenario 1: Abnormal newborn screening (NBS) result

Currently, NBS for OTC deficiency in the US is primarily based on quantification of the analyte citrulline on dried blood spots, either alone or as a ratio with other biochemical markers, which may help to improve the accuracy of the test [Merritt et al 2018]. Messina et al [2021] recommend the use of the glutamine-to-glutamate ratio to distinguish individuals with a urea cycle disorder from healthy individuals.

Citrulline values outside the range established by the screening laboratory are considered positive and require follow-up biochemical testing, which may include plasma ammonia, plasma amino acid profile, urine organic acid profile, and urine orotic acid quantification.

If follow-up biochemical testing supports the likelihood of OTC deficiency, additional testing is required to establish the diagnosis (see Establishing the Diagnosis).

Current NBS methods of screening for OTC deficiency vary greatly in sensitivity and specificity; as a result, medical intervention in response to receipt of an abnormal NBS result is also variable. However, in any scenario, an individual with an out-of-range NBS with evidence of unexplained altered neurologic status or poor feeding requires immediate medical attention and rapid testing of plasma ammonia. Individuals with an elevated ammonia may require dietary protein restriction, alternative pathway medications, and citrulline/arginine and/or renal replacement therapy.

Scenario 2: Symptomatic individual with atypical findings or untreated neonatal-onset OTC deficiency

A symptomatic individual may have either atypical findings associated with later-onset OTC deficiency or untreated neonatal-onset OTC deficiency resulting from any of the following:

• Infant symptomatic prior to the results of NBS
• NBS not performed
• False negative NBS result
• Caregivers not adherent to recommended treatment following a positive NBS result

Supportive (but nonspecific) clinical findings and preliminary laboratory findings can include the following.

Establishing the Diagnosis

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

• A hemizygous pathogenic (or likely pathogenic) variant in OTC by molecular genetic testing (See Table 1.)
• A markedly abnormal increase of orotic acid excretion (≥20 umol/mmol creatinine) in a random urine collection or after an allopurinol challenge test (see Allopurinol Challenge Test), along with a past medical history of biochemical features consistent with OTC deficiency (e.g., elevated ammonia, elevated glutamine, and low-to-normal citrulline), as well as the absence of biochemical or DNA evidence suggestive of another inborn error of metabolism
• Decreased OTC enzyme activity in liver (See OTC Enzyme Activity in Liver.)

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

• A heterozygous pathogenic (or likely pathogenic) variant in OTC identified by molecular genetic testing (see Table 1)
• A markedly abnormal increase of orotic acid excretion in a random urine sample or after an allopurinol challenge test (see Allopurinol Challenge Test) with or without a family history of OTC deficiency

Note: (1) Liver biopsy is not recommended to establish the diagnosis in females, due to the possibility of false negative results (see OTC Enzyme Activity in Liver). (2) (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a hemizygous or heterozygous OTC variant of uncertain significance does not establish or rule out the diagnosis.

Molecular Genetic Testing Approaches

Scenario 1: Abnormal newborn screening (NBS) result. When NBS results and other laboratory findings suggest the diagnosis of OTC deficiency, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

• Single-gene testing. Sequence analysis of OTC is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. (2) Deep intronic OTC pathogenic variants (c.540+265G>A, c.867+1126A>G, and c.1005+1091C>G) have been reported [Engel et al 2008, Kumar et al 2021]; sequencing methodologies that can detect splice donor and acceptor variants should be considered.
• A multigene panel that includes OTC and other genes of interest (see Differential Diagnosis) is likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) 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. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. (5) Sequencing methodologies that can detect splice donor and acceptor variants should be included.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Scenario 2: A symptomatic individual who has atypical findings associated with later-onset OTC deficiency or untreated neonatal-onset OTC deficiency (resulting from NBS not performed, illness presenting before NBS results are reported, or false negative NBS result). When the diagnosis of OTC deficiency has not been considered, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is an option. Exome sequencing is most commonly used; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Ornithine Transcarbamylase (OTC) Deficiency

Clinical Description

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

While neonatal-onset OTC deficiency accounted for approximately 60% of all OTC deficiency in the older literature, in its first eight years the longitudinal study of the Urea Cycle Disorders Consortium (UCDC) of the NICHD-supported Rare Disease Clinical Research Network (RDCRN) had enrolled 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]. This discrepancy may be the result of an ascertainment bias both in the older literature (in which undiagnosed individuals with milder symptoms are presumably underrepresented) as well as in the natural history study data, where individuals with very severe neonatal-onset OTC deficiency who die before study enrollment are underrepresented.

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 with 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 canonic 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 variant [McCullough et al 2000, Caldovic et al 2015]. In most individuals, OTC deficiency manifests in females heterozygous for pathogenic variants that cause severe neonatal-onset disease in hemizygous males. However, symptoms of OTC deficency were reported in females heterozygous for a hypomorphic OTC pathogenic variant [Luksan et al 2010, Pinner et al 2010].
• 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].

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).

An early estimated prevalence of OTC deficiency was 1:14,000 live births [Brusilow & Maestri 1996]. However, other surveys of incidence of OTC deficiency in Italy, Finland, and New South Wales, Australia, have revealed a lower prevalence of 1:70,000, 1:62,000, and 1:77,000 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.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with OTC deficiency, the evaluations summarized in Table 2 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 2.

