"Ornithine Transcarbamylase Deficiency" – What Is It?
Ornithine transcarbamylase deficiency (OTC deficiency) is an X-linked metabolic disorder caused by mutations, i.e., genetic changes in the OTC gene. This defect leads to a faulty breakdown of ammonia. Due to a significantly increased ammonia content in the blood, it can lead to coma and severe brain damage in male newborns. However, a later age of onset and a milder course of the disease are also possible, although females can also be affected.
How Is "Ornithine Transcarbamylase Deficiency" Diagnosed?
Suspected Diagnosis
OTC deficiency is suspected if the following findings are present:
Clinic – Newborn Boys:
- Normal at birth
- Development of poor drinking behavior with reduced sucking
- Acute damage to the brain (impaired consciousness, drowsiness) with accelerated breathing and low body temperature
Clinic – Children, Adolescents, Adults (Male or Female):
- Behavioral changes due to brain damage or psychotic episodes
- Recurrent vomiting
- Migraine headaches
- Reye’s syndrome (vomiting, fever, irritability, hypoglycemia, impaired consciousness, seizures, cerebral edema)
- Seizures
- Unexplained movement disorders
Family History:
Death of male newborns in the family: within the first week of life from blood poisoning, unexplained drowsiness, refusal to feed, excessive respiratory rate or severe illness
Laboratory Findings:
Please note: In Germany, OTC deficiency is not included in newborn screening!
High levels of ammonia and certain amino acids in the blood, as well as elevated levels of orotic acid in the urine, may indicate an OTC deficiency.
Diagnostic Criteria
Male Persons:
The diagnosis of “OTC deficiency” is considered confirmed if those mentioned above clinical and laboratory findings are present and/or if at least one of the following findings is present:
- Detected mutation in the OTC gene
- Abnormally high increase in orotic acid excretion after allopurinol exposure test with or without a positive family history of OTC deficiency
- Reduced OTC enzyme activity in the liver
Female Persons:
The diagnosis of “OTC deficiency” is considered confirmed if those mentioned above clinical and laboratory findings are present and/or if at least one of the following findings is present:
- Detected mutation in the OTC gene
- Abnormally high increase in orotic acid excretion after allopurinol exposure test with or without a positive family history of OTC deficiency
A liver biopsy is not recommended to diagnose OTC deficiency in females.
Genetic Diagnostics
Genetically, the diagnosis of “OTC deficiency” is confirmed by the detection of a mutation, i.e., a genetic change in the OTC gene.
What Is the Risk of Cancer?
Liver cancer (hepatocellular carcinoma) has been described in the context of OTC deficiency. The risk of developing this malignant liver tumor is probably higher in patients with long-term liver damage who have not undergone a transplant. However, the exact risk cannot yet be quantified.
Clinically, OTC deficiency can occur either as a severe disease in male newborns (extremely rare in female newborns) or after the neonatal period (post-neonatal) in both males and females.
Occurrence in the Neonatal Period
Typically, the affected children appear healthy at birth, but from the second to the third day of life, there is an increasing loss of sucking behavior and, thus, reduced food intake. Affected newborns become increasingly limp and sleepy, and a significantly increased ammonia content in the blood can lead to coma. This is accompanied by accelerated breathing, which can lead to seizures, a lowered body temperature, and severe damage to the brain.
After a coma caused by increased ammonia levels in the blood, there is still an increased risk of increased ammonia levels. A liver transplant is usually required at around 6 months (sometimes earlier) to prevent further brain damage and improve quality of life.
Occurrence after the Neonatal Period
In males and females affected by partial OTC deficiency, the disease can manifest itself for the first time from infancy to adulthood. The first symptoms often appear as phasic vomiting, impaired consciousness, excitability, failure to thrive, or developmental delay when switching from breastfeeding to bottle feeding or cow’s milk.
