Late-Onset Presentation of Ornithine Transcarbamylase Deficiency in a Young Woman With Hyperammonemic Coma

Transcription

1 NEUROLOGY/CASE REPORT Late-Onset Presentation of Ornithine Transcarbamylase Deficiency in a Young Woman With Hyperammonemic Coma Rita Gaspari, MD Andrea Arcangeli, MD Sonia Mensi, MD Denise Schembri Wismayer, MD Tommaso Tartaglione, MD Daniela Antuzzi, MD Giorgio Conti, MD Rodolfo Proietti, MD From the Departments of Anaesthesiology and Intensive Care (Gaspari, Arcangeli, Mensi, Wismayer, Conti, Proietti), Radiology (Tartaglione), and Pediatrics (Antuzzi), Catholic University of Rome, Rome, Italy. Ornithine transcarbamylase deficiency (OTCD) is an X-linked inherited disease and the most common inborn error in urea synthesis in human patients. In adult heterozygous patients, OTCD can be responsible for life-threatening hyperammonemic coma. We report the case of a 32-year-old woman admitted to our hospital with seizures after a recent high protein load. Her parents related a history of recurrent episodes of vomiting, meat refusal, lethargy, and convulsions since childhood, and measurement of plasma ammonemia levels was the key to early diagnosis of OTCD. We report the pathophysiologic characteristics, clinical features, clinical course, and differential diagnosis of OTCD and discuss the therapeutic options, including continuous venovenous hemodiafiltration and pharmacologic therapy for reduction of plasma ammonemia levels. A diagnosis of OTCD should be considered in adult nonhepatic patients with hyperammonemic coma, particularly if they have a history of protein avoidance and neurologic symptoms. Early recognition and appropriate treatment are critical to avoid severe brain damage and death. [Ann Emerg Med. 2003;41: ] Copyright 2003 by the American College of Emergency Physicians /2003/$ doi: /mem ANNALS OF EMERGENCY MEDICINE 41:1 JANUARY 2003

2 INTRODUCTION Ornithine transcarbamylase deficiency (OTCD) is an X-linked disorder of the mitochondrial urea cycle associated with hyperammonemia affecting mainly male patients. 1 During the neonatal period or after a variable period without clinical signs, patients have severe hyperammonemia associated with stupor, lethargy, and coma. Frequently, they die during the neonatal period, unless an early diagnosis and intensive management are carried out. Some patients with partial enzyme deficiencies might be asymptomatic until adulthood, 2 when a protein load might produce symptoms ranging from recurrent episodes of irritability and aggressiveness to stupor, lethargy, and coma related to increased plasma ammonia levels. Heterozygous female patients exhibit a wide range of clinical manifestations. They might be asymptomatic or be affected as homozygous male patients. This is due mainly to the random inactivation of X chromosomes. 3,4 The onset of clinical signs can occur from early infancy to adulthood. High protein intake, infections, or stress can provoke clinical attacks of hyperammonemia, leading to neurologic abnormalities and even severe cerebral edema and death. Despite several reported cases, OTCD is a very uncommon disorder, and the clinical variability in adult patients makes early diagnosis difficult. We report a case of a young woman with hyperammonemic coma and seizures who was successfully given a diagnosis of late-onset OTCD. CASE REPORT A 32-year-old woman presented to the emergency department by ambulance with generalized tonic-clonic seizures, coma, tongue biting, and urinary incontinence. On arrival, her vital signs were as follows: blood pressure 125/70 mm Hg, pulse rate 75 beats/min, and respiratory rate 18 breaths/min. No fever, nuchal rigidity, or focal neurologic deficits were observed. Pupils were miotic but responsive to light. Initial treatment with diazