Late-onset carbamoyl phosphate synthetase 1 deficiency in an adult cured by liver transplantation


  • Timothy R. Bates,

    Corresponding author
    1. Department of Internal Medicine, Swan District Hospital, Middle Swan, Western Australia, Australia
    2. School of Medicine and Pharmacology, Perth, Western Australia, Australia
    • Department of Internal Medicine, Swan District Hospital, Eveline Road, Middle Swan, Western Australia, Australia 6056
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  • Barry D. Lewis,

    1. Department of Clinical Biochemistry, PathWest Princess Margaret Hospital, Perth, Western Australia, Australia
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  • John R. Burnett,

    1. School of Medicine and Pharmacology, Perth, Western Australia, Australia
    2. School of Pathology and Laboratory Medicine, University of Western Australia, Perth, Western Australia, Australia
    3. Department of Core Clinical Pathology and Biochemistry, PathWest Royal Perth Hospital, Perth, Western Australia, Australia
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  • Kenji So,

    1. Western Australian Liver Transplant Service, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
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  • Andrew Mitchell,

    1. Western Australian Liver Transplant Service, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
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  • Luc Delriviere,

    1. Western Australian Liver Transplant Service, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
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  • Gary P. Jeffrey

    1. School of Medicine and Pharmacology, Perth, Western Australia, Australia
    2. Western Australian Liver Transplant Service, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
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Urea cycle disorders (UCDs) are rare causes of hyperammonemic encephalopathy in adults. Most UCDs present in childhood and, if unrecognized, are rapidly fatal. Affected individuals who survive to adulthood may remain undiagnosed because of clinicians' unawareness of the condition or atypical presentations. We describe the case of a 49-year-old man who initially presented with a stroke and developed hyperammonemic encephalopathy over a period of 8 months. A diagnosis of carbamoyl phosphate synthetase type 1 deficiency was made, and the patient was referred for liver transplantation. One year after liver transplantation, the patient had normal plasma ammonia concentrations and had returned to work. Liver Transpl, 2011. © 2011 AASLD.

Urea cycle disorders (UCDs) are rare causes of hyperammonemic encephalopathy in adults. The clinical presentation of these conditions is varied, and the diagnosis may be delayed by clinicians' unawareness of this group of inborn errors of metabolism. We describe a case of late-onset carbamoyl phosphate synthetase type 1 (CPS1) deficiency in an adult who was cured by liver transplantation, and we briefly describe the diagnosis and management of UCDs.


CPS1, carbamoyl phosphate synthetase type 1; UCD, urea cycle disorder; RI, reference interval.


Patient consent and institutional approval was obtained for publication. A 49-year-old right-handed man presented with dysarthria and right-sided facial and upper limb weakness upon waking. A clinical diagnosis of a left subcortical stroke was made. This was subsequently confirmed by diffusion-weighted magnetic resonance imaging of the brain. A T1 sagittal flair sequence also revealed mild cerebral atrophy and nonspecific white matter change not in keeping with the patient's age. An extensive search for the cause of the stroke, which included clinical risk factors, imaging of the intracranial and extracranial circulation, transesophageal echocardiography, and Holter monitoring, was unremarkable. The patient was treated with conventional poststroke therapy (a statin, aspirin, and an angiotensin-converting enzyme inhibitor) and was discharged. At discharge, the weakness and dysarthria had almost resolved.

In the weeks after his discharge, the patient's spouse reported a significant personality change, episodes of confusion (especially at night), nausea, myalgia, emotional lability, and periods of apathy. Furthermore, there were periods of bilateral upper limb tremors lasting several hours. Unfortunately, many of the physical signs were not present during the clinical review. However, the symptoms prevented a return to work.

An extensive investigation that included neurological imaging and laboratory testing was nondiagnostic, and medication alterations did not lead to clinical improvement.

