Undiagnosed Partial Ornithine Transcarbamylase Deficiency Presenting Postoperatively as Agitated Delirium

Abstract

Partial ornithine transcarbamylase deficiency (pOTCD), an enzymatic defect within the urea cycle, is an increasingly recognized etiology for hyperammonemia of unclear source following a stressor within female adults. Here we present a case of newly diagnosed pOTCD following a systemic stressor and prolonged hospitalization course. From a neurological perspective, prompt recognition provided the patient with a swift and near complete recovery. We briefly review the pertinent literature pertaining to this genetically based condition including historical context and current therapeutic approaches. Given the potential morbidity of prolonged hyperammonemia, neurohospitalists need to be aware of partial ornithine transcarbamylase as an entity.

Introduction

Ornithine transcarbamylase (OTC) is an enzyme responsible for maintenance of nitrogen homeostasis. The OTC deficiency (OTCD) is inherited through an X-linked fashion. Classically, male neonates with OTCD present with lethargy, poor appetite, and eventual coma.¹ However, skewed X-chromosome inactivation in females creates a spectrum of adult disease, known as partial ornithine transcarbamylase deficiency (pOTCD), due to variable residual enzymatic function, which may be difficult to detect.^2,3

In this case report, we discuss a patient who presented to the inpatient neurology consultation service with progressively worsening postoperative agitated delirium. The patient described provided verbal consent for reporting her case.

Case Description

Mrs MN is a 59-year-old right-handed woman of European ancestry with a medical history of West Nile encephalitis diagnosed in 2004 without residual deficits, alcohol abuse currently in remission, and fibromyalgia. In the autumn of 2016, she presented to the outpatient gynecologic surgery service for treatment of worsening rectal prolapse with urinary incontinence. Ultimately, in December 2016, she underwent a robotic sacrocolpopexy and rectopexy. Her postoperative course was complicated by poor wound healing, small bowel perforation, abdominal peritonitis, and gram-negative septicemia, ultimately requiring exploratory laparotomy for repair. Additionally, she developed acute respiratory failure requiring intubation and subsequent tracheostomy with recurrent admissions to the surgical intensive care unit. Concurrently, she developed progressively worsening agitated delirium and disorientation without focal neurological deficits initially attributed to a nonspecific metabolic encephalopathy. However, continued encephalopathy despite improvement in her infectious and respiratory conditions prompted an inpatient neurology consultation.

Results

Initial examination showed inattention, pressured speech, asymmetric pupils (3 mm OD, 4 mm OS), intermittent multifocal myoclonus, and diffuse hyperreflexia. She had normal axial and appendicular tone. She continued to require a tracheostomy for airway protection, though she was ventilating without mechanical support and oxygenating well on room air. At the time of interview, a general metabolic and toxic serologic screening demonstrated an ammonia of 45 mcmol/L (normal <30 mcmol/L) with alkaline phosphatase 95 U/L (normal 46-118 U/L), alanine aminotransferase 8 U/L (normal 7-45 U/L), and aspartate aminotransferase 13 U/L (normal 8-43 U/L). Review of previous laboratory values revealed a fluctuating, though persistently elevated serum ammonia, without evidence of hepatic dysfunction. Further testing including a head computed tomography and brain magnetic resonance imaging did not show signs of cerebral edema or findings of intracranial pathology. An awake electroencephalogram revealed generalized slowing. Family members present in the room noted that the patient’s clinical state worsened over the preceding week, prompting investigation into possible precipitating factors. Due to her prolonged hospitalization and malnutrition, she was started on total parenteral nutrition several weeks prior to this encounter and recently underwent significant uptitration in the protein concentration in the feedings. At the time of interview, her protein goal was 75 to 101 g/d total, which was achieved by Nutren 1.5 at a rate of 50 mL/h (17 g protein/250 mL) and Proteinex 10 g twice daily. Because of her unexplained hyperammonemia and cognitive decline coincided with increased protein feeds, the suspicion for a metabolic abnormality arose. A urine orotic acid was then obtained, revealing a concentration of 2 mmol/moles creatinine (Cr; normal 0.4-1.2 mmol/moles Cr), suggestive of a urea cycle defect. Our hypothesis was further supported by a premorbid preference for vegetarianism, dyspepsia with protein intake throughout adulthood, and a maternal grandmother with similar symptoms. At this point, we recommended the primary team to consult a biochemical geneticist who supported the clinical diagnosis of probable pOTCD.

Following this consultation, she was placed on intravenous arginine 600 mg/kg/d to provide partial urea cycle function, 10% dextrose in normal saline at a rate of 125 cc/h for caloric support, insulin infusion to promote anabolism, initiation of nitrogen scavenging medicine in the form of sodium phenylbutyrate, and a protein-restricted diet. Over the subsequent days, she progressively improved in mentation and her neurologic examination normalized. Follow-up laboratory data revealed normalization of the serum ammonia levels and a reduction in orotic aciduria. She was discharged to inpatient rehabilitation shortly thereafter and was followed in the biochemical genetics clinic for outpatient management.