Recommended Evaluations Following Initial Diagnosis of Ornithine Transcarbamylase (OTC) Deficiency

Treatment of Manifestations

Treatment is best provided by a metabolic physician / biochemical geneticist and a metabolic dietitian.

In the acute phase, the mainstays of treatment are the following.

Table 3.

Acute Inpatient Treatment of Manifestations in Individuals with Ornithine Transcarbamylase (OTC) Deficiency

Table 4.

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

Long-Term Treatment

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

Table 5.

Long-Term Treatment of Manifestations in Individuals with Ornithine Transcarbamylase (OTC) Deficiency

Table 6.

Recommended Protein Intake for Individuals with Ornithine Transcarbamylase (OTC) Deficiency

Prevention of Primary Manifestations

Surveillance

Table 7.

Recommended Surveillance for Individuals with Ornithine Transcarbamylase (OTC) Deficiency

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

Pregnancy Management

Heterozygous females are at risk of becoming catabolic during pregnancy and especially in the postpartum period [Torkzaban et al 2019].

A symptomatic heterozygous female needs to be treated throughout pregnancy according to her pre-pregnancy protocol with adaptation for her needs during pregnancy. Care should be given to the increased protein needs in pregnancy and adjustment to intact versus essential amino acid supplementation may be needed. 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

For treatment of OTC deficiency, Clinical Trials NCT02991144 and NCT04442347 currently under way include gene delivery with either an adeno-associated virus (AAV) or lipid nanoparticle mRNA. AAV8-based OTC delivery has been tried in a small cohort, with some individuals showing marked improvement while others appear to show very little change. A long-term follow-up clinical trial (NCT03636438) is in place to better understand the stability of gene delivery. Several groups are planning AAV-based clinical trials (NCT05092685), although at the time of writing, recruiting has not yet started.

Other strategies to reduce blood ammonia levels include attempts to modulate the microbiome (NCT03933410); however, in another study in which Synb1020 (an engineered E coli Nissle strain) was introduced, ammonia levels were not sufficiently reduced to warrant continuation (NCT03447730). While microbiome modulation appears promising, the complexity of the gut microbiome introduces challenges that will need to be overcome.

In preclinical studies, genome editing holds great promise, with data showing in vivo correction of specific OTC alterations in the spf-ash mouse, as well as development of a "universal" vector which introduces an expression cassette with promoter and OTC cDNA into the OTC locus containing the mutation [Yang et al 2016, Wang et al 2020]. This latter approach nearly eliminates the need to develop multiple guide RNAs and to meet regulatory approval for each of the OTC pathogenic variants to be corrected. As with other gene-editing approaches, not just limited to CRISPr/Cas9, efficiency of gene conversion, concerns for off-target editing, availability of protospacer motifs, and the potential for apoptosis in response to double-stranded DNA breaks are all issues that will need to be addressed. An ex-vivo approach in which OTC gene correction was performed in hepatocytes from an individual with OTC deficiency that then were implanted into a mouse model showed nearly 60% correction and no off-target editing by deep sequencing [Zabulica et al 2021].

Animal models of OTC deficiency had been until recently limited to several mouse strains; however, the ease of genome editing will allow greater control and tailoring of animal models. Of particular note is the recent development of an OTC-deficient pig [Enosawa et al 2021]. Therapies such as cell transplantation as well as other surgical and medical interventions will be more readily explored in this large animal model.

For the most current information see ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe. (ClinicalTrials.gov also lists some European studies.)

Mode of Inheritance

Ornithine transcarbamylase (OTC) deficiency is inherited in an X-linked manner.

Risk to Family Members

Parents of a male proband

• The father of a male with an OTC pathogenic variant will not have OTC deficiency nor will he be hemizygous for the OTC pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• If a male is the only affected family member (i.e., a simplex case):
  • The mother may be a heterozygote.
  • The mother may have somatic/germline mosaicism. Germline mosaicism has been reported in OTC deficiency [Komaki et al 1997, Bowling et al 1999].
  • The affected male may have a de novo pathogenic variant (in which case the mother is not a heterozygote). Rüegger et al [2014] reported a spontaneous mutation rate of 26% in male probands.
• If a molecular diagnosis has been established in the proband, molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.

Parents of a female proband

• A female who is heterozygous for an OTC pathogenic variant may have inherited the pathogenic variant from either her mother or her father, or the pathogenic variant may be de novo. Rüegger et al [2014] reported a spontaneous mutation rate of 67% in female probands.
  Note: Misattributed parentage can also be explored as an alternative explanation for an apparent de novo pathogenic variant.
• Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a de novo pathogenic variant from those with an inherited pathogenic variant. If a molecular diagnosis has been established in the proband, molecular genetic testing of the mother (and subsequently the father) can determine if the pathogenic variant was inherited.