Eight months after his presentation, the patient returned to the hospital with delirium and a coarse tremor consistent with asterixis. At this time, his serum aminotransferases and liver ultrasonography were both normal. His plasma ammonia concentration was 157 μmol/L (normal < 50 μmol/L), and mild respiratory alkalosis was noted. A presumptive a diagnosis of either a UCD or a portosystemic shunt was made; the latter was excluded radiologically. At this point, a personal history of protein aversion was found. Furthermore, the patient's sister had died of an encephalopathic illness after a blood transfusion for postpartum hemorrhaging in the 1970s. Initial metabolic testing revealed an increased plasma glutamine level of 1391 μmol/L (RI = 205-756 μmol/L), an increased alanine level of 820 μmol/L (RI = 177-583 μmol/L), a low to normal citrulline level of 13 μmol/L (RI = 12-55 μmol/L), and normal arginine, lysine, and ornithine concentrations; this was suggestive of a UCD. An allopurinol challenge test showed normal orotate excretion. The patient underwent liver biopsy. The liver histology was normal; however, his hepatic CPS1 activity (Enzyme Commission number was decreased at 0.14 nmol/minute/mg of protein (normal control activity = 0.50 nmol/minute/mg of protein, affected control activity = 0.15 nmol/minute/mg of protein), and this was consistent with CPS1 deficiency (Online Mendelian Inheritance in Man number 237300). The enzyme activity for ornithine transcarbamylase (Enzyme Commission number in the liver was 1050 nmol/minute/mg of protein (normal activity > 200 nmol/minute/mg of protein).

Exon-by-exon sequencing of the CPS1 gene failed to identify any mutations. However, a complementary DNA analysis using phytohemagglutinin-stimulated and cycloheximide-treated peripheral blood leukocytes showed that the patient was missing exon 26 from 1 allele. A genomic DNA analysis confirmed the presence of an ∼2.5-kb heterozygous deletion involving exon 26 and parts of introns 25 and 26 (according to RefSeq NM_001875.3). Although a second mutation was not confirmed on the other allele, a presumptive diagnosis of CPS1 deficiency was made. The sequencing of the N-acetylglutamate synthetase gene (Online Mendelian Inheritance in Man number 237310) was normal.

The patient was treated with an ammonia-scavenging agent (sodium benzoate), L-arginine (the level of this amino acid is frequently low with CPS1), and dietary protein restriction. Despite this, periods of tremor and encephalopathy persisted. Multiple electroencephalograms showed changes consistent with metabolic encephalopathy. The plasma ammonia concentration never normalized. Because of the refractory symptoms, the patient was referred for liver transplantation. No contraindications to transplantation were found during the workup.

After 4 months on the waiting list, the patient underwent uncomplicated orthotopic liver transplantation. After surgery, the patient received sodium benzoate and sodium phenylbutyrate infusions for 2 days until the serum ammonia concentration normalized. The plasma glutamine and alanine concentrations also normalized after transplantation. Liver function test findings transiently deteriorated around the time of the transplant, but they gradually improved. He was started on tacrolimus, azathioprine, and prednisolone as his immunosuppressant regimen. Subjectively, his cognition significantly improved and almost returned to his premorbid level of function. Subsequent electroencephalograms were normalized. One year after transplantation, the patient had returned to work.


In humans, the urea cycle is the major route for excreting waste nitrogen. Nitrogen accumulates in the form of ammonia, and the failure of the urea cycle pathway will result in hyperammonemia.1-3 There are multiple causes of hyperammonemia, with a hepatic etiology being the most common.4 In patients with normal hepatic function, other causes should be sought (see Fig. 1). These causes include medications (including certain chemotherapy agents and valproic acid) that specifically inhibit the urea cycle, urease-producing bacterial infections, certain surgical treatments, hyperalimentation, and UCDs. The diagnosis of a UCD is based on clinical, biochemical, and molecular data.1-3

Figure 1.

Suggested algorithm for the investigation of a patient presenting with hyperammonemia.

