Carbamoyl phosphate synthetase I deficiency

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Carbamoyl phosphate synthetase I deficiency
Other namesCPS I deficiency
Specialty Medical genetics

Carbamoyl phosphate synthetase I deficiency (CPS I deficiency) [1] is an autosomal recessive metabolic disorder that causes ammonia to accumulate in the blood due to a lack of the enzyme carbamoyl phosphate synthetase I. Ammonia, which is formed when proteins are broken down in the body, is toxic if the levels become too high. The nervous system is especially sensitive to the effects of excess ammonia.

Contents

Signs and symptoms

Carbamoyl phosphate synthetase I deficiency often becomes evident in the first few days of life. [2] An infant with this condition may be lacking in energy (lethargic) or unwilling to eat, and have a poorly controlled breathing rate or body temperature. [2] Some babies with this disorder may experience seizures or unusual body movements, or go into a coma. [2] Complications of carbamoyl phosphate synthetase I deficiency may include developmental delay and mental retardation.

In some affected individuals, signs and symptoms of carbamoyl phosphate synthetase I deficiency may be less severe, and may not appear until later in life.

Genetics

Carbamoyl phosphate synthetase I deficiency has an autosomal recessive pattern of inheritance. Autosomal recessive - en.svg
Carbamoyl phosphate synthetase I deficiency has an autosomal recessive pattern of inheritance.

CPS I deficiency is inherited in an autosomal recessive manner. [1] This means the defective gene responsible for the disorder is located on an autosome, and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.

Pathophysiology

Mutations in the CPS1 gene cause carbamoyl phosphate synthetase I deficiency. 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.

Diagnosis

Prenatal diagnosis can occur through fetal liver biopsy or by using genomic DNA from amniotic fluid. [3]

Treatment

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. 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. 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.

Related Research Articles

The urea cycle (also known as the ornithine cycle) is a cycle of biochemical reactions that produces urea (NH2)2CO from ammonia (NH3). Animals that use this cycle, mainly amphibians and mammals, are called ureotelic.

<span class="mw-page-title-main">Ornithine transcarbamylase</span> Mammalian protein found in Homo sapiens

Ornithine transcarbamylase (OTC) is an enzyme that catalyzes the reaction between carbamoyl phosphate (CP) and ornithine (Orn) to form citrulline (Cit) and phosphate (Pi). There are two classes of OTC: anabolic and catabolic. This article focuses on anabolic OTC. Anabolic OTC facilitates the sixth step in the biosynthesis of the amino acid arginine in prokaryotes. In contrast, mammalian OTC plays an essential role in the urea cycle, the purpose of which is to capture toxic ammonia and transform it into urea, a less toxic nitrogen source, for excretion.

<span class="mw-page-title-main">Carbamoyl phosphate</span> Chemical compound

Carbamoyl phosphate is an anion of biochemical significance. In land-dwelling animals, it is an intermediary metabolite in nitrogen disposal through the urea cycle and the synthesis of pyrimidines. Its enzymatic counterpart, carbamoyl phosphate synthetase I, interacts with a class of molecules called sirtuins, NAD dependent protein deacetylases, and ATP to form carbamoyl phosphate. CP then enters the urea cycle in which it reacts with ornithine to form citrulline.

<span class="mw-page-title-main">Hyperammonemia</span> Medical condition

Hyperammonemia is a metabolic disturbance characterised by an excess of ammonia in the blood. It is a dangerous condition that may lead to brain injury and death. It may be primary or secondary.

<span class="mw-page-title-main">Ornithine transcarbamylase deficiency</span> Medical condition

Ornithine transcarbamylase deficiency also known as OTC deficiency is the most common urea cycle disorder in humans. Ornithine transcarbamylase, the defective enzyme in this disorder, is the final enzyme in the proximal portion of the urea cycle, responsible for converting carbamoyl phosphate and ornithine into citrulline. OTC deficiency is inherited in an X-linked recessive manner, meaning males are more commonly affected than females.

<span class="mw-page-title-main">Citrullinemia</span> Medical condition

Citrullinemia is an autosomal recessive urea cycle disorder that causes ammonia and other toxic substances to accumulate in the blood.

<span class="mw-page-title-main">Argininosuccinate synthase</span> Enzyme

Argininosuccinate synthase or synthetase is an enzyme that catalyzes the synthesis of argininosuccinate from citrulline and aspartate. In humans, argininosuccinate synthase is encoded by the ASS gene located on chromosome 9.

<span class="mw-page-title-main">Argininosuccinic aciduria</span> Medical condition

Argininosuccinic aciduria is an inherited disorder that causes the accumulation of argininosuccinic acid in the blood and urine. Some patients may also have an elevation of ammonia, a toxic chemical, which can affect the nervous system. Argininosuccinic aciduria may become evident in the first few days of life because of high blood ammonia, or later in life presenting with "sparse" or "brittle" hair, developmental delay, and tremors.