Discussion

Emergency and inpatient services often consult neurologists for encephalopathy, of which carries a broad differential. Clinical features that may warrant assessment of serum ammonia include progressive inattention, somnolence, altered awareness of unclear source, generalized hyperreflexia, and either positive or negative myoclonus. Hyperammonemic encephalopathy that fails to improve or worsens despite improvement in systemic illnesses should prompt OTCD consideration, especially in the setting of normal liver function panels. Specifically, obtaining urinary orotic acid may be of benefit in these specific scenarios to evaluate for dysfunction of ammonia metabolism.

The OTCD was first recognized in the late 1950s and early 1960s in neonates. It was not until 1969 that the first suspected case of an adult with pOTCD was reported.¹ Following this report, an increasing number of pOTCD cases were reported within women. Based on family studies with pOTCD, the condition was determined to be X linked.² Further studies in women revealed that within populations of hepatocytes, where OTC is found in high concentrations, there may be variable degrees of functioning OTC due to random X-chromosome inactivation, creating different thresholds for symptom onset.³ The OTC molecular studies revealed that there are less than 10% of recurrent pathogenic variants within the population of patients with OTC, suggesting the majority of pathogenic variants involving the OTC gene are novel, family-specific, and may occur due to de novo events.^4,5 As this condition is inherited in an X-linked fashion, 50% of the children produced by a female with pOTCD will have the pathologic variant. Obtaining genetic testing is a personal decision, however, it remains important for subsequent generations to be cognizant and warn clinicians of the potential for emergence of this condition with metabolic stressors.

Physiologically, OTC is critical in maintaining nitrogen homeostasis. The OTC is found most prominently within the mitochondria of hepatocytes and serves as an enzyme within the urea cycle, which converts ammonia to urea for excretion. In OTCD hepatocytes, ammonia is not metabolized effectively, leading to systemic buildup, and is subsequently shunted to an alternative route for elimination. One such alternative route produces a clinically relevant marker, orotic acid, which may be used to detect urea cycle (especially OTC deficiency) abnormalities (Figure 1). Elevated orotic acid in conjunction with hyperammonemia is highly sensitive to OTCD, however, elevated urinary orotic acid without elevated ammonia is suggestive of abnormalities in the metabolism of orotic acid itself.^6,7 Catabolic states and diets high in protein, which is subsequently metabolized to nitrogen-based compounds, may produce hyperammonemia with elevated urinary orotic acid, such as in our patient.

Figure 1.

Ammonium is converted to carbamoyl phosphate in preparation for entering the urea cycle. Deficiency in OTC yields surplus serologic ammonia and shunting of the carbamoyl phosphate toward pyrimidine synthesis which produces orotate/orotic acid as part of the metabolic cascade. CP indicates carbamoyl phosphate; CPSI, carbamoyl phosphate synthetase I; NH4⁺, ammonium; OTC, ornithine transcarbamylase.¹

Clinically asymptomatic patients with pOTCD may nonetheless have adverse consequences of the condition. A study of OTCD heterozygotes showed significant differences between verbal and performance IQ scores when compared to individuals without the condition.⁶ This study also reported a correlation between decline in IQ score and the degree of OTC impairment.⁶ When restudied years later, investigators found that subtle cognitive and executive functional impairment was associated with hemispheric white matter changes on diffusion tensor imaging and reduced white matter integrity in the superior corpus callosum.⁸ Individuals with previously asymptomatic pOTCD may develop profound symptoms related to hyperammonemia following a precipitating event such as medication exposures (eg, valproate⁹), nutrient extremes (eg, anorexia nervosa¹⁰), and surgical procedures (eg, cholecystectomy,¹¹ orthotopic liver transplantation¹²). Of note, this patient’s history of West Nile virus encephalitis did not elicit similar encephalopathic symptoms.

The general therapeutic approach for pOTCD involves redirecting ammonia toward alternative pathways by nitrogen scavenger therapy, reducing protein intake and therefore load on the urea cycle, promotion of anabolism during acute events with intravenous insulin, and close monitoring of metabolic status. Sodium phenylbutyrate conjugates with glutamine, a highly abundant plasma amino acid, to form phenylacetylglutamine which is then excreted via the urine, bypassing the urea cycle. In addition, sodium phenylbutyrate depletes plasma branched chain amino acids, therefore, careful monitoring of essential amino acids is essential to long-term metabolic control.^11,13 Sodium benzoate, another nitrogen scavenger, conjugates with glycine to form hippuric acid, which is then excreted in the urine. Acute therapy for hyperammonemia may be targeted by hemodialysis or intravenous nitrogen scavenger therapy such as the combination of sodium phenylacetate (the active form of sodium phenylbutyrate) and sodium benzoate.¹⁴ Ultimately, orthotopic liver transplantation corrects the underlying metabolic disturbances, although this is usually not indicated for pOTCD.¹⁵ Another important factor in the management of patients with known pOTCD includes prevention of symptom emergence. Maintenance of a protein-restricted diet, avoidance of corticosteroids or other instigating medications, and continuation of nitrogen scavenger therapy remain prudent.

Conclusion

Neurohospitalists are frequently consulted for complex cases of encephalopathy. Hyperammonemia of unclear etiology following a metabolic stressor should raise concern for an underlying metabolic deficiency, such as pOTCD. Although commonly overlooked, a review of nutritional intake should be included in neurological assessments.