Carbamoyl phosphate synthetase deficiency

Murotsuki J, Uehara S, Okamura K, Yajima A, Oura T, Miyabayashi S. Fetal Ever biopsy for prenatal diagnosis of carbamoyl phosphate synthetase deficiency. Am J Perinatology 1994 11 160-2. 

The two conditions can be distinguished by an increase in orotic add and uracil, which occurs in ornithine transcarbamoylase deficiency, but not in the defldency of carbamoyl phosphate synthetase. Orotic acid and uracil are intermediates in pyrimidine synthrais (see Chapter 18). This pathway is stimulated by the accumulation of carbamoyl phosphate, the substrate for ornithine transcarbamoylase in the urea cycle and for aspartate transcarbamoylase in pyrimidine synthesis. 

In view of the toxicity of ammonia, complete absence of any one of the enzymes of the cycle is fatal. Nonetheless, disorders of the cycle do occur, which are caused by a low activity of one of the enzymes or carbamoyl phosphate synthetase. In addition, defects in N-acetylglutamate synthase have been reported, but they are very rare. With the exception of ornithine transcarbamoylase, the deficiencies have an autosomal recessive mode of inheritance. The transcarbamoylase deficiency is inherited as an X-linked dominant trait, usually lethal in male patients. A deficiency of carbamoyl phosphate synthetase, ornithine transcarbamoylase or argininosuccinate synthetase results in accumulation and excretion of citrulline. A deficiency of argininosuccinate lyase results in the accumulation and excretion of argininosuccinate and arginine (Table 10.5). The abbreviations CPSD, OTCD, ASD, ALD and AD stand, respectively, for the deficiencies of these enzymes, where D stands for deficiency. 

Carbamoyl phosphate synthetase formation in liver taken from tadpoles treated with thyroxine is enhanced by the addition of orotic acid, uracil or uridine (cytosine and adenosine had no effect). The synthesis of this enzyme is not affected by these pyrimidines in untreated animals. This indicates that there is a relative pyrimidine deficiency during thyroxine-induced metamorphosis [140]. 

Other therapies are more specific to a particular enzyme deficiency. Deficiency of Ai-acetylglutamate synthase results in the absence of the normal activator of carbamoyl phosphate synthetase I (Fig. 18-13). This condition can be treated by administering carbamoyl glutamate, an analog of Af-acetylglutamate that is effective in activating carbamoyl phosphate synthetase I. 

Carbamoyl phosphate synthetase 1 deficiency <0.5 Urea synthesis Carbamoyl phosphate synthetase 1 Lethargy convulsions early death... 

Metabolism of nitrogen in a patient with a deficiency in the urea cycle enzyme carbamoyl phosphate synthetase I. Treatment with phenylbutyrate converts nitrogenous waste to a form that can be excreted. 

Figure 23.20. Treatment of Carbamoyl Phosphate Synthetase and Ornithine Transcarbamoylase Deficiencies.

Aoshima T, Kajita M, Sekido Y, Kikuchi S, Yasuda I, Saheld T, et al. Novel mutations (H337R and 238-362del) in the CPSl gene cause carbamoyl phosphate synthetase I deficiency. Hum Heredity 2001 52 99-101. 

Finckh U, Kohlschutter A, Schafer H, Sperhake K, Colombo JP, Gal A. Prenatal diagnosis of carbamoyl phosphate synthetase I deficiency by identification of a missense mutation in CPSI. Hum Mutat 1998 12 206-11. 

Yoshino M, Nishiyori A, Koga Y, Mizushima Y, Maeshiro H, Inoue T, et al. Potential pitfall of prenatal enzymatic diagnosis of carbamoyl-phosphate synthetase I deficiency. J Tuber Metab Dis 1997 20 ... 

Figure 23.21 Treatment of carbamoyl phosphate synthetase and ornithine transcarbamoylase deficiencies,...

A number of inherited diseases are associated with the urea cycle. The mutations result in changes in either Vm or Km as defective proteins are produced. These include disruptions of N- acety 1 gl utam ate synthase, carbamoyl phosphate synthetase, ornithine transcarbamoylase (the most prevalent of the urea cycle deficiencies), argininosuccinate synthetase, argininosuccinate lyase, and arginase. In these diseases, when applicable, treatments are low-protein diets, to put less strain on urea cycle flux and, when appropriate, addition of amino acids as required, such as ornithine and/or arginine. 

Elevated levels of ammonia in the blood can be caused by a deficiency of mitochondrial carbamoyl phosphate synthetase or a deficiency of any of the urea cycle enzymes. These two types of disorders can be distinguished by the presence of orotic acid or related metabolites in the urine. 

CPS deficiency Carbamoyl phosphate synthetase CPS Markedly elevated Absent to low... 

Carbamoyl phosphate synthetase (CPS) deficiency Carbamoyl phosphate synthetase Hyperammonemia, respiratory alktilosis Lethargy, vomiting, apnea, coma and death if imtreated intellectueil disability Protein restriction essential amino acid and arginine supplementation (in conjunction with nitrogen scavenging medications) None... 

When ornithine transcarbamoylase is deficient (urea cycle disorder), excess carbamoyl phosphate from the mitochondria leaks into the cytoplasm. The elevated levels of cytoplasmic carbamoyl phosphate lead to pyrimidine production, as the regulated step of the pathway, the reaction catalyzed by carbamoyl synthetase II, is being bypassed. Thus, orotic aciduria results. 

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