<span class="mw-page-title-main">Sodium phenylbutyrate</span> Chemical compound

Sodium phenylbutyrate, sold under the brand name Buphenyl among others, is a salt of an aromatic fatty acid, 4-phenylbutyrate (4-PBA) or 4-phenylbutyric acid. The compound is used to treat urea cycle disorders, because its metabolites offer an alternative pathway to the urea cycle to allow excretion of excess nitrogen.

Carbamoyl phosphate synthetase I (CPS I) is a ligase enzyme located in the mitochondria involved in the production of urea. Carbamoyl phosphate synthetase I (CPS1 or CPSI) transfers an ammonia molecule to a molecule of bicarbonate that has been phosphorylated by a molecule of ATP. The resulting carbamate is then phosphorylated with another molecule of ATP. The resulting molecule of carbamoyl phosphate leaves the enzyme.

<span class="mw-page-title-main">N-Acetylglutamate synthase deficiency</span> Medical condition

N-Acetylglutamate synthase deficiency is an autosomal recessive urea cycle disorder.

Glutathione synthetase deficiency (GSD) is a rare autosomal recessive metabolic disorder that prevents the production of glutathione. Glutathione helps prevent damage to cells by neutralizing harmful molecules generated during energy production. Glutathione also plays a role in processing medications and cancer-causing compounds (carcinogens), and building DNA, proteins, and other important cellular components.

<span class="mw-page-title-main">Ornithine translocase deficiency</span> Medical condition

Ornithine translocase deficiency, also called hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, is a rare autosomal recessive urea cycle disorder affecting the enzyme ornithine translocase, which causes ammonia to accumulate in the blood, a condition called hyperammonemia.

<span class="mw-page-title-main">Carbamoyl phosphate synthetase</span> Class of enzymes

Carbamoyl phosphate synthetase catalyzes the ATP-dependent synthesis of carbamoyl phosphate from glutamine or ammonia and bicarbonate. This enzyme catalyzes the reaction of ATP and bicarbonate to produce carboxy phosphate and ADP. Carboxy phosphate reacts with ammonia to give carbamic acid. In turn, carbamic acid reacts with a second ATP to give carbamoyl phosphate plus ADP.

<span class="mw-page-title-main">Phenylacetylglutamine</span> Chemical compound

Phenylacetylglutamine is a product formed by the conjugation of phenylacetate and glutamine. It is a common metabolite that occurs naturally in human urine.

In enzymology, an aminoacylase (EC 3.5.1.14) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Argininemia</span> Medical condition

Argininemia is an autosomal recessive urea cycle disorder where a deficiency of the enzyme arginase causes a buildup of arginine and ammonia in the blood. Ammonia, which is formed when proteins are broken down in the body, is toxic if levels become too high; the nervous system is especially sensitive to the effects of excess ammonia.

Transient hyperammonemia of the newborn (THAN) is an idiopathic disorder occasionally present in preterm newborns but not always symptomatic. Continuous dialysis or hemofiltration have proven to be the most effective treatment. Nutritional support and sodium benzoate have also been used to treat THAN.

<span class="mw-page-title-main">Citrullinemia type I</span> Medical condition

Citrullinemia type I (CTLN1), also known as arginosuccinate synthetase deficiency, is a rare disease caused by a deficiency in argininosuccinate synthetase, an enzyme involved in excreting excess nitrogen from the body. There are mild and severe forms of the disease, which is one of the urea cycle disorders.

Carbamoyl phosphate synthetase III is one of the three isoforms of the carbamoyl phosphate synthetase, an enzyme that catalyzes the active production of carbamoyl phosphate in many organisms.

References

  1. 1 2 Online Mendelian Inheritance in Man (OMIM): 237300
  2. 1 2 3 "Carbamoyl-phosphate synthetase 1 deficiency". Genetic and Rare Diseases Information Center. National Center for Advancing Translational Sciences, National Institutes of Health. February 2023. Retrieved 26 October 2023.
  3. Aoshima, Tsutomu; Kajita, Mitsuharu; Sekido, Yoshitaka; Mimura, Shunji; Itakura, Atsuo; Yasuda, Izumi; Saheki, Takeyori; Watanabe, Kazuyoshi; Shimokata, Kaoru; Niwa, Toshimitsu (2001). "Carbamoyl phosphate synthetase I deficiency: molecular genetic findings and prenatal diagnosis". Prenatal Diagnosis. Wiley. 21 (8): 634–637. doi:10.1002/pd.123. ISSN   0197-3851. PMID   11536261. S2CID   30688532.