Acute hyperammonemic encephalopathy in adult onset ornithine transcarbamylase deficiency

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Intensive Care Med (2008) 34:1922–1924 DOI 10.1007/s00134-008-1217-2

Ogee Mer Panlaqui Khoa Tran Amanda Johns Jim McGill Hayden White


Keywords Ornithine transcarbamylase deficiency  Hyperammonemic encephalopathy  Hemodiafiltration


Acute hyperammonemic encephalopathy in adult onset ornithine transcarbamylase deficiency

Case report A 48-year-old man was admitted to the intensive care unit following a sudden loss of consciousness. Three days prior to admission, he developed flu like symptoms and was observed to be sleepy. He presented to the emergency department with non-specific symptoms. He was noted to have asterixis and investigations including an ammonium level were performed. He later lost consciousness and he was intubated. The patient was a body builder and previously well. Collaborative history revealed a 6 months period of decline in memory and disordered behavior. There was no evidence of alcohol or recreational drug abuse, or intake of pesticides, acetaminophen or anticonvulsants. Neurologic examination on arrival to ICU revealed reactive pupils, no papilloedema, no primitive reflexes, no hyperreflexia, and no meningism. Initial blood chemistries (Table 1) revealed markedly elevated plasma ammonia and alanine transferase (ALT). The chest radiograph, head

Ornithine transcarbamylase deficiency (OTCD) is the most common inborn error of the urea cycle with an incidence of one per 42,000 live births [1]. OTCD is an X-linked Received: 1 February 2008 disorder of urea synthesis leading to Accepted: 19 June 2008 hyperammonemia. The gene Published online: 24 July 2008 responsible is located on the short Ó Springer-Verlag 2008 arm of the X chromosome on band Xp21.1 [2]. As the inheritance is Abstract Objectives: To report the X-linked, males are usually more severely affected. Consequently, clinical manifestations of acute hyperammonemic encephalopathy in 15% of female carriers become symptomatic [3]. Clinical manifesadult onset ornithine transcarbamylase deficiency (OTCD). tations of hyperammonemia are nonspecific often leading to a delay in Design: Case report. the diagnosis of OTCD. Setting: Intensive care unit of a We report a case of a 48-year-old tertiary medical centre. male body builder who presented Patient: A 48-year-old Caucasian with acute hyperammonemic male body builder who developed encephalopathy and findings consisacute loss of consciousness after a tent with late onset OTCD. febrile illness. Interventions: The patient was immediately started on hemodiaTable 1 Blood chemistries, plasma and urine amino acids levels filtration, protein elimination and ammonia scavenging medications. Admission Third hospital day Normal values Measurements and results: Serum ammonium was elevated and plasma Sodium 137 138 135–145 mmol/l 4.3 4.2 3.2–4.5 mmol/l and urine amino acids had a pattern Potassium Chloride 105 113 100–110 mmol/l indicative of a urea cycle defect. ALT 61 78 \45 U/l DNA studies revealed a mutation of AST 28 37 \40 U/l the urea cycle enzyme, ornithine GGT 19 20 \50 U/l Ammonium 390 39 \50 umol/l transcarbamylase. The Plasma amino acids encephalopathy resolved and the Glutamine 1,300 490 420–700 umol/l patient slowly recovered though with Glutamate 140 69 10–50 umol/l some cognitive impairment. Citrulline 10 4 20–60 umol/l Ornithine 26 57 20–70 umol/l Conclusions: Adult presentation of Arginine 53 180 68–104 umol/l OTCD is rare and the mortality and Lysine 660 210 120–240 umol/l morbidity rates are high. However, Urine Amino Acids survival is possible with rapid Glutamine 170 \100 mmol/mol creat correction of hyperammonemia. As Citrulline \1 \5 mmol/mol creat Ornithine \1 \10 mmol/mol creat the clinical manifestations are non120 \5 mmol/mol crea specific, a high index of suspicion is Orotic acid necessary for the correct diagnosis ALT (alanine transferase), AST (aspartate transaminase), GGT (gamma-glutamyl transferase) and management.