Sibs of a male proband. The risk to sibs depends on the genetic status of the mother:

• If the mother of the proband has an OTC pathogenic variant, the chance of transmitting it in each pregnancy is 50%.
  • 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. 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 (see Clinical Description, Heterozygous Females).
• If the proband represents a simplex case and has an OTC pathogenic variant that cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal germline mosaicism (the general background risk of germline mosaicism is estimated to be 3%-4%).

Sibs of a female proband. The risk to sibs depends on the genetic status of the parents:

• If the mother of the proband has an OTC pathogenic variant, the chance of transmitting it in each pregnancy is 50% (see Sibs of a male proband).
• If the father of a female proband has an OTC pathogenic variant, he will transmit it to all of his daughters and none of his sons.
• If the proband represents a simplex case and has an OTC pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a male proband

• Males with neonatal-onset OTC deficiency used to die before reproductive age or be too debilitated to reproduce. However, prospective treatment as soon as the child is born and improved rescue therapy followed by liver transplant now allow some such males to reach reproductive age and reproduce.
• Males with late-onset, moderate-to-mild partial OTC deficiency transmit the OTC pathogenic variant to:
  • All of their daughters, who will be heterozygotes and may or may not develop clinical symptoms related to the disorder (see Clinical Description, Heterozygous Females);
  • None of their sons.

Offspring of a female proband. Women with an OTC pathogenic variant have a 50% chance of transmitting the pathogenic variant to each child:

• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygotes and may or may not develop clinical symptoms related to the disorder (see Clinical Description, Heterozygous Females).

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the OTC pathogenic variant, members of the parent's family may be at risk.

Note: Molecular genetic testing may be able to identify the family member in whom a de novo pathogenic variant arose, information that could help determine genetic risk status of the extended family.

Heterozygote Detection

Molecular genetic testing to identify female heterozygotes is possible if the OTC deficiency-causing pathogenic variant has been identified in the family.

Note: The phenotype of females who are heterozygous for an OTC pathogenic variant can range from asymptomatic to significant symptoms with recurrent hyperammonemia and neurologic compromise (see Clinical Description, Heterozygous Females).

If the OTC deficiency-causing pathogenic variant in the family cannot be identified, an allopurinol challenge may help clarify the genetic status of female family members (see Establishing the Diagnosis).

Related Genetic Counseling Issues

See Evaluating Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• Both asymptomatic and symptomatic women who are heterozygous for an OTC pathogenic variant may become catabolic during pregnancy and the postpartum period. They should be counseled about this risk and receive preventive treatment (see Pregnancy Management).
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, have an OTC deficiency-causing pathogenic variant, or are at risk of having an OTC deficiency-causing pathogenic variant.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the OTC deficiency-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for OTC deficiency are possible.

Because males with a neonatal presentation are more severely affected than heterozygous females, knowing the fetal sex may provide additional information helpful to families and health care providers in the newborn period.

• In a family with a history of neonatal-onset disease, it is likely (but not certain) that subsequently affected males will have a similar presentation.
• Because of the unpredictability of X-chromosome inactivation, it is not possible to predict the presentation in heterozygous females (see Genotype-Phenotype Correlations).

Molecular Pathogenesis

OTC catalyzes formation of citrulline from ornithine and carbamylphosphate in the liver and small intestine [Brusilow & Horwich 2001, Yamaguchi et al 2006]. The only known function of OTC in the human body is synthesis of citrulline, either as an intermediate of the urea cycle or a precursor of arginine biosynthesis [Brusilow & Horwich 2001].

Reduced abundance or complete absence of functional OTC enzyme can result from the following types of pathogenic variants:

• Frameshift and nonsense variants that cause premature protein termination, missense variants that impair or abolish substrate binding and catalysis, and missense variants that reduce OTC enzyme stability and/or prevent its folding [Shi et al 1998]
• Variants that affect mRNA splicing result either in a defective OTC transcript or reduced levels of functional transcript, leading to complete absence or reduced abundance of functional OTC enzyme
• Variants in OTC upstream regulatory regions that result in reduced abundance of OTC transcript and OTC enzyme [Jang et al 2018]
• Structural variants that result in defective OTC transcript due to deletion, duplication or inversion of one or more OTC exons

Mechanism of disease causation. OTC deficiency occurs via a loss-of-function mechanism as detailed above.

Notable OTC variants. For a list of notable variants, see Table 8 (pdf).

Author Notes

Ljubica Caldovic, PhD and Hiroki Morizono, PhD have worked for decades on the molecular biology of ornithine transcarbamylase.

Ornithine Transcarbamylase Deficiency website

Dr Caldovic's web page

Dr Morizono's web page

Nicholas Ah Mew, MD is director of the Inherited Metabolic Disorders Program at Children’s National Hospital and is associate professor of Pediatrics at The George Washington University. He is a clinical geneticist and clinical biochemical geneticist whose primary research interests include urea cycle disorders, organic acidemias, and other disorders of ammonia metabolism. He is the principal investigator or co-PI of several projects funded through the National Institutes of Health and Patient-Centered Outcomes Research Institute. Dr Ah Mew is the Children’s National site-PI and an active member of the NIH-funded Urea Cycle Disorders Consortium (UCDC). He has authored multiple publications and book chapters on hyperammonemia and urea cycle disorders and has lectured internationally on these topics.

