Carbamoyl Phosphate Synthetase (CPS) Deficiency

Carbamoyl phosphate synthetase (CPS) deficiency is a urea cycle defect that results from a deficiency in an enzyme that mediates the normal path for incorporation of ammonia. CPS is derived from catabolism of amino acids into a 1-carbon compound (H2 N-CO-PO32 -), in which the carbon atom is derived from bicarbonate. The process is exclusively mitochondrial and requires the expenditure of one ATP molecule. See the image below.

Two hepatocellular enzymes exist: CPS I and CPS II. CPS I is exclusively intramitochondrial, and its deficiency is responsible for the disease. CPS I is the most plentiful single protein in hepatic mitochondria, accounting for about 20% of the matrix protein. CPS II is exclusively cytosolic and is an important enzyme in de novo synthesis of pyrimidine nucleotides. The regulation of CPS I activity depends on the levels of N -acetylglutamate (see N-Acetylglutamate Synthetase (NAGS) Deficiency).

In patients with homozygous CPS I deficiency, the ability to fix waste nitrogen is completely absent, resulting in increasing levels of free ammonia with the attendant effects on the CNS. A recent molecular and functional examination of the mutational effects showed that, although some mutations affect both substrate affinity and efficiency of the reaction, others affect one more than the other.[1] Some mutations are associated with enhanced RNA instability, which leads to diminished protein synthesis. More than 190 mutations have been reported to cause CPS deficiency.[2]

The hepatic urea cycle is the major route for waste nitrogen disposal. Waste nitrogen is chiefly generated from protein and amino acid metabolism. Low-level synthesis of certain cycle intermediates in extrahepatic tissues also makes a small contribution to waste nitrogen disposal. A portion of the cycle is mitochondrial in nature; mitochondrial dysfunction may impair urea production and may result in hyperammonemia. Overall, activity of the cycle is regulated by the rate of synthesis of N -acetylglutamate, the enzyme activator of CPS I, which initiates incorporation of ammonia into the cycle.

Frequency

United States

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.

International

According a study of urea cycle diseases in Finland, 3 cases of CPS deficiency had been reported by 2007.[3] A study in Italy provided an overview of clinical findings and biochemical and molecular data concerning 13 Italian patients.[4]

Mortality/Morbidity

Mortality and morbidity rates are high. Untreated CPS deficiency is likely fatal.

Sex

CPS deficiency is autosomal recessive; thus, the incidence between the sexes is approximately equal.

Age

CPS deficiency has been reported in patients of all ages, from newborns to adults.

In adults, some individuals remain unaffected until onset in early-to-mid adulthood, whereas others gradually sustain brain damage from infancy until diagnosis.

In newborns, CPS deficiency is generally catastrophic in nature and leads to rapid demise without immediate recognition and treatment.

A positive outcome is extremely unlikely in individuals with neonatal onset.

Usually, the best prognosis is an infant who will be seriously impaired and will develop recurrent hyperammonemic episodes throughout infancy and childhood, sustaining further insults to the CNS.

As an autosomal recessive trait, each parent is assumed to be an obligate heterozygote for CPS I deficiency. The likelihood of a recurrence is 25% (1:4) with each subsequent pregnancy, regardless of fetal sex.

Prenatal diagnosis is available. If desired, contact the laboratory as early as possible.

In homozygous neonates, early-onset lethargy and, in some cases, seizures are often the first signs of abnormality. Because the fetus is generally anabolic and maternal metabolism can usually manage the additional ammonia load from the fetus, intrauterine development is completely unaffected. Therefore, infants are usually born at term following a completely uneventful pregnancy and delivery.

Ammonia levels begin to rise after the maternal-fetal circulation is interrupted at birth, with a brief period of fasting. The baby becomes irritable, then lethargic, and, if untreated, comatose. Without rapid recognition and aggressive treatment, the infant suffers devastating CNS damage, coma, and death.

Some individuals with carbamoyl phosphate synthetase (CPS) deficiency reach adulthood prior to diagnosis. One known case involved a college-educated homozygous woman whose clinical onset occurred within hours after childbirth and resulted in death.[5]

The multiple primary causes of hyperammonemia, specifically those due to urea cycle enzyme deficiencies, vary in manifestation, diagnostic features, and management. For these reasons, the urea cycle defects are considered individually in this article; however, hyperammonemia is the common denominator and generally manifests clinically as a common constellation of signs and symptoms. As a consequence, the most striking clinical findings of each individual urea cycle disorder relate to this constellation of symptoms and rough temporal sequence of events. Symptoms include the following:

• Anorexia

• Irritability

• Heavy or rapid breathing

• Lethargy

• Vomiting

• Disorientation

• Somnolence

• Asterixis (rare)

• Combativeness

• Obtundation

• Coma

• Cerebral edema

• Death (if treatment is not forthcoming or effective)

General

Signs of severe hyperammonemia may be present (see Hyperammonemia).

Poor growth may be evident.

Head, ears, eyes, nose, and throat (HEENT)

Papilledema may be present if cerebral edema and increased intracranial pressure have occurred.

Pulmonary

See the list below:

• Tachypnea or hyperpnea may be present.

