Alternative titles; symbols
SNOMEDCT: 765329008; ORPHA: 147; DO: 9280;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q34 | Carbamoylphosphate synthetase I deficiency | 237300 | Autosomal recessive | 3 | CPS1 | 608307 |
A number sign (#) is used with this entry because hyperammonemia due to carbamoyl phosphate synthetase I deficiency is caused by homozygous or compound heterozygous mutation in the CPS1 gene (608307) on chromosome 2q34.
Carbamoyl phosphate synthetase I deficiency is an autosomal recessive inborn error of metabolism of the urea cycle which causes hyperammonemia. There are 2 main forms: a lethal neonatal type and a less severe, delayed-onset type (summary by Klaus et al., 2009).
Urea cycle disorders are characterized by the triad of hyperammonemia, encephalopathy, and respiratory alkalosis. Five disorders involving different defects in the biosynthesis of the enzymes of the urea cycle have been described: ornithine transcarbamylase deficiency (311250), carbamyl phosphate synthetase deficiency, argininosuccinate synthetase deficiency, or citrullinemia (215700), argininosuccinate lyase deficiency (207900), and arginase deficiency (207800).
Early-Onset Form
This disorder was first reported by Freeman et al. (1970) in a patient with congenital hyperammonemia and decreased levels of carbamoyl phosphate synthetase. A family with 3 affected sibs was reported by Hommes et al. (1969) and by Ebels (1972). One affected infant had severe cerebral damage. Gelehrter and Snodgrass (1974) reported a case and commented on the fact that it is mitochondrial carbamoyl phosphate synthetase that is deficient in this condition.
Suzuki et al. (1986) described a female infant with CPS I deficiency who died on the ninth postnatal day. They could detect no enzyme protein or mRNA activity for CPS I.
Finckh et al. (1998) reported a male infant with severe CPS I deficiency who died at 11 days of age. The parents were consanguineous. Three days after normal term delivery, he developed hyperammonemic coma. Histopathologic examination of the liver showed diffuse microvesicular steatosis, distinct focal hepatocellular and Kupffer cell glycogenosis, and no enzymatic CPS I activity. A mutation in the CPS1 gene was detected (608307.0002).
Delayed-Onset Form
Granot et al. (1986) reported an Arab child in whom the diagnosis of partial CPS deficiency was first made when she presented at 9 years of age with hyperammonemic coma simulating Reye syndrome. Despite intensive therapy directed toward lowering of ammonia levels, she sustained irreversible brain damage. History showed that on the seventh day of life, the child developed seizures for which phenobarbitone was administered. Her psychomotor development was slow. She attended a regular school but was a below-average student. She was on a regular diet with no apparent aversion to protein. At the age of 6 years she began to experience episodes of vomiting, mild abdominal pain, and muscle weakness. These episodes were not associated with any intercurrent infection or dietary change; they lasted for 2 or 3 days and occurred up to 3 times a year. During these attacks she remained mentally alert.
Verbiest et al. (1992) described a 32-year-old woman who was first discovered to have CPS I deficiency when investigated after valproic acid-induced coma. Valproic acid had been added to the regimen for control of generalized seizures a few days before the development of coma. The seizures were attributed to head trauma at the age of 16. 'Valproate sensitivity' has been observed also with ornithine transcarbamylase deficiency and citrullinemia, 2 other causes of hyperammonemia. Wong et al. (1994) described a 26-year-old college graduate and teacher who presented with coma after childbirth and was found to have CPS I deficiency. Ten hours after delivery of her only pregnancy, she became disoriented and agitated and progressed within a few hours to coma and decerebrate posturing. Within 24 hours, she developed generalized tonic-clonic seizures. Three days after delivery she was flaccid, did not have spontaneous respiration, and had diabetes insipidus. Urinary orotic acid level was somewhat elevated. She was declared dead at 3 days after delivery at which time EEG showed no cerebral electrical activity. The history reported by the authors indicated that she had been on a self-selected diet with little or no meat or dairy products and that she had occasionally complained of spells of confusion and disorientation and had been diagnosed as having complex partial seizures.
Batshaw et al. (2014) reported the results of an analysis of 614 patients with urea cycle disorders (UCDs) enrolled in the Urea Cycle Disorders Consortium's longitudinal study protocol. Carbamyl phosphate synthetase deficiency was found in 17 individuals (3%). Batshaw et al. (2014) found the risk of mortality (neonatal plus late onset) to be 42%.
In a review of inherited metabolic disorders and stroke, Testai and Gorelick (2010) noted that patients with urea cycle defects, including CPS1 deficiency, OTC deficiency (311250), and citrullinemia (215700) can rarely have strokes.