Dr Ah Mew's web page

Uta Lichter-Konecki, MD, PhD is the director of the Metabolism Program in the Division of Genetic and Genomics Medicine at UPMC Children’s Hospital and Professor of Pediatrics at the University of Pittsburgh. As a clinician, she sees patients with inborn errors of metabolism. Her main research interest is delineating the causes of intellectual disability in patients with metabolic diseases and developing neuroprotective therapies to prevent compromise of intellectual function through translational research and improvement of treatment for all metabolic diseases but especially phenylketonuria, urea cycle disorders, and mitochondrial disorders. She is an active member of the NIH-funded Urea Cycle Disorders Consortium (UCDC) and has authored multiple publications and book chapters on hyperammonemia and urea cycle disorders.

Dr Lichter-Konecki's web page

Acknowledgments

We would like to acknowledge the support of the National Urea Cycle Disorders Foundation (NUCDF), which partners with physicians with a special focus on urea cycle disorders to further the well-being of patients with urea cycle disorders.

We would also like to acknowledge the Urea Cycle Disorders Consortium (UCDC) which has provided a platform for our work and has furthered our knowledge and understanding of OTC deficiency.

Revision History

• 26 May 2022 (ha) Revision: variants added to Molecular Genetic Testing Approaches, Scenario 1; Table 8 (pdf)
• 2 December 2021 (ha) Comprehensive update posted live
• 14 April 2016 (ma) Comprehensive update posted live
• 29 August 2013 (me) Review posted live
• 31 December 2012 (ul-k) Original submission

Literature Cited

• Ahrens MJ, Berry SA, Whitley CB, Markowitz DJ, Plante RJ, Tuchman M. Clinical and biochemical heterogeneity in females of a large pedigree with ornithine transcarbamylase deficiency due to the R141Q mutation. Am J Med Genet. 1996;66:311-5. [PubMed: 8985493]

• Anderson A, Gropman A, Le Mons C, Stratakis C, Gandjbakhche A. Evaluation of neurocognitive function of prefrontal cortex in ornithine transcarbamylase deficiency. Mol Genet Metab. 2020;129:207-12. [PMC free article: PMC7416502] [PubMed: 31952925]

• Arn PH, Hauser ER, Thomas GH, Herman G, Hess D, Brusilow SW. Hyperammonemia in women with a mutation at the ornithine carbamoyltransferase locus. A cause of postpartum coma. N Engl J Med. 1990;322:1652-5. [PubMed: 2342525]

• Ausems MG, Bakker E, Berger R, Duran M, van Diggelen OP, Keulemans JL, de Valk HW, Kneppers AL, Dorland L, Eskes PF, Beemer FA, Poll-The BT, Smeitink JA. Asymptomatic and late-onset ornithine transcarbamylase deficiency caused by a A208T mutation: clinical, biochemical and DNA analyses in a four-generation family. Am J Med Genet. 1997;68:236-9. [PubMed: 9028466]

• Balasubramaniam S, Rudduck C, Bennetts B, Peters G, Wilcken B, Ellaway C. Contiguous gene deletion syndrome in a female with ornithine transcarbamylase deficiency. Mol Genet Metab. 2010;99:34-41. [PubMed: 19783189]

• Batshaw ML, MacArthur RB, Tuchman M. Alternative pathway therapy for urea cycle disorders: twenty years later. J Pediatr. 2001;138:S46-54; discussion S-5. [PubMed: 11148549]

• Batshaw ML, Msall M, Beaudet AL, Trojak J. Risk of serious illness in heterozygotes for ornithine transcarbamylase deficiency. J Pediatr. 1986;108:236-41. [PubMed: 3944708]

• Batshaw ML, Tuchman M, Summar M, Seminara J. A longitudinal study of urea cycle disorders. Mol Genet Metab. 2014;113:127-30. [PMC free article: PMC4178008] [PubMed: 25135652]

• Ben-Ari Z, Dalal A, Morry A, Pitlik S, Zinger P, Cohen J, Fattal I, Galili-Mosberg R, Tessler D, Baruch RG, Nuoffer JM, Largiader CR, Mandel H. Adult-onset ornithine transcarbamylase (OTC) deficiency unmasked by the Atkins' diet. J Hepatol. 2010;52:292-5. [PubMed: 20031247]

• Berry GT, Steiner RD. Long-term management of patients with urea cycle disorders. J Pediatr. 2001;138:S56-60; discussion S-1. [PubMed: 11148550]

• Bireley WR, Van Hove JL, Gallagher RC, Fenton LZ. Urea cycle disorders: brain MRI and neurological outcome. Pediatr Radiol. 2012;42:455-62. [PubMed: 21989980]

• Bowling F, McGown I, McGill J, Cowley D, Tuchman M. Maternal gonadal mosaicism causing ornithine transcarbamylase deficiency. Am J Med Genet. 1999;85:452-4. [PubMed: 10405441]

• Brusilow SW, Horwich AL. Urea cycle enzymes. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The Metabolic & Molecular Bases of Inherited Disease. 8 ed. McGraw-Hill; 2001:1909-63.