UCDs are genetic defects caused by a deficiency in any of the urea cycle enzymes.1-3 CPS1, a 1463-amino acid polypeptide, catalyzes the first step (the rate-determining step) of the urea cycle. In this reaction, carbamoyl phosphate is synthesized from ammonia, bicarbonate, and adenosine triphosphate; the cofactor N-acetylglutamate is synthesized by N-acetylglutamate synthetase. CPS1 deficiency is a rare, autosomal-recessive inborn error of the urea cycle characterized by episodes of life-threatening hyperammonemia.5, 6 The population frequency of CPS1 deficiency is uncertain, but it is estimated to be ∼1 per million. CPS1 deficiency is caused by mutations in the CPS1 gene or a lack of its activator N-acetylglutamate.5, 6 The human CPS1 gene is located on chromosome 2q34-35 and comprises 38 exons.7, 8

CPS1 deficiency most commonly affects the pediatric population, and in general, the prognosis is poor; however, it may rarely present in adulthood.9-13 In the neonatal period, the presentation is nonspecific with symptoms of poor feeding, vomiting, somnolence, irritability, and tachypnea.1-3 Those who present in adulthood usually have milder symptoms than children, and they can also be asymptomatic. Episodes of hyperammonemia in these patients can be triggered by an illness (a stroke, pneumonia, or myocardial infarction) or catabolic stress (surgery, trauma, or pregnancy).9-13 Clinical symptoms can include a loss of appetite, cyclic vomiting, lethargy, protein avoidance and behavioral abnormalities.1-3 If UCDs are diagnosed before an irreversible cerebral insult, patients with late-onset UCDs may have normal neurodevelopment. However, most patients have learning difficulties, mild intellectual impairment, and a protein aversion.1-3 Cerebral magnetic resonance imaging of patients with late-onset UCDs has shown cortical injuries, including acute ischemia, ventricular dilatation, and myelination defects.14

The immediate therapeutic goal for patients with acute hyperammonemia is the rapid removal of ammonia to prevent irreversible cerebral damage. An emergency management protocol for UCDs and hyperammonemia is available from the British Inherited Metabolic Disease Group.15 Protein should be removed from the diet, and dialysis may be required. Patients may benefit from glucose infusions in the acute phase to enhance anabolism. Other measures to reduce plasma ammonia concentrations include intravenous infusions of sodium benzoate and sodium phenylacetate, which create alternate pathways for nitrogen excretion.16 Once the acute hyperammonemic crisis is past, the long-term goals are the promotion of normal growth, development, and function and the prevention of recurrent attacks. The mainstays of treatment are dietary protein restriction, arginine or citrulline supplements, and oral alternative pathway therapy with sodium benzoate and sodium phenylbutyrate. Plasma glutamine seems to predict hyperammonemia and may be the best single guide to the effectiveness of treatment.

Orthotopic liver transplantation should be considered for patients with more severe UCDs because of the poor prognosis.17-21 Other indications for transplantation include recurrent symptomatic hyperammonemia despite optimal medical management, poor access to tertiary care, and argininosuccinate lyase deficiency (for patients who develop progressive liver disease). Leonard and McKiernan17 reported that after 59 transplants for UCDs (reported up to 2004), the overall survival rate was 93% with a mean follow-up period of 3 years. In 2005, Morioka et al.18 reviewed 51 patients who underwent liver transplantation for UCDs; the age range was 0 to 62 years (median = 31.5 months), and the median time from the onset of symptoms to liver transplantation was 9 months (range = 0.5-202 months). The cumulative patient survival rate was found to be more than 90% 5 years after transplantation. Hyperammonemia and the need for dietary restrictions and alternative pathway medications were completely eradicated by liver transplantation in all surviving patients.

In summary, UCDs are rare inborn errors that can present with a multitude of different symptoms and signs. In adulthood, the symptoms are usually milder, and treatment with supplements and alternative pathway therapy may suffice. However, in refractory cases, liver transplantation can result in successful outcomes. We have described a case of late-onset CPS1 deficiency in an adult cured by liver transplantation.