Carbamoyl phosphate synthetase deficiency
Description, Causes and Risk Factors:
Carbamoyl phosphate synthetase (CPS): A phosphotransferase catalyzing the formation of carbamoyl phosphate. There are two significant isozymes. Carbomoyl phosphate synthetase I is a mitochondrial enzyme that catalyzes the reaction of 2ATP, NH3
, and H2
O to carbamoyl phosphate, 2ADP, and orthophosphate. It is activated by N-acetylglutamate and participates in urea biosynthesis. A deficiency of carbamoyl phosphate synthetase I can result in hyperammonemia. Carbamoyl phosphate synthetase II is a cytosolic enzyme that, under physiological conditions, uses L-glutamine as the nitrogen source (producing L-glutamate) instead of NH3
, is not activated by N-acetylglutamate, and participates in pyrimidine biosynthesis.
Mutations in the CPS1 gene cause carbamoyl phosphate synthetase I deficiency. The structural gene for the enzyme is assigned to chromosome 2 and mapped to band 2q35. It has been sequenced and cloned. Carbamoyl phosphate synthetase I deficiency belongs to a class of genetic diseases called urea cycle disorders. The urea cycle is a sequence of reactions that occurs in liver cells. This cycle processes excess nitrogen, generated when protein is used by the body, to make a compound called urea that is excreted by the kidneys.
In carbamoyl phosphate synthetase I deficiency, the enzyme that regulates the urea cycle is damaged or missing. The urea cycle cannot proceed normally, and nitrogen accumulates in the bloodstream in the form of ammonia. Ammonia is especially damaging to the nervous system, and excess ammonia causes neurological problems and other signs and symptoms of carbamoyl phosphate synthetase I deficiency.
This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder. As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.
CPS deficiency is rare. As with all the urea cycle defects, as well as most of the inborn errors, citing incidence figures is impossible because new cases are generally diagnosed randomly without the benefit of population screening.
Signs of severe hyperammonemia may be present.Poor growth may be evident.
Head, ears, eyes, nose, and throat (HEENT): Papilledema may be present if cerebral edema and increased intracranial pressure (ICP) have occurred.
or hyperpnea may be present.
- Apnea and respiratory failure may occur in later stages.
Abdominal: Hepatomegaly may be present and is usually mild.
- Hypotonia or hypertonia.
- Seizures and hypothermia.
- Lethargy progressing to combativeness, obtundation, and coma.
- Decorticate or decerebrate posturing.
Routine laboratory studies are of no diagnostic help. The clue to the presence of carbamoyl phosphate synthetase (CPS) deficiency may be a BUN (blood urea nitrogen) level below the reference range. In contrast to older studies, this is merely a clue, is not always present, may occur in early fasting, and is quite unreliable. Nonetheless, when present, a BUN level below the reference range should trigger a search for hyperammonemia.
Liver function is normal unless hypoxia has occurred in association with seizures. The same is true of renal function.
The sole laboratory criterion for early diagnosis is a blood ammonia level. Obtain a blood level simultaneously with the usual laboratory workup as a part of the investigation of a critically ill neonate or infant. Determine blood ammonia level in adults with unexplained lethargy or coma.
Ammonia levels are usually 10-20 times higher than reference range.Ammonia values greater than 1000 mg/dL are common.Blood amino acid changes are not specific to provide a diagnosis but are important in the differentiation of CPS deficiency from other urea cycle disorders.
Urine orotic acid levels are within the reference range.Urine organic acid analysis is important to rule out organic acid disorders.
Definitive testing requires liver biopsy and enzyme analysis.
A report suggests that single-voxel magnetic resonance spectroscopy permits the monitoring of brain glutamine and brain glutamate levels. This may be a more accurate means of monitoring the effects of an acute hyperammonemic episode on the brain than monitoring blood ammonia levels as treatment proceeds.
Treatment of acute hyperammonemia caused by CPS deficiency includes hemodialysis, peritoneal dialysis or arteriovenous hemofiltration. Several drugs conjugate major amino acids, forming metabolites that are excreted in the urine, which eliminates a major source of nitrogen from being converted to ammonia. Administration of sodium phenylbutyrate (or phenylacetate) conjugates glutamine, forming phenylacetylglutamine, which is excreted by the kidneys and removes waste nitrogen. In a similar fashion, citrulline is given to conjugate aspartic acid forming argininosuccinic acid. Administration of sodium benzoate results in conjugation of glycine, which is subsequently excreted in the urine. Patients who survive the initial presentation are placed on chronic treatment with phenylbutyrate, benzoate and supplemental arginine along with dietary protein restriction. Patients having onset in the newborn period face a poor outcome and significant risk of neurological damage or demise.
Because the diagnosis and therapy of CPS deficiency is complex, the pediatrician is strongly advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient's physician.
NOTE: The above information is for processing purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.
DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.