• Brusilow SW, Maestri NE. Urea cycle disorders: diagnosis, pathophysiology, and therapy. Adv Pediatr. 1996;43:127-70. [PubMed: 8794176]

• Buerger C, Garbade SF, Dietrich Alber F, Waisbren SE, McCarter R, Kolker S, Burgard P, Urea Cycle Disorders C. Impairment of cognitive function in ornithine transcarbamylase deficiency is global rather than domain-specific and is associated with disease onset, sex, maximum ammonium, and number of hyperammonemic events. J Inherit Metab Dis. 2019;42:243-53. [PMC free article: PMC7439789] [PubMed: 30671983]

• Caldovic L, Abdikarim I, Narain S, Tuchman M, Morizono H. Genotype-Phenotype Correlations in Ornithine Transcarbamylase Deficiency: A Mutation Update. J Genet Genomics. 2015;42:181-94. [PMC free article: PMC4565140] [PubMed: 26059767]

• Chiong MA, Bennetts BH, Strasser SI, Wilcken B. Fatal late-onset ornithine transcarbamylase deficiency after coronary artery bypass surgery. Med J Aust. 2007;186:418-9. [PubMed: 17437397]

• Deardorff MA, Gaddipati H, Kaplan P, Sanchez-Lara PA, Sondheimer N, Spinner NB, Hakonarson H, Ficicioglu C, Ganesh J, Markello T, Loechelt B, Zand DJ, Yudkoff M, Lichter-Konecki U. Complex management of a patient with a contiguous Xp11.4 gene deletion involving ornithine transcarbamylase: a role for detailed molecular analysis in complex presentations of classical diseases. Mol Genet Metab. 2008;94:498-502. [PMC free article: PMC2572572] [PubMed: 18524659]

• Di Stefano C, Lombardo B, Fabbricatore C, Munno C, Caliendo I, Gallo F, Pastore L. Oculo-facio-cardio-dental (OFCD) syndrome: the first Italian case of BCOR and co-occurring OTC gene deletion. Gene. 2015;559:203-6. [PubMed: 25620158]

• Dionisi-Vici C, Rizzo C, Burlina AB, Caruso U, Sabetta G, Uziel G, Abeni D. Inborn errors of metabolism in the Italian pediatric population: a national retrospective survey. J Pediatr. 2002;140:321-7. [PubMed: 11953730]

• Dolman CL, Clasen RA, Dorovini-Zis K. Severe cerebral damage in ornithine transcarbamylase deficiency. Clin Neuropathol. 1988;7:10-5. [PubMed: 3370859]

• Engel K, Nuoffer JM, Mühlhausen C, Klaus V, Largiadèr CR, Tsiakas K, Santer R, Wermuth B, Häberle J. Analysis of mRNA transcripts improves the success rate of molecular genetic testing in OTC deficiency. Mol Genet Metab. 2008;94:292-7. [PubMed: 18440262]

• Enosawa S, Hsu HC, Yanagi Y, Matsunari H, Uchikura A, Nagashima H. Characterization and treatment responsiveness of genetically engineered ornithine transcarbamylase-deficient pig. J Clin Med. 2021;10:3226. [PMC free article: PMC8347267] [PubMed: 34362010]

• Gallant NM, Gui D, Lassman CR, Yong WH, Teitell M, Mandelker D, Lorey F, Martinez-Agosto JA, Quintero-Rivera F. Novel liver findings in ornithine transcarbamylase deficiency due to Xp11.4-p21.1 microdeletion. Gene. 2015;556:249-53. [PubMed: 25434494]

• Gerstein MT, Markus AR, Gianattasio KZ, Le Mons C, Bartos J, Stevens DM, Mew NA. Choosing between medical management and liver transplant in urea cycle disorders: A conceptual framework for parental treatment decision-making in rare disease. J Inherit Metab Dis. 2020;43:438-58. [PMC free article: PMC7318329] [PubMed: 31883128]

• Häberle J, Boddaert N, Burlina A, Chakrapani A, Dixon M, Huemer M, Karall D, Martinelli D, Sanjurjo Crespo P, 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. [PMC free article: PMC3488504] [PubMed: 22642880]

• Honeycutt D, Callahan K, Rutledge L, Evans B. Heterozygote ornithine transcarbamylase deficiency presenting as symptomatic hyperammonemia during initiation of valproate therapy. Neurology. 1992;42:666-8. [PubMed: 1549234]

• Hu WT, Kantarci OH, Merritt JL, 2nd, McGrann P, Dyck PJ, Lucchinetti CF, Tippmann-Peikert M. Ornithine transcarbamylase deficiency presenting as encephalopathy during adulthood following bariatric surgery. Arch Neurol. 2007;64:126-8. [PubMed: 17210820]

• Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389-97. [PMC free article: PMC9314484] [PubMed: 35834113]

• Jang YJ, LaBella AL, Feeney TP, Braverman N, Tuchman M, Morizono H, Ah Mew N, Caldovic L. Disease-causing mutations in the promoter and enhancer of the ornithine transcarbamylase gene. Hum Mutat. 2018;39:527-36. [PMC free article: PMC7388160] [PubMed: 29282796]