McReynolds et al. (1981) showed that hepatic mitochondrial carbamoyl phosphate synthetase deficiency is autosomal recessive: in liver biopsy material, they showed that 2 affected sisters had markedly reduced enzyme activity (about 6% of normal), while their normal brother had normal levels and their unaffected parents had intermediate levels (32% and 54% of normal).
Prenatal Diagnosis
By chorionic villus sampling, Finckh et al. (1998) diagnosed a 12-week-old fetus with CPS I deficiency. Pathologic examination of the fetal liver showed hepatocellular changes consistent with the disorder.
Batshaw et al. (1982) reported on therapy of 26 patients with inborn errors of urea synthesis by activation of alternative pathways of waste nitrogen synthesis and excretion. In 7 with deficiency of argininosuccinate synthetase (citrullinemia) and 10 with deficiency of argininosuccinate lyase (argininosuccinic aciduria), excretion of citrulline and argininosuccinate served as waste nitrogen products because they contain nitrogen normally destined for urea synthesis; synthesis and excretion of these substances was enhanced by arginine supplementation. Administration of sodium benzoate further diverted ammonium nitrogen from the defective urea pathway to hippurate synthesis by way of the glycine cleavage complex in the above 2 disorders as well as in ornithine transcarbamylase deficiency and hyperammonemia due to carbamoyl phosphate synthetase deficiency.
Brusilow et al. (1984) reported the successful treatment of episodic hyperammonemia in children with carbamoyl phosphate synthetase deficiency, ornithine transcarbamylase deficiency, and citrullinemia. Treatment made use of intravenous sodium benzoate, sodium phenylacetate and arginine, nitrogen-free intravenous alimentation, and, when other measures failed, dialysis.
In a newborn Japanese girl with CPS I deficiency (237300), Hoshide et al. (1993) identified a homozygous missense mutation in the CPS1 gene (608307.0001).
In 16 of 18 Japanese patients with a clinical diagnosis of CPS I deficiency, Kurokawa et al. (2007) identified 25 different mutations in the CPS1 gene, including 19 novel mutations (see, e.g., 608307.0007-608307.0009). Two patients with confirmed CPS I deficiency had later onset at ages 13 and 31 years, respectively. Genotype/phenotype correlations were not observed.
By analyzing tissue and DNA samples from 205 individuals with CPS I deficiency spanning 24 years, Haberle et al. (2011) identified 192 different pathogenic mutations in the CPS1 gene, including 130 novel mutations. When combined with previously reported mutations, it was clear that most mutations (90%) were private, occurring in only 1 family each. The few recurrent mutations tended to occur at CpG dinucleotides. Most missense mutations occurred around exon 24, at the boundary between both homologous halves of the region encoding the 120-kD catalytic moiety of the enzyme. Mutations also clustered at the bicarbonate and carbamate phosphorylation domains, at the NAG cofactor binding domain, and at the interface between the large and small subunit-like moieties. Comparative modeling using the E. coli enzyme showed that the location of missense mutations correlated with evolutionary importance and included internal residues, suggesting that they affect protein folding.
Klaus et al. (2009) reported a man and his grandson, who were of Lebanese origin, with variable clinical manifestations of CPS I deficiency despite having the same genotype. The man presented at age 45 years with episodes of confusion and bizarre behavior. He was initially thought to have some form of epileptic encephalopathy, until an elevated ammonia level led to further metabolic investigations consistent with CPS I deficiency. History revealed that he had voluntarily been on a low-protein diet for most of his life, and his acute illness was managed. His grandson presented at 2 days of age with life-threatening neonatal hyperammonemia with encephalopathy, respiratory alkalosis, and dehydration. He had elevated ammonia and metabolic studies suggesting a proximal urea cycle disorder. At age 3 years, the boy died during pneumonia. CPS1 sequencing of both patients showed that both were compound heterozygous for 2 splice site mutations (608307.0010 and 608307.0011). Cloning experiments in E. coli indicated that the proportioning of the allelic expression was different between the 2 patients: the more severely affected grandson had a skewed 3-fold higher expression of 1 of the mutations compared to his grandfather, who had equal expression of both mutations. Although the mechanism for this skewing of allelic expression was unclear, Klaus et al. (2009) concluded that it contributed to the clinical variability in this family.
Nagata et al. (1991) estimated that the incidence of CPS I deficiency in Japan is 1 in 800,000.
The prevalence of CPS I deficiency is estimated to be between 1 in 200,000 to 1 in 800,000 (Testai and Gorelick, 2010).
Batshaw, M., Brusilow, S., Walser, M. Treatment of carbamoyl-phosphate-synthetase deficiency with keto analogues of essential amino acids. New Eng. J. Med. 292: 1085-1090, 1975. [PubMed: 165404] [Full Text: https://doi.org/10.1056/NEJM197505222922101]
Batshaw, M. L., Brusilow, S., Waber, L., Blom, W., Brubakk, A. M., Burton, B. K., Cann, H. M., Kerr, D., Mamunes, P., Matalon, R., Myerberg, D., Schafer, I. A. Treatment of inborn errors of urea synthesis: activation of alternative pathways of waste nitrogen synthesis and excretion. New Eng. J. Med. 306: 1387-1392, 1982. [PubMed: 7078580] [Full Text: https://doi.org/10.1056/NEJM198206103062303]
Batshaw, M. L., Tuchman, M., Summar, M., Seminara, J., Members of the Urea Cycle Disorders Consortium. A longitudinal study of urea cycle disorders. Molec. Genet. Metab. 113: 127-130, 2014. [PubMed: 25135652] [Full Text: https://doi.org/10.1016/j.ymgme.2014.08.001]
Brusilow, S. W., Danney, M., Waber, L. J., Batshaw, M., Burton, B., Levitsky, L., Roth, K., McKeethren, C., Ward, J. Treatment of episodic hyperammonemia in children with inborn errors of urea synthesis. New Eng. J. Med. 310: 1630-1634, 1984. [PubMed: 6427608] [Full Text: https://doi.org/10.1056/NEJM198406213102503]
Ebels, E. J. Neuropathological observations in a patient with carbamyl-phosphate-synthetase deficiency and in two sibs. Arch. Dis. Child. 47: 47-51, 1972. [PubMed: 4111816] [Full Text: https://doi.org/10.1136/adc.47.251.47]
Farriaux, J.-P., Ponte, C., Pollitt, R. J., Lequien, P., Formstecher, P., Dhondt, J. P. Carbamyl-phosphate-synthetase deficiency with neonatal onset of symptoms. Acta Paediat. Scand. 66: 529-534, 1977. [PubMed: 197778] [Full Text: https://doi.org/10.1111/j.1651-2227.1977.tb07940.x]
Finckh, U., Kohlschutter, A., Schafer, H., Sperhake, K., Colombo, J.-P., Gal, A. Prenatal diagnosis of carbamoyl phosphate synthetase I deficiency by identification of a missense mutation in CPS1. Hum. Mutat. 12: 206-211, 1998. [PubMed: 9711878] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1998)12:3<206::AID-HUMU8>3.0.CO;2-E]
Freeman, J. M., Nicholson, J. F., Schimke, R. T., Rowland, L. P., Carter, S. Congenital hyperammonemia: association with hyperglycinemia and decreased levels of carbamyl phosphate synthetase. Arch. Neurol. 23: 430-437, 1970. [PubMed: 5471650] [Full Text: https://doi.org/10.1001/archneur.1970.00480290050006]
Gelehrter, T. D., Snodgrass, P. J. Lethal neonatal deficiency of carbamyl phosphate synthetase. New Eng. J. Med. 290: 430-433, 1974. [PubMed: 4811018] [Full Text: https://doi.org/10.1056/NEJM197402212900804]
Granot, E., Matoth, I., Lotan, C., Shvil, Y., Lijovetzky, G., Yatziv, S. Partial carbamyl phosphate synthetase deficiency, simulating Reye's syndrome, in a 9-year-old girl. Isr. J. Med. Sci. 22: 463-465, 1986. [PubMed: 3759432]
Haberle, J., Shchelochkov, O. A., Wang, J., Katsonis, P., Hall, L., Reiss, S., Eeds, A., Willis, A., Yadav, M., Summar, S., the Urea Cycle Disorders Consortium, Lichtarge, O., Rubio, V., Wong, L.-J., Summar, M. Molecular defects in human carbamoyl phosphate synthetase I: mutational spectrum, diagnostic and protein structure considerations. Hum. Mutat. 32: 579-589, 2011. [PubMed: 21120950] [Full Text: https://doi.org/10.1002/humu.21406]
Hommes, F. A., De Groot, C. J., Wilmink, C. W., Jonxis, J. H. P. Carbamylphosphate synthetase deficiency in an infant with severe cerebral damage. Arch. Dis. Child. 44: 688-693, 1969. [PubMed: 5356974] [Full Text: https://doi.org/10.1136/adc.44.238.688]