• Apnea and respiratory failure may occur in later stages.

Abdominal

Hepatomegaly may be present and is usually mild.

Neurologic

See the list below:

• Poor coordination

• Dysdiadochokinesia

• Hypotonia or hypertonia

• Ataxia

• Tremor

• Seizures and hypothermia

• Lethargy progressing to combativeness, obtundation, and coma

• Decorticate or decerebrate posturing

CPS I deficiency is autosomal recessive. The structural gene for the enzyme is assigned to chromosome 2 and mapped to band 2q35. It has been sequenced and cloned.

Urea cycle defects with resulting hyperammonemia are due to deficiencies of the enzymes involved in the metabolism of waste nitrogen. The enzyme deficiencies lead to disorders with nearly identical clinical presentations. The exception is arginase, the last enzyme of the cycle; arginase deficiency causes a somewhat different set of signs and symptoms (see Arginase Deficiency).

Routine laboratory studies are of no diagnostic help. The clue to the presence of carbamoyl phosphate synthetase (CPS) deficiency may be a BUN 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 no longer requires liver biopsy; molecular diagnosis is available.

Postmortem findings are completely nonspecific, and, as a mitochondrial enzyme, CPS I is liable to rapid inactivation. Therefore, obtain hepatic samples for enzyme diagnosis during life, if possible, or immediately after death.

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.

A 2013 report details the MRI findings in neonates.[6]

Electroencephalography reveals nonspecific diffuse encephalopathy.

Molecular genetic diagnosis is available.[7]

Approach lumbar puncture with great caution because of the potential for cerebral edema.

Depending on clinical status and the blood ammonia level, the logical first step is to reduce protein intake and to attempt to maintain energy intake. Initiate intravenous infusion of 10% glucose (or higher, if administered through a central line) and lipids.

Intravenous sodium benzoate and sodium phenylacetate may be helpful. Arginine is usually administered with benzoate and phenylacetate. This is best administered in the setting of a major medical center where facilities for hemodialysis in infants is available.

Glycerol phenylbutyrate is a pre-prodrug that undergoes metabolism to form phenylacetate. Results of a phase 3 study comparing ammonia control in adults showed glycerol phenylbutyrate was noninferior to sodium phenylbutyrate.[8] In a separate study involving young children ages 2 months through 5 years, glycerol phenylbutyrate resulted in a more evenly distributed urinary output of PAGN over 24 hours and accounted for fewer symptoms from accumulation of phenylacetate.[9]

In patients with an extremely high blood ammonia level, rapid treatment with hemodialysis is indicated.

Metabolic disease specialists should provide long-term care with very close and frequent follow-up.

See the list below:

• Medical geneticist

• Metabolic disease specialist

• Dietitian

An appropriate diet must meet minimal protein requirements for growth and must include scrupulous monitoring.

These requirements change with age, and caloric needs must also be met in order to appropriately use the requisite protein.

A biochemical geneticist or metabolic disease specialist should closely observe any patient with a diagnosed urea cycle defect, whether partial or complete. Dosage adjustments of oral sodium phenylbutyrate and arginine are often needed.

A trained nutritionist should scrupulously monitor the diet of a patient with carbamoyl phosphate synthetase (CPS) deficiency.

Periodic intellectual and neurologic evaluations are essential to ensure adequacy of treatment.

Intravenous sodium benzoate and sodium phenylacetate may be helpful. Phenylbutyrate is more acceptable as a form of oral therapy because of a diminished odor but is not available for intravenous use.

Class Summary

The use of benzoate and phenylacetate is based on the need to provide alternate routes for waste nitrogen disposition. Benzoate is transaminated to form hippuric acid, which is rapidly cleared by the kidney. Phenylacetate is converted to phenylacetyl coenzyme A (CoA) and then conjugated with glutamine to form phenylacetylglutamine. Each of these 2 pathways results in disposition of 1 and 2 molecules of ammonia, respectively. Phenylbutyrate is more acceptable as a form of oral therapy because of a diminished odor but is not available for intravenous use.

Sodium benzoate and sodium phenylacetate (Ucephan, Ammonul)

Combines with glycine to form hippurate, which is excreted in urine. One mol of benzoate removes 1 mol of nitrogen. The PO product (Ucephan) and IV product (Ammonul) contain a combination of sodium benzoate 10 g and sodium phenylacetate 10 g/100 mL (100 mg of each/mL).

Sodium phenylbutyrate (Buphenyl)

Prodrug rapidly converted orally to phenylacetylglutamine, which serves as substitute for urea and is excreted in the urine carrying 2 mol of nitrogen per mol of phenylacetylglutamine, assisting in clearance of nitrogenous waste.

Glycerol phenylbutyrate (Ravicti)

Glycerol phenylbutyrate is a nitrogen-binding agent for chronic management of adult and pediatric patients (including newborns) with urea cycle disorders who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. It is a pre-prodrug that is metabolized by ester hydrolysis and pancreatic lipases to phenylbutyrate and then by beta oxidation to phenylacetate. Glutamine is conjugated with phenylacetate to form phenylacetylglutamine, a nitrogen waste product that is excreted in the urine. It is not indicated for treatment of hyperammonemia.