• Keegan CE, Martin DM, Quint DJ, Gorski JL. Acute extrapyramidal syndrome in mild ornithine transcarbamylase deficiency: metabolic stroke involving the caudate and putamen without metabolic decompensation. Eur J Pediatr. 2003;162:259-63. [PubMed: 12647200]

• Keskinen P, Siitonen A, Salo M. Hereditary urea cycle diseases in Finland. Acta Paediatr. 2008;97:1412-9. [PubMed: 18616627]

• Komaki S, Matsuura T, Oyanagi K, Hoshide R, Kiwaki K, Endo F, Shimadzu M, Matsuda I. Familial lethal inheritance of a mutated paternal gene in females causing X-linked ornithine transcarbamylase (OTC) deficiency. Am J Med Genet. 1997;69:177-81. [PubMed: 9056557]

• Krivitzky L, Babikian T, Lee HS, Thomas NH, Burk-Paull KL, Batshaw ML. Intellectual, adaptive, and behavioral functioning in children with urea cycle disorders. Pediatr Res. 2009;66:96-101. [PMC free article: PMC2746951] [PubMed: 19287347]

• Kumar RD, Burrage LC, Bartos J, Ali S, Schmitt E, Nagamani SCS, LeMons C. A deep intronic variant is a common cause of OTC deficiency in individuals with previously negative genetic testing. Mol Genet Metab Rep. 2021;26:100706. [PMC free article: PMC7809430] [PubMed: 33489762]

• Leão M. Valproate as a cause of hyperammonemia in heterozygotes with ornithine-transcarbamylase deficiency. Neurology. 1995;45:593-4. [PubMed: 7898728]

• Lipskind S, Loanzon S, Simi E, Ouyang DW. Hyperammonemic coma in an ornithine transcarbamylase mutation carrier following antepartum corticosteroids. J Perinatol. 2011;31:682-4. [PubMed: 21956151]

• Luksan O, Jirsa M, Eberova J, Minks J, Treslova H, Bouckova M, Storkanova G, Vlaskova H, Hrebicek M, Dvorakova L. Disruption of OTC promoter-enhancer interaction in a patient with symptoms of ornithine carbamoyltransferase deficiency. Hum Mutat. 2010;31:E1294-303. [PubMed: 20127982]

• Marcus N, Scheuerman O, Hoffer V, Zilbershot-Fink E, Reiter J, Garty BZ. Stupor in an adolescent following Yom Kippur fast, due to late-onset ornithine transcarbamylase deficiency. Isr Med Assoc J. 2008;10:395-6. [PubMed: 18605371]

• McCullough BA, Yudkoff M, Batshaw ML, Wilson JM, Raper SE, Tuchman M. Genotype spectrum of ornithine transcarbamylase deficiency: correlation with the clinical and biochemical phenotype. Am J Med Genet. 2000;93:313-9. [PubMed: 10946359]

• Merritt JL 2nd, Brody LL, Pino G, Rinaldo P. Newborn screening for proximal urea cycle disorders: Current evidence supporting recommendations for newborn screening. Mol Genet Metab. 2018;124:109-13. [PubMed: 29703588]

• Messina M, Raudino F, Iacobacci R, Meli C, Fiumara A. New ratio as a useful marker for early diagnosis of proximal urea cycle disorders. Clin Chim Acta. 2021;520:154-9. [PubMed: 34116006]

• Msall M, Batshaw ML, Suss R, Brusilow SW, Mellits ED. Neurologic outcome in children with inborn errors of urea synthesis. Outcome of urea-cycle enzymopathies. N Engl J Med. 1984;310:1500-5. [PubMed: 6717540]

• Mustafa A, Clarke JT. Ornithine transcarbamoylase deficiency presenting with acute liver failure. J Inherit Metab Dis. 2006;29:586. [PubMed: 16802108]

• Oechsner M, Steen C, Sturenburg HJ, Kohlschutter A. Hyperammonaemic encephalopathy after initiation of valproate therapy in unrecognised ornithine transcarbamylase deficiency. J Neurol Neurosurg Psychiatry. 1998;64:680-2. [PMC free article: PMC2170080] [PubMed: 9598692]

• Panlaqui OM, Tran K, Johns A, McGill J, White H. Acute hyperammonemic encephalopathy in adult onset ornithine transcarbamylase deficiency. Intensive Care Med. 2008;34:1922-4. [PubMed: 18651132]

• Pinner JR, Freckmann ML, Kirk EP, Yoshino M. Female heterozygotes for the hypomorphic R40H mutation can have ornithine transcarbamylase deficiency and present in early adolescence: a case report and review of the literature. J Med Case Rep. 2010;4:361. [PMC free article: PMC2997096] [PubMed: 21070677]

• Posner JB, Saper CB, Schiff ND, Claasen J. Plum and Posner's Diagnosis and Treatment of Stupor and Coma. 5 ed. Oxford, UK: Oxford University Press; 2019.

