Case Patient

A 26-year-old white woman was admitted to the hospital in active labor. Her mother had had an uncomplicated full-term pregnancy and delivery. Her childhood was unremarkable, but she had a self-selected diet with little or no meat or dairy products, and she occasionally complained of spells of confusion and disorientation and was diagnosed with complex partial seizures. She completed college and worked as a teacher. Her only pregnancy was uncomplicated, with prenatal care throughout. The patient had a brief episode of disorientation 1 day before delivery. Ten hours after delivery, she became disoriented and agitated; she progressed within a few hours to coma and decerebrate posturing. Blood chemistry results at that time were essentially unremarkable. Within 24 hours, the patient developed generalized tonic-clonic seizures and was transferred to a tertiary care hospital. Hyperammonemia (1000 µmol/L; normal, <35 µmol/L) was present in the absence of hepatitis; an electroencephalogram showed diffuse encephalopathy and seizure activity. A percutaneous liver biopsy specimen, to rule out the Reye syndrome, was normal. Three days after delivery she was flaccid, did not have spontaneous respiration, and had diabetes insipidus. Plasma amino acid levels showed a glutamine level of 857 µmol/L (normal, 578 ±85 µmol/L), a glutamic acid level of 507 µmol/L (normal, 24 ±12 µmol/L), an alanine level of 1065 µmol/L (normal, 373 ±87 µmol/L), and a citrulline level of 14 µmol/L (normal, 35 ±10 µmol/L). The urinary orotic acid level was 62 µmol/g creatinine (normal, <60 µmol/g creatinine). An electroencephalogram showed no cerebral electrical activity, ventilatory support was discontinued, and she was declared dead. An autopsy showed evidence of cerebral edema but was otherwise unremarkable.

The analysis of the liver obtained at autopsy showed that the patient had normal activity of ornithine transcarbamylase but had virtually no activity (<1%) of carbamoyl-phosphate synthetase I (Table 1). The almost complete absence of carbamoyl-phosphate synthetase I activity in this woman is surprising, and it was not clear how she had survived to this age with only minor symptoms. One possible explanation is that the enzyme was markedly unstable and that our in vitro assays did not reflect the activity in vivo. When equal amounts of liver extract from the patient and a normal control person were analyzed by Western blot, a markedly decreased amount of antibody-reactive carbamoyl-phosphate synthetase I polypeptides was found in the patient's sample (Figure 1, panel A). Because of the marked discrepancy in the quantity of the enzyme in the normal compared with patient samples, we diluted the normal liver extract by 50-fold and repeated the analysis (Figure 1, panel B). Although some degradation was apparent in the normal sample (panel B, lane N), much more degradation was apparent in the patient sample (panel B, lane P). When electrophoresis was done for longer periods (Figure 1, panel C), little, if any, protein from the patient corresponded to normal, full-length 160 000-dalton carbamoyl-phosphate synthetase I protein. These data indicate that the enzyme in this patient was unstable and turned over more rapidly because of proteolysis than did the normal protein. Instability of carbamoyl-phosphate synthetase I in a patient has been observed before [2], but no immunologic studies were done.

View larger version (78K): [in this window] [in a new window]   Figure 1. Western blot analysis of carbamoyl-phosphate synthetase I in liver extracts from a normal person and from the patient. Panel A. Lanes contain 2 mg of liver protein from a normal person (N) and the patient (P). Panel B. Lanes contain 0.04 mg of liver protein from a normal (N) person and 2 mg of liver protein from the patient (P). Panel C. Same as panel B, except that electrophoresis was done for 1.3 hours instead of 0.75 hours. Arrows indicate the position of migration of the normal carbamoyl-phosphate synthetase I protein.

Discussion

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Carbamoyl-phosphate synthetase I deficiency is an autosomal recessive disorder [4]. Most clinical cases of this disease have had a neonatal presentation [2, 5-9], but several cases have been reported in which patients presented latter in life [4, 10]. Several clinical features of this case are of interest, and they highlight the difficulty in making this diagnosis on only clinical grounds. Previous episodes of confusion reported by the patient's family probably were mild, self-limited episodes of hyperammonemia. After hyperammonemia was recognized, the lack of laboratory evidence of hepatic failure that would account for her hyperammonemia suggested an inborn error of metabolism. The results of plasma amino acid analysis were consistent with hyperammonemia but were not diagnostic of a classic urea cycle deficiency. Citrulline levels are commonly used as a diagnostic marker in urea cycle disorders and would be essentially zero in a neonatal patient with carbamoyl-phosphate synthetase I deficiency. Normal or near normal levels of citrulline occur in adult patients with urea cycle deficiencies.

This case emphasizes that unexplained alterations in mental status and coma after childbirth may be due to hyperammonemia caused by inherited deficiencies of the enzymes in the urea cycle. Patients who have problems metabolizing ammonia are at particular risk during any episode where increased catabolism is occurring, such as after childbirth, infectious disease, or menses. These events place an increased demand on the liver to metabolize ammonia, and when the threshold is reached, plasma ammonia levels increase and result in life-threatening hyperammonemia. Prompt recognition and treatment of these disorders are required for optimal outcome [1].