Urea cycle disorders

Other Names: UCD

A urea cycle disorder is a genetic disorder that results in a deficiency of one of the six enzymes in the urea cycle. These enzymes are responsible for removing ammonia from the blood stream. The urea cycle involves a series of biochemical steps in which nitrogen, a waste product of protein metabolism, is changed to a compound called urea and removed from the blood. Normally, the urea is removed from the body through the urine. In urea cycle disorders, nitrogen builds up in the blood in the form of ammonia, a highly toxic substance, resulting in hyperammonemia (elevated blood ammonia). Ammonia then reaches the brain through the blood, where it can cause irreversible brain damage, coma and/or death. The onset and severity of urea cycle disorders is highly variable. The severity correlates with the amount of urea cycle enzyme function.

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The urea cycle

• Is the sole source of endogenous production of arginine, ornithine, and citrulline;
• Is the principal mechanism for the clearance of waste nitrogen resulting from protein turnover;
• Is the principal mechanism for the metabolism of other nitrogenous metabolic compounds such as adenosine monophosphate;
• Includes enzymes that overlap with the nitric oxide production pathway (ASS1 and ASL).

Five catalytic enzymes:

• Carbamoylphosphate synthetase I (CPS1)
• Ornithine transcarbamylase (OTC)
• Argininosuccinic acid synthetase (ASS1)
• Argininosuccinic acid lyase (ASL)
• Arginase (ARG1)

One cofactor-producing enzyme:

• N-acetyl glutamate synthetase (NAGS)

Two amino acid transporters:

• Ornithine translocase (ORNT1; ornithine/citrulline carrier; solute carrier family 25, member 15)
• Citrin (aspartate/glutamate carrier; solute carrier family 25, member 13)

Cause

Urea cycle disorders (UCDs) result from inherited deficiencies in any one of the six enzymes or two transporters of the urea cycle pathway (CPS1, OTC, ASS1, ASL, ARG1, NAGS, ORNT1, or citrin).

Individual disorders

• N-Acetylglutamate synthase deficiency(NAGS)
• Carbamoyl phosphate synthetase deficiency(CPS)
• Ornithine transcarbamoylase deficiency (OTC)
• Citrullinemia Type I (Deficiency of argininosuccinic acid synthase)
• Argininosuccinic aciduria (Deficiency of argininosuccinic acid lyase)
• Argininemia (Deficiency of arginase)
• Hyperornithinemia, hyperammonemia, homocitrullinuria (HHH) syndrome (Deficiency of the mitochondrial ornithine transporter)

Inheritance

All urea cycle defects, except OTC deficiency, are inherited in an autosomal recessive manner. OTC deficiency is inherited as an X-linked recessive disorder, although some females can show symptoms. Most urea cycle disorders are associated with hyperammonemia, however argininemia and some forms of argininosuccinic aciduria do not present with elevated ammonia.

Symptoms

Typically, the baby begins nursing well and seems normal. However, over time the baby develops poor feeding, vomiting, and sleepiness, which may be so deep that the baby is difficult to awaken. This most often occurs within the first week after birth.

Symptoms include:

• Confusion
• Decreased food intake
• Dislike of foods that contain protein
• Increased sleepiness, difficulty waking up
• Nausea, vomiting

Diagnosis

Signs may include:

• Abnormal amino acids in blood and urine
• Abnormal level of orotic acid in blood or urine
• High blood ammonia level
• Normal level of acid in blood

Tests may include:

• Arterial blood gas
• Blood ammonia
• Blood glucose
• Plasma amino acids
• Urine organic acids
• Genetic tests
• Liver biopsy
• MRI or CT scan

Treatment

Limiting protein in the diet can help treat these disorders by reducing the amount of nitrogen waste the body produces. (The waste is in the form of ammonia.) Special low-protein infant and toddler formulas are available.

It is important that a provider guides protein intake. The provider can balance the amount of protein the baby gets so that it is enough for growth, but not enough to cause symptoms.

It is very important for people with these disorders to avoid fasting.

People with urea cycle abnormalities must also be very careful under times of physical stress, such as when they have infections. Stress, such as a fever, can cause the body to break down its own proteins. These extra proteins can make it hard for the abnormal urea cycle to remove the byproducts.

Develop a plan with your provider for when you are sick to avoid all protein, drink high carbohydrate drinks, and get enough fluids.

Most people with urea cycle disorders will need to stay in the hospital at some point. During such times, they may be treated with medicines that help the body remove nitrogen-containing wastes. Dialysis may help rid the body of excess ammonia during extreme illness. Some people may need a liver transplant.

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

• Benzoate and phenylacetate (Brand name: Ammonul®)Adjunctive therapy in the treatment of acute hyperammonemia and associated encephalopathy in patients with deficiencies in enzymes of the urea cycle.
• Sodium phenylbutyrate (Brand name: Buphenyl®)Adjunctive therapy in the chronic managment of patients with urea cycle disorders involving deficiencies of carbamylphosphate synthetase, ornithine transcarbamylase, or argininosuccinic acid synthetase.
• Glycerol phenylbutyrate (Brand name: Ravicti)Use as a nitrogen-binding adjunctive therapy for chronic management of adult and pediatric patients at least 2 months of age with urea cycle disorders (UCDs) that cannot be managed by dietary protein restriction and/or amino acid supplementation alone. RAVICTI must be used with dietary protein restriction and, in some cases, dietary supplements (eg, essential amino acids, arginine, citrulline, protein-free calorie supplements).
• Benzoate and phenylacetate (Brand name: Ucephan )For adjunctive therapy in the prevention and treatment of hyperammonemia in patients with urea cycle enzymopathy due to carbamylphosphate synthetase, ornithine, transcarbamylase, or argininosuccinate synthetase deficiency.

Prognosis

How well people do depends on:

• Which urea cycle abnormality they have
• How severe it is
• How early it is discovered
• How closely they follow a protein-restricted diet

Babies diagnosed in the first week of life and put on a protein-restricted diet right away may do well.

Sticking to the diet can lead to normal adult intelligence. Repeatedly not following the diet or having stress-induced symptoms can lead to brain swelling and brain damage.

Major stresses, such as surgery or accidents, can be complicated for people with this condition. Extreme care is needed to avoid problems during such periods.