• Posset R, Garbade SF, Gleich F, Gropman AL, de Lonlay P, Hoffmann GF, Garcia-Cazorla A, Nagamani SCS, Baumgartner MR, Schulze A, Dobbelaere D, Yudkoff M, Kolker S, Zielonka M, et al. Long-term effects of medical management on growth and weight in individuals with urea cycle disorders. Sci Rep. 2020;10:11948. [PMC free article: PMC7371674] [PubMed: 32686765]

• Posset R, Gropman AL, Nagamani SCS, Burrage LC, Bedoyan JK, Wong D, Berry GT, Baumgartner MR, Yudkoff M, Zielonka M, Hoffmann GF, Burgard P, Schulze A, McCandless SE, Garcia-Cazorla A, Seminara J, Garbade SF, Kolker S, et al. Impact of diagnosis and therapy on cognitive function in urea cycle disorders. Ann Neurol. 2019;86:116-28. [PMC free article: PMC6692656] [PubMed: 31018246]

• Raina R, Bedoyan JK, Lichter-Konecki U, Jouvet P, Picca S, Mew NA, Machado MC, Chakraborty R, Vemuganti M, Grewal MK, Bunchman T, Sethi SK, Krishnappa V, McCulloch M, Alhasan K, Bagga A, Basu RK, Schaefer F, Filler G, Warady BA. Consensus guidelines for management of hyperammonaemia in paediatric patients receiving continuous kidney replacement therapy. Nat Rev Nephrol. 2020;16:471-82. [PMC free article: PMC7366888] [PubMed: 32269302]

• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]

• Rubenstein JL, Johnston K, Elliott GR, Brusilow SW. Haloperidol-induced hyperammonaemia in a child with citrullinaemia. J Inherit Metab Dis. 1990;13:754-5. [PubMed: 2246861]

• Rüegger CM, Lindner M, Ballhausen D, Baumgartner MR, Beblo S, Das A, Gautschi M, Glahn EM, Grünert SC, Hennermann J, Hochuli M, Huemer M, Karall D, Kölker S, Lachmann RH, Lotz-Havla A, Möslinger D, Nuoffer JM, Plecko B, Rutsch F, Santer R, Spiekerkoetter U, Staufner C, Stricker T, Wijburg FA, Williams M, Burgard P, Häberle J. Cross-sectional observational study of 208 patients with non-classical urea cycle disorders. J Inherit Metab Dis. 2014;37:21-30. [PMC free article: PMC3889631] [PubMed: 23780642]

• Scaglia F, Brunetti-Pierri N, Kleppe S, Marini J, Carter S, Garlick P, Jahoor F, O'Brien W, Lee B. Clinical consequences of urea cycle enzyme deficiencies and potential links to arginine and nitric oxide metabolism. J Nutr. 2004;134:2775S-82S. [PubMed: 15465784]

• Shchelochkov OA, Li FY, Geraghty MT, Gallagher RC, Van Hove JL, Lichter-Konecki U, Fernhoff PM, Copeland S, Reimschisel T, Cederbaum S, Lee B, Chinault AC, Wong LJ. High-frequency detection of deletions and variable rearrangements at the ornithine transcarbamylase (OTC) locus by oligonucleotide array CGH. Mol Genet Metab. 2009;96:97-105. [PubMed: 19138872]

• Shi D, Morizono H, Ha Y, Aoyagi M, Tuchman M, Allewell NM. 1.85-A resolution crystal structure of human ornithine transcarbamoylase complexed with N-phosphonacetyl-L-ornithine. Catalytic mechanism and correlation with inherited deficiency. J Biol Chem. 1998;273:34247-54. [PubMed: 9852088]

• Sprouse C, King J, Helman G, Pacheco-Colon I, Shattuck K, Breeden A, Seltzer R, VanMeter JW, Gropman AL. Investigating neurological deficits in carriers and affected patients with ornithine transcarbamylase deficiency. Mol Genet Metab. 2014;113:136-41. [PMC free article: PMC4458385] [PubMed: 24881970]

• Takanashi J, Barkovich AJ, Cheng SF, Weisiger K, Zlatunich CO, Mudge C, Rosenthal P, Tuchman M, Packman S. Brain MR imaging in neonatal hyperammonemic encephalopathy resulting from proximal urea cycle disorders. Am J Neuroradiol. 2003;24:1184-7. [PMC free article: PMC8148992] [PubMed: 12812952]

• Thakur V, Rupar CA, Ramsay DA, Singh R, Fraser DD. Fatal cerebral edema from late-onset ornithine transcarbamylase deficiency in a juvenile male patient receiving valproic acid. Pediatr Crit Care Med. 2006;7:273-6. [PubMed: 16575347]

• Torkzaban M, Haddad A, Baxter JK, Berghella V, Gahl WA, Al-Kouatly HB. Maternal ornithine transcarbamylase deficiency, a genetic condition associated with high maternal and neonatal mortality every clinician should know: A systematic review. Am J Med Genet A. 2019;179:2091-100. [PubMed: 31441224]

• Tuchman M, Lee B, Lichter-Konecki U, Summar ML, Yudkoff M, Cederbaum SD, Kerr DS, Diaz GA, Seashore MR, Lee HS, McCarter RJ, Krischer JP, Batshaw ML. Cross-sectional multicenter study of patients with urea cycle disorders in the United States. Mol Genet Metab. 2008;94:397-402. [PMC free article: PMC2640937] [PubMed: 18562231]