In adults with very mild disease, the first symptoms usually appear after a trigger such as major injuries, after surgery or pregnancy, during cancer therapy, after prolonged fasting, a high-protein diet, high-dose cortisone therapy, or a febrile illness.
Affected Females Individuals
Affected female individuals in whom only one of the two X chromosomes has a genetic alteration in the OTC gene can present without any symptoms but can also show clear clinical signs. The degree of severity depends on the inactivation of the X chromosome. Around 15% of those affected develop symptoms throughout their lives.
What Is Known About the Development of "Ornithine Transcarbamylase Deficiency "?
OTC deficiency is caused by mutations, i.e., genetic changes in the OTC gene. This gene codes for the OTC protein, which is necessary to break ammonia in the so-called urea cycle.
If the gene is present in an altered form, the corresponding protein is not produced correctly and can no longer fulfill its actual function. As a result, ammonia can no longer be broken down, excreted, or accumulated in the body, leading to severe liver and brain damage.
OTC deficiency can be passed on from parents to their children, whereby the inheritance is X-linked. This means that it is inherited via the X chromosome. People of the male sex have one X and one Y chromosome; two X chromosomes characterize people of the female sex. If the OTC gene on the X chromosome is genetically altered in a male newborn, there is a complete loss of the OTC protein and, therefore, a severe course of the disease. Female-affected individuals in whom one X chromosome has the genetic alteration still have a “healthy” X chromosome, which is why the course of OTC deficiency is usually much milder here.
Is There Any Form of Treatment Available?
Treatment should be interdisciplinary and involve the relevant specialist disciplines.
In the acute phase, the ammonia level should be lowered quickly. Dialysis is the treatment of choice for both newborns and older patients. In addition, therapy with ammonia-binding medication can be used.
Long-term treatment includes reduced protein intake and therapy with ammonia-binding drugs.
Liver transplantation may be necessary as a result of coma or crises due to elevated ammonia levels.
Diagnosis of " Ornithine Transcarbamylase Deficiency" What's Next?
If you have been diagnosed with this cancer predisposition syndrome, it is important to see a specialist. The following section explains whether cancer screening tests or other measures are needed and how they should be carried out. We also give you some valuable tips on what you can do yourself. If you have any questions, please do not hesitate to contact us or your doctor.
Diagnosis of " Ornithine Transcarbamylase Deficiency" What's Next?
If you have been diagnosed with this cancer predisposition syndrome, it is important to see a specialist. The following section explains whether cancer screening tests or other measures are needed and how they should be carried out. We also give you some valuable tips on what you can do yourself. If you have any questions, please do not hesitate to contact us or your doctor.
Medical Measures for Early Detection
- At the start of therapy, blood ammonia levels should be measured regularly: Initially at least every 2 weeks, then further extended to every 4 months as treatment progresses
- At the start of therapy, an amino acid analysis should be carried out on the blood: Initially at least every 2 weeks, then extended to every 4 months as the treatment progresses
- Liver function tests depending on symptoms every 3-6 months or more frequently if elevated
- Neuropsychological examinations at times when developmental milestones should have been reached (e.g., at 6-9 months, 18 months, 3 years)
- Fasting, stress, and drug therapy with valproate, haloperidol, or the systemic administration of cortisone should be avoided.
- Patients should be made aware of a possible increased risk of liver cancer. Targeted cancer screening is not recommended.
Ornithine Transcarbamylase Deficiency- What You Can Do Yourself
You Should Pay Attention to This
You should consult a doctor as soon as a newborn baby shows signs of refusal to drink with loss of sucking behavior, drowsiness, increasingly weakening muscles, seizures, or impaired consciousness. After the infant period, episodic vomiting, excitability, loss of consciousness, failure to thrive, or developmental delay should be noted and reported to a doctor. You should also consult a doctor if you notice any new abnormalities or complaints.
Further Information
Patients can also register for the CPS registry at any time or have this done by the doctors looking after them.
Any further questions?
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