What is ornithine transcarbamylase deficiency?

Ornithine transcarbamylase deficiency (OTC deficiency,) is an X-chromosome linked, hereditary metabolic disease caused by mutations – or genetic changes – in the OTC gene. This defect leads to the incorrect breakdown of ammonia, which can cause comas and result in severe brain damage in male newborns due to very elevated levels of ammonia in the blood. However, a later onset of the disease and a milder progression is also possible, and it may also affect females.

How is ornithine transcarbamylase deficiency diagnosed?

Suspected Diagnosis

OTC deficiency is suspected with presentation of the following:

Clinical symptoms – newborn boys:

  • Normal at birth

  • Development of poor drinking behavior with reduced sucking

  • Acute brain damage (consciousness disorder, sleepiness) with accelerated respiration and low body temperature

Clinical symptoms – children, adolescents, adults (male or female):

  • Behavioral change due to brain damage or psychotic episodes

  • Recurring vomiting

  • Migraines

  • Reye-like syndrome (vomiting, fever, irritability, hypoglycemia, consciousness disorders, cramping seizures, brain edema)

  • Cramping seizures

  • Unexplained movement disorders

Family history:

Death of a male newborn in the family due to blood poisoning, unexplained sleepiness, refusal to eat, excessively rapid breathing rate, or severe illness within the first week after birth

Laboratory findings:

Note: In Germany, OTC deficiency is not included in newborn screening!

A high ammonia level, a certain amino acid constellation in the blood, and an elevated concentration of orotic acid in the urine may indicate OTC deficiency.

Diagnostic Criteria

Males:

The diagnosis of “OTC deficiency” is confirmed by clinical and laboratory chemical findings listed above and/or by the presence of at least one of the following findings:

  • A proven mutation in the OTC gene

  • Abnormally large increase in the excretion of orotic acid after an allopurinol loading test with or without a positive family history of OTC deficiency

  • Reduced OTC enzyme activity in the liver

Females:

The diagnosis of “OTC deficiency” is confirmed by the clinical and laboratory chemical findings listed above and/or by the presence of at least one of the following findings:

  • A proven mutation in the OTC gene

  • Abnormally large increase in the excretion of orotic acid after an allopurinol loading test with or without a positive family history of OTC deficiency

A liver biopsy to diagnose OTC deficiency is not recommended for females.

Genetic Diagnostics

Genetically, the diagnosis of “OTC deficiency” is verified by evidence of a mutation – or genetic change – in the OTC gene.

What is the risk of cancer?

Liver cancer (hepatocellular carcinoma) is described as being associated with OTC deficiency. The risk of developing this malignant liver tumor is probably the highest in patients exhibiting long-term liver damage who have not undergone a transplant. The exact risk, cannot yet be quantified.

Clinically, OTC deficiency can occur either as a severe disease affecting male newborns (it very rarely affects female newborns) or after the newborn period (post-neonatal) in males and females.

Occurrence during the newborn period

Affected children typically appear to be healthy at birth; however, they increasingly lose their sucking behavior when they are two to three days old, resulting in reduced food intake. Affected newborns become increasingly limp and sleepy, and the high level of ammonia in the blood can result in coma. In addition, breathing is accelerated, which can lead to cramping seizures, low body temperature, and severe brain damage.

Even after suffering a coma induced by high blood ammonia levels, the increased risk of an elevated ammonia level remains ever present. Generally, a liver transplant at around 6 months (sometimes earlier) is necessary to prevent further brain damage and increase the quality of life.

Occurrence after the newborn period

In affected males and 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 intermittent vomiting, consciousness disorders, irritability, failure to thrive, or developmental delays, occur when a change is made from nursing to baby formula or cow’s milk.

In adults with a very mild form of the disease, initial symptoms often manifest after a trigger, such as major injuries, following surgery, after a pregnancy, during cancer therapy, after prolonged fasting, a protein-rich diet, high-dosage cortisone therapy, or an illness associated with fever.

Affected females

Females who only carry the OTC gene alteration on one of their two X-chromosomes can either present with clear clinical signs or have no obvious symptoms. The extent of symptoms depends on which X-chromosome is inactivated . Around 15% of affected females develop symptoms over the course of their lives.

What causes ornithine transcarbamylase deficiency?

OTC deficiency is caused by mutations – or genetic changes – in the OTC gene. This gene encodes for the OTC protein, which is needed for the breakdown of ammonia in the urea cycle.

Now if the gene is altered, the corresponding protein will not be produced properly and will no longer be able to perform its normal function. Therefore, it will no longer be possible for ammonia to be broken down and excreted, resulting in an accumulation in the body that can cause severe liver and brain damage.

OTC deficiency can be passed on by parents to their children, whereby the heredity is X-linked. This means that it is passed on via the X-chromosome. Males have one X and one Y-chromosome, whereas females have two X-chromosomes. Now if the OTC gene on the X-chromosome is altered in a male newborn, this will result in the complete loss of the OTC protein and therefore lead to a very severe progression of the disease. Females with an X-chromosome exhibiting a genetic change still have one “healthy” X-chromosome, which is why the progression of OTC deficiency is generally milder for them.

Is there a treatment?

Die Behandlung sollte interdisziplinär unter Beteiligung der entsprechenden Fachdisziplinen erfolgen.

In der Akutphase sollte der Ammoniakspiegel so rasch wie möglich gesenkt werden. Therapie der Wahl hierzu ist sowohl bei Neugeborenen als auch bei älteren Patienten die Dialyse. Darüber hinaus kann eine Therapie mit Ammoniak-bindenden Medikamenten erfolgen.

Die Langzeitbehandlung beinhaltet eine reduzierte Proteinzufuhr sowie die Therapie mit Ammoniak-bindenden Medikamenten.
Als Folge eines Komas oder von Krisen, die auf einen erhöhten Ammoniakspiegel zurückzuführen sind, kann eine Lebertransplantation erforderlich sein.

Surveillance Recommendations for the Early Detection of Cancer

Surveillance Recommendations

  • The ammonia level in the blood should be measured on a regular basis when starting treatment: at first every 2 weeks, then less frequently as time goes on, and ultimately every 4 months.

  • An amino acid analysis of the blood should be conducted when starting treatment: at first every 2 weeks, then less frequently as time goes on, and ultimately every 4 months.

  • Depending on the symptoms, liver function tests every 3-6 months or more regularly if symptoms increase

  • 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 systematic administering of cortisone should be avoided.

  • Patients should be informed of their potentially increased risk of liver cancer. Specific cancer surveillance is not recommended.

Self-Care and Support

What should I pay special attention to?

You should consult a doctor as soon as a newborn exhibits a refusal to drink with a loss of sucking behavior, sleepiness, muscle weakness, cramping seizures, or consciousness disorders. After the newborn period, any episodic vomiting, irritability, consciousness disorders, failure to thrive, or developmental delay should be noted and reported to a doctor. You should likewise go to a doctor if new anomalies or complaints develop.

Support Groups and Additional Information