• Tuchman M, Tsai MY, Holzknecht RA, Brusilow SW. Carbamyl phosphate synthetase and ornithine transcarbamylase activities in enzyme-deficient human liver measured by radiochromatography and correlated with outcome. Pediatr Res. 1989;26:77-82. [PubMed: 2771513]

• UCD Conference Group. Consensus statement from a conference for the management of patients with urea cycle disorders. J Pediatr. 2001;138:S1-5. [PubMed: 11148543]

• Vasquez-Loarte T, Thompson JD, Merritt JL 2nd. Considering proximal urea cycle disorders in expanded newborn screening. Int J Neonatal Screen. 2020;6:6. [PMC free article: PMC7712149] [PubMed: 33124615]

• Waisbren SE, Gropman AL, Batshaw ML, et al. Improving long term outcomes in urea cycle disorders-report from the Urea Cycle Disorders Consortium. J Inherit Metab Dis. 2016;39:573-84. [PMC free article: PMC4921309] [PubMed: 27215558]

• Waisbren SE, He J, McCarter R. Assessing psychological functioning in metabolic disorders: validation of the Adaptive Behavior Assessment System, Second Edition (ABAS-II), and the Behavior Rating Inventory of Executive Function (BRIEF) for identification of individuals at risk. JIMD Rep. 2015;21:35-43. [PMC free article: PMC4470946] [PubMed: 25712381]

• Wakiya T, Sanada Y, Urahashi T, Ihara Y, Yamada N, Okada N, Ushijima K, Otomo S, Sakamoto K, Murayama K, Takayanagi M, Hakamada K, Yasuda Y, Mizuta K. Impact of enzyme activity assay on indication in liver transplantation for ornithine transcarbamylase deficiency. Mol Genet Metab. 2012;105:404-7. [PubMed: 22264779]

• Wang L, Yang Y, Breton C, Bell P, Li M, Zhang J, Che Y, Saveliev A, He Z, White J, Latshaw C, Xu C, McMenamin D, Yu H, Morizono H, Batshaw ML, Wilson JM. A mutation-independent CRISPR-Cas9-mediated gene targeting approach to treat a murine model of ornithine transcarbamylase deficiency. Sci Adv. 2020;6:eaax5701. [PMC free article: PMC7015695] [PubMed: 32095520]

• Wilson JM, Shchelochkov OA, Gallagher RC, Batshaw ML. Hepatocellular carcinoma in a research subject with ornithine transcarbamylase deficiency. Mol Genet Metab. 2012;105:263-5. [PMC free article: PMC3273986] [PubMed: 22129577]

• Wiwattanadittakul N, Prust M, Gaillard WD, Massaro A, Vezina G, Tsuchida TN, Gropman AL. The utility of EEG monitoring in neonates with hyperammonemia due to inborn errors of metabolism. Mol Genet Metab. 2018;125:235-40. [PubMed: 30197275]

• Wong DA. Ornithine transcarbamylase deficiency: are carrier females suitable donors? Pediatr Transplant. 2012;16:525-7. [PubMed: 22672071]

• Yamaguchi S, Brailey LL, Morizono H, Bale AE, Tuchman M. Mutations and polymorphisms in the human ornithine transcarbamylase (OTC) gene. Hum Mutat. 2006;27:626-32. [PubMed: 16786505]

• Yamanouchi H, Yokoo H, Yuhara Y, Maruyama K, Sasaki A, Hirato J, Nakazato Y. An autopsy case of ornithine transcarbamylase deficiency. Brain Dev. 2002;24:91-4. [PubMed: 11891099]

• Yang Y, Wang L, Bell P, McMenamin D, He Z, White J, Yu H, Xu C, Morizono H, Musunuru K, Batshaw ML, Wilson JM. A dual AAV system enables the Cas9-mediated correction of a metabolic liver disease in newborn mice. Nat Biotechnol. 2016;34:334-8. [PMC free article: PMC4786489] [PubMed: 26829317]

• Yorifuji T, Muroi J, Uematsu A, Tanaka K, Kiwaki K, Endo F, Matsuda I, Nagasaka H, Furusho K. X-inactivation pattern in the liver of a manifesting female with ornithine transcarbamylase (OTC) deficiency. Clin Genet. 1998;54:349-53. [PubMed: 9831349]

• Zabulica M, Srinivasan RC, Akcakaya P, Allegri G, Bestas B, Firth M, Hammarstedt C, Jakobsson T, Jakobsson T, Ellis E, Jorns C, Makris G, Scherer T, Rimann N, van Zuydam NR, Gramignoli R, Forslow A, Engberg S, Maresca M, Rooyackers O, Thony B, Haberle J, Rosen B, Strom SC. Correction of a urea cycle defect after ex vivo gene editing of human hepatocytes. Mol Ther. 2021;29:1903-17. [PMC free article: PMC8116578] [PubMed: 33484963]

• Zecavati N, Lichter-Konecki U, Singh R, Crawford J, Seltzer R, Gropman AL, editors. Seizures in urea cycle disorders (UCDs): An under-recognized symptom in patients outside of the acute metabolic phase. American Society of Human Genetics 58th Annual Meeting; 2008; Philadelphia, PA.