Definition
Ornithine transcarbamylase deficiency (OTC deficiency, OMIM #311250) is an X-chromosomal, hereditary metabolic disease caused by mutations in the OTC gene. This defect in the urea cycle can lead to severe encephalopathy in male newborns as part of a hyperammonemic coma. However, a later onset of the disease and a milder progression is also possible, and may also affect women.
Key Data
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Synonyms | OTC deficiency, ornithine carbamoyltransferase deficiency |
Gene | OTC |
Gene product | OTC |
Function | Part of the urea cycle |
Heredity | X-chromosomal recessive or X-chromosomal dominant |
Prevalence | Varies from 1:14.000 to 1:77.000 depending on the study |
Genotype-phenotype correlation | Missense mutations resulting in neonatal occurrence in hemizygous boys.
Both nonsense mutations, insertions, and deletions that cause a frameshift as well as single-nucleotide variants lead to a complete loss of OTC function and result in neonatal occurrence. Affected heterozygous females can also develop symptoms later on. |
Penetrance | Complete in affected hemizygous males |
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Diagnosis
Suspected Diagnosis
OTC deficiency is suspected with the following findings:
Clinical Symptoms – Newborn Boys:
Clinical Symptoms – Children, Adolescents, Adults (Male or Female):
Family History:
Death of a male newborn in the family: due to sepsis within the first week after birth, unexplained somnolence, refusal to eat, tachypnea, or severe illness
Laboratory Findings:
Please note: In Germany, OTC deficiency is not included in newborn screening!
Diagnostic Criteria
Male Individuals:
The diagnosis of “OTC deficiency” is confirmed by the clinical and laboratory-chemical findings listed above and/or with at least one of the following findings:
Female Individuals:
The diagnosis of “OTC deficiency” is confirmed by the clinical and laboratory-chemical findings listed above and/or with at least one of the following findings:
A liver biopsy to diagnose OTC deficiency is not recommended for females.
Genetic Diagnostics
Genetic evidence of a mutation in the OTC gene can be provided by sequence analysis and, if necessary, a subsequent targeted deletion/duplication analysis. Panel examinations consisting of multiple genes may also be helpful.
Differential Diagnoses
Clinical Presentation
OTC deficiency can occur as a severe disease in male neonates (very rarely in female neonates) or as a post-neonatal disease (partial deficiency) in male and female individuals.
Neonatal Occurrence
Typically, affected children appear to be healthy at birth; when they are two to three days old, however, they increasingly lose their sucking behavior, resulting in a reduced food intake and hypotension, followed by somnolence and even a hyperammonemic coma. Other symptoms are hyperventilation leading to respiratory alkalosis, cramping seizures, decreased body temperature, and severe encephalopathy.
Following a hyperammonemic coma, there continues to be an increased risk of an elevated level of ammonia. Generally, a liver transplant at around 6 months (sometimes earlier) is necessary to prevent further brain damage and increase the quality of life.
Post-Neonatal Occurrence
In affected hemizygous males and heterozygous females with partial OTC deficiency, the disease can manifest for the first time anywhere from infancy to adulthood. It is often the case that initial symptoms, such as episodic vomiting, lethargy, irritability, failure to thrive, or developmental delay, occur when a change is made from nursing to baby formula or cow’s milk.
In adults with very mild forms of the disease, initial symptoms often manifest after a trigger, such as major injuries, following surgery, after giving birth, during cancer therapy, after prolonged fasting, a protein-rich diet, high-dosage steroid therapy, or a feverish illness.
Affected Heterozygous Females
Affected heterozygous females may either be without phenotypic symptoms or suffer from significant symptoms. The degree of expression depends on the inactivation of the X-chromosome. Approximately 15% of affected females develop symptoms over the course of their lives.
Hepatocellular Carcinoma (HCC)
The risk of developing HCC is probably the highest in patients exhibiting long-term liver damage who have not undergone a transplant.
Therapeutic Considerations
The treatment should be interdisciplinary and involve the corresponding specialist disciplines.
The level of ammonia should be lowered as quickly as possible during the acute phase. Hemodialysis is the treatment of choice for this in both newborns as well as older patients. In addition, ammonia-binding medications can be administered as well.
Long-term treatments include restricting protein consumption and therapy with ammonia-binding medications.
A liver transplant may be necessary following hyperammonemic crises or a hyperammonemic coma.
Surveillance Recommendations
Surveillance Recommendations
Additional Information
Open Clinical Trials / Registries
There are currently no open clinical trials/registries for patients with ornithine transcarbamylase deficiency that we can recommend to you for more information.