CT scan, abdominal ultrasound and lumbar puncture were all normal. The sudden changes in sensorium with acute hyperammonemia without evidence of hepatic decompensation suggested the possibility of an abnormality of amino acid metabolism. Measurement of plasma amino acids revealed elevated levels of glutamine, low citrulline and arginine (Table 1). There was increased urinary orotic acid and glutamine. These findings are consistent with OTCD. DNA studies revealed a single R40H mutation and the patient was heterozygous for the mutation as described by Tuchmann [4]. Management was directed at the rapid clearing of plasma ammonia using continuous venovenous hemodiafiltration (CVVHDF). Intravenous L-arginine HCl 10% 210 mg/kg per day and sodium benzoate in glucose 10% at 250 mg/kg per day were administered. Enteral protein free glucose polymer 15% (12 kcal/kg per day) was initiated. During the subsequent days, ammonia level continued to decrease with hemodialysis and ammonia scavenging therapy. An MRI of the brain (Fig. 1) was requested which demonstrated appearances consistent with a metabolic encephalopathy due to hyperammonemia. The patient showed signs of improvement neurologically with reversal of hyperammonemia and continued to receive parenteral sodium benzoate Fig. 1 MR images of the patient on admission (a) showing swelling and increased T2 signal affecting cortical gray matter with sparing of the perirolandic and occipital gyri. Repeat MR images (b) a week after. There was reduction in swelling and T2 prolongation of the cortical gray matter

and L-arginine. An enteral protein restricted feed (Renal Novasource) 0.5 gm/kg per day was slowly introduced and glucose polymer 15% was continued hence providing total calorie of 2,555 kcal/day (70% carbohydrates and 20% fats). With improvement he was weaned from the ventilator and transferred to a brain injury unit for neurocognitive and physical rehabilitation. During the period of rehabilitation, marked improvements have been made in all facets of independent living. However, neuropsychological assessment at 6 months has demonstrated generalized cognitive deficits. It is expected that he will require significant support and rehabilitation for the foreseeable future.

Discussion Ornithine transcarbamylase deficiency is a urea cycle disorders wherein a genetic alteration of ornithine transcarbamylase enzyme in the hepatic mitochondria (Fig. 2) leads to the accumulation of ammonia and its metabolites. The clinical presentation of OTCD depends on the degree of impaired enzyme activity. The physiologic mechanisms can be categorized as: (a) increased nitrogen turnover and load from catabolism (b) diminished

access to processing in the liver (c) reduced capacity of the urea cycle to process the nitrogen load [5]. For our patient, the stress of body building, high dietary intake of protein and an acute febrile illness were likely responsible for the cascade of events leading to hyperammonemia. The disease usually presents in the newborn; however, there are several case reports of late onset manifestations of OTCD mostly in heterozygous female patients over a wide age range. This case is one of the few reported late onset presentations in a male [5–7] to survive OTCD. The initial management of hyperammonemia includes: protection from cerebral oedema, seizure prevention, and cooling. Adjunct medications can be administered such as mannitol, lactulose, antibiotics and anti-fungals [8]. Once an inborn error of metabolism is ascertained, management is directed to removal of excess ammonia, dietary protein restriction and ammonia scavenging medications. Removal of toxins can be achieved through hemodialysis. Early continuous venovenous hemofiltration (CVVH) appeared to be the most effective modality with removal 12,600 ug of ammonia/h [2]. Nutrition management of patients with OTCD remains a challenge. The principal goal is dietary protein withdrawal to minimize nitrogen flux in the urea cycle. Initiate with