Hoshide, R., Matsuura, T., Haraguchi, Y., Endo, F., Yoshinaga, M., Matsuda, I. Carbamyl phosphate synthetase I deficiency: one base substitution in an exon of the CPS I gene causes a 9-basepair deletion due to aberrant splicing. J. Clin. Invest. 91: 1884-1887, 1993. [PubMed: 8486760] [Full Text: https://doi.org/10.1172/JCI116405]
Jackson, M. J., Beaudet, A. L., O'Brien, W. E. Mammalian urea cycle enzymes. Annu. Rev. Genet. 20: 431-464, 1986. [PubMed: 3545062] [Full Text: https://doi.org/10.1146/annurev.ge.20.120186.002243]
Klaus, V., Vermeulen, T., Minassian, B., Israelian, N., Engel, K., Lund, A. M., Roebrock, K., Christensen, E., Haberle, J. Highly variable clinical phenotype of carbamylphosphate synthetase 1 deficiency in one family: an effect of allelic variation in gene expression? Clin. Genet. 76: 263-269, 2009. [PubMed: 19793055] [Full Text: https://doi.org/10.1111/j.1399-0004.2009.01216.x]
Kline, J. J., Hug, G., Schubert, W. K., Berry, H. Arginine deficiency syndrome: its occurrence in carbamyl phosphate synthetase deficiency. Am. J. Dis. Child. 135: 437-442, 1981. [PubMed: 7234771]
Kurokawa, K., Yorifuji, T., Kawai, M., Momoi, T., Nagasaka, H., Takayanagi, M., Kobayashi, K., Yoshino, M., Kosho, T., Adachi, M., Otsuka, H., Yamamoto, S., and 11 others. Molecular and clinical analyses of Japanese patients with carbamoylphosphate synthetase 1 (CPS1) deficiency. J. Hum. Genet. 52: 349-354, 2007. [PubMed: 17310273] [Full Text: https://doi.org/10.1007/s10038-007-0122-9]
Mantagos, S., Tsagaraki, S., Burgess, A., Oberholzer, V., Palmer, T., Sacks, J., Baibas, S., Valaes, T. Neonatal hyperammonaemia with complete absence of liver carbamyl phosphate synthetase activity. Arch. Dis. Child. 53: 230-234, 1978. [PubMed: 206210] [Full Text: https://doi.org/10.1136/adc.53.3.230]
McReynolds, J. W., Crowley, B., Mahoney, M. J., Rosenberg, L. E. Autosomal recessive inheritance of human mitochondrial carbamyl phosphate synthetase deficiency. Am. J. Hum. Genet. 33: 345-353, 1981. [PubMed: 7246541]
Nagata, N., Matsuda, I., Oyanagi, K. Estimated frequency of urea cycle enzymopathies in Japan. (Letter) Am. J. Med. Genet. 39: 228-229, 1991. [PubMed: 2063931] [Full Text: https://doi.org/10.1002/ajmg.1320390226]
Suzuki, Y., Matsushima, A., Ohtake, A., Mori, M., Tatibana, M., Orii, T. Carbamyl phosphate synthetase I deficiency with no detectable mRNA activity. Europ. J. Pediat. 145: 406-408, 1986. [PubMed: 3792387] [Full Text: https://doi.org/10.1007/BF00439249]
Testai, F. D., Gorelick, P. B. Inherited metabolic disorders and stroke part 2: homocystinuria, organic acidurias, and urea cycle disorders. Arch. Neurol. 67: 148-153, 2010. [PubMed: 20142522] [Full Text: https://doi.org/10.1001/archneurol.2009.333]
van der Heiden, C., Beemer, F. A., van Dijk, H. A., Desplanque, J., Gerards, L. J. A lethal neonatal variant of carbamoyl-phosphate synthetase deficiency in combination with an intermediate activity of L-ornithine:2-oxoglutarate aminotransferase. Clin. Genet. 23: 363-368, 1983. [PubMed: 6851228] [Full Text: https://doi.org/10.1111/j.1399-0004.1983.tb00447.x]
Verbiest, H. B. C., Straver, J. S., Colombo, J. P., van der Vijver, J. C. M., van Woerkom, T. C. A. M. Carbamyl phosphate synthetase-1 deficiency discovered after valproic acid-induced coma. Acta Neurol. Scand. 86: 275-279, 1992. [PubMed: 1414247] [Full Text: https://doi.org/10.1111/j.1600-0404.1992.tb05085.x]
Wong, L.-J. C., Craigen, W. J., O'Brien, W. E. Postpartum coma and death due to carbamoyl-phosphate synthetase I deficiency. Ann. Intern. Med. 120: 216-217, 1994. [PubMed: 8273985] [Full Text: https://doi.org/10.7326/0003-4819-120-3-199402010-00007]