Phosphate Synthetase Deficiency

No proved example of a gross deficiency solely of carbamyl phosphate synthetase (Fig. 12) has as yet been recorded. Prior to the characterization and separation of the two carbamyl phosphate synthetases, it 

HjNCO-O-HaPOa + 2ADP + H3PO4 Carbamyl phosphate 

A second report (H4) concerned a female infant who was hospitalized at 20 days of age because of difficulty in feeding, lethargy, and convulsions. Two sibs had died with similar symptoms at 4 weeks of age, but two other sibs were normal. Blood ammonia levels on a relatively low protein intake (1.5 g/kg/day) ranged between 25 and 100 /ig/lOO ml, and blood urea between 2 and 14 mg/100 ml. Her general condition improved on the low protein diet, but later it deteriorated and she died at 7 2 months of age, weighing little more than her birth weight of 3.25 kg. Liver function tests were normal there was a slight metabolic alkalosis. 

A third instance has been briefly reported by Kirkman and Kiesel (KIO). They described a male infant who was admitted to hospital at 1 month of age because of vomiting, severe growth failure, and tremulousness. The blood ammonia was very high, 356 /j.g/100 ml. Neurological development was normal. Biochemical findings were an acidosis, organic aciduria, and lysinuria. There was also a moderate hyperglycinemia. When the protein intake was restricted to 1.5g/kg/day, the blood ammonia fell to 80-260 ig/100 ml. The liver biopsy obtained by needle aspiration showed a normal ornithine transcarbamylase activity which also had normal Km values. On the other hand, the carbamyl phosphate synthetase activity was only half that of specimens obtained at necropsy. 

None of these cases can be considered as established examples of an isolated carbamyl phosphate synthetase deficiency. Although in the first the clinical history and the presence of severe hyperammonemia support the diagnosis of a defect of urea synthesis, the normal finding of levels of plasma amino acids, apart from glycine, is against it. No actual numerical data on the level of activity of the urea cycle enzymes are given. 

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Diagnosis of CPS or OTC deficiency may not be apparent from the blood aminogram. Ornithine levels typically are normal. The presence of hyperammonemia, hyperglu-taminemia, hyperalaninemia and orotic aciduria in a critically ill infant affords presumptive evidence for OTC deficiency. The presence of this blood aminogram without orotic aciduria suggests carbamyl phosphate synthetase deficiency. 

Carbamyl phosphate synthetase deficiency. Carbamyl phosphate synthetase deficiency is rare. Neonates quickly develop lethargy, hypothermia, vomiting and irritability. The hyperammonemia typically is severe, even exceeding 1 mmol/1. Occasional patients with a partial enzyme deficiency have had a relapsing syndrome of lethargy and irritability upon exposure to protein. Brain damage can occur in both neonatal and late-onset groups. 

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. 

Tuchman M, Mauer SM, Holzknecht RA, Summar ML, Vnencak-Jones CL. Prospective versus clinical diagnosis and therapy of acute neonatal hyperam-monaemia in two sisters with carbamyl phosphate synthetase deficiency. J Inher Metab Dis 1992 15 269-77. 

Fig. 12. Postulated block in carbam> l phosphate synthetase deficiency.

H4. Hommes, F. A., Degroot, C. J., Wilmink, C. W., and Jonxis, J. H. P., Carbamyl phosphate synthetase deficiency in an infant with severe cerebral damage. Arch. Dis. Childhood 44, 688-693 (1969). 

Kotani Y, et al. Carbamyl phosphate synthetase deficiency and postpartum hyperammonemia. Am J Obstet Gynecol. 2010 203(l) el0-l. 

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. 

Propionyl CoA inhibits A(-acetylglutamate synthetase competitively with respect to acetyl CoA, forming A(-propionylglutamate and reducing the synthesis of A(-acetylglutamate. This is an obligatory activator of carbamyl phosphate synthetase, the first enzyme of urea synthesis. Vitamin B12 deficiency may result in some degree of protein intolerance and hyperammonemia. 

Although the bundle sheath chloroplasts contain all the enzymes of the RPP cycle, there is now evidence that some of the 3-PGA formed by the activity of rubisco is exported to the mesophyll cells [9]. Bundle sheath chloroplasts of maize are deficient in photosystem II activity and apparently cannot produce sufficient NADPH to reduce all of the 3-PGA formed to triose phosphate. Responsibility for this step is thus shared with the mesophyll chloroplasts which recycle triose phosphate to the bundle sheath as DHAP. This transport of 3-PGA from bundle sheath to mesophyll permits the synthesis of sucrose in the mesophyll cell cytoplasm. The evidence suggests that the mesophyll cells are the major site of sucrose synthesis [10-13]. Sucrose phosphate synthetase, one of the regulatory enzymes of sucrose synthesis and fructose 6-phosphate, 2-kinase (Fru-6-P,2K), the enzyme synthesizing fructose 2,6-bisphosphate — a potent regulator of cytoplasmic sucrose synthesis (see Section 5.4.1) — are both almost completely confined to the mesophyll cells. 

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. 

Call G, Seay AR, Sherry R, Qureshi lA. Clinical features of carbamyl phosphate synthetase-I deficiency in an adult. Ann Neurol 1984 16 90-3. 

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. 

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 CPSI gene causes a 9-basepair deletion due to aberrant splicing. J Clin Invest 1993 91 1884-7. 

Lo WD, Sloan HR, Sotos JF, Klinger RJ. Late clinical presentation of partial carbamyl phosphate synthetase I deficiency Am J Dis Child 1993 147 267-9. 

Sassaman EA, Zartler AS, Mulick JA. Cognitive functioning in two sisters with carbamyl phosphate synthetase I deficiency, f Ped Psychol 1981 6 171-5. 

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 ... 

Zimmer KP, Naim HY, Koch HG, Golombo JP, Rossi R, Schmid KW, et al. Survival after early treatment for carbamyl phosphate synthetase (CPS) I deficiency associated with increase of intramitochondrial CPS I. Lancet 1995 346 1530-1. 

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