4. Tuchman M, Plante RJ, McCann MT, Qureshi AA (1994) Seven new mutations in the human ornithine transcarbamylase orotic acid gene. Hum Mutat 4:57–60 Carbamyl Phosphate Aspartate 5. Summar ML, Barr F, Dawling S, Smith W, Lee B, Singh RH, Rhead WJ, King Citruline ASS Citruline OTC LS, Christman BW (2005) Unmasked adult-onset urea cycle disorders in the Ornithine critical care setting. Crit Care Clin Argininosuccinate 21:S1–S8 6. Costello DJ, Rohininath T, Treacy E, CYTOSOL Lynch T (2004) Late presentation of Ornithine ornithine transcarbamylase deficiency in a sixty year old male. Neurology 62:S5 ASL 7. Schultz REH, Salo MK (2000) Under recognition of late onset ornithine Urea Arginine transcarbamylase deficiency. Arch Dis ARG Child 82:390–391 Fumarate 8. Clay SA, Hainline BE (2007) Hyperammonemia in the ICU. Chest Fig. 2 Urea cycle pathway. ARG arginase, ASL arginosuccinic acid lyase, ASS 132:1368–1378 arginosuccinic acid synthetase, CPSI carbamyl phosphate synthetase 1, OTC ornithine 9. Singh RH, Rhead WJ, Smith W, Lee B, transcarbamylase. (Reproduced with permission from Marshall L. Summar MD) King LS, Summar ML (2005) Nutrition management of urea cycle disorders. Crit Care Clin 21:S27–S35 parenteral therapy of glucose 12–30% 10. Rimbaux S, Hommet C, Perrier D, Conclusions solution and fat emulsion (Intralipid) Cottier JP, Legras A, Labarthe F, Lemarcis L, Autret A, Maillot F (2004) 20% or enterally by using protein free We have described one of the few Adult onset ornithine transcarbamylase formulas. Then as the plasma surviving cases of a male with acute deficiency: an unusual cause of ammonia normalizes, protein can be semantic disorders. J Neurol Neurosurg hyperammonemic encephalopathy reintroduced at best enterally Psychiatry 75:1073–1075. doi: due to late onset OTCD. Early recapproximately 25–50% of the pre10:1136/jnnp.2003.026542 HCO3 + NH4 + 2ATP CPS-I

MITOCHONDRIA N-acetylglutamate

scribed dietary allowance. This prescription aims to meet the energy requirement and prevent catabolism [9]. Administering L-arginine in urea cycle disorders can meet this requirement at a dose of 100–500 mg/ kg per day [6]. In conjunction with amino acid supplementation, ammonia scavengers are required. These include sodium benzoate or sodium phenylbutyrate. In this case, we initially administered L-arginine HCl and sodium benzoate intravenously and later orally. Once the acute effects of hyperammonemia resolved, our patient began to awaken. However, it was clear that significant cognitive and motor deficits had developed. There can be persistent impairment of retrograde memory [10] or global deficits in executive functions. The neurophysiologic mechanisms for these deficits are still unknown.

ognition of hyperammonemia is critical in limiting the long term sequelae of late onset OTCD. Indeed, as clinical presentations vary among these groups of patients a high index of suspicion is required for early diagnosis.

References 1. Kleppe S, Mian A, Lee B (2003) Urea cycle disorders. Curr Treat Opt Neurol 5:309–319 2. Chang MY, Fang JT, Chen YC, Huang CC (1999) Continuous venovenous haemofiltration in hyperammonemic coma of an adult with non-diagnosed partial ornithine transcarbamylase deficiency. Nephrol Dial Transplant 14:1282–1284 3. King LS, Singh RH, Rhead WJ, Smith W, Lee B, Summar ML (2005) Genetic counselling issues in urea cycle disorders. Crit Care Clin 21:S37–S44

O. M. Panlaqui  K. Tran ())  H. White Intensive Care Unit, Logan Hospital, Cnr Armstrong and Loganlea Rds, Meadowbrook, QLD 4131, Australia e-mail: [email protected] Tel.: +617-3299-8899 Fax: +617-3299-8376 H. White e-mail: [email protected] A. Johns The Spinal Rehabilitation Unit, Princess Alexandria Hospital, Brisbane, QLD, Australia e-mail: [email protected] J. McGill Department of Chemical Pathology, Pathology Queensland and Metabolic Medicine, Royal Children’s Hospital, Brisbane, QLD, Australia e-mail: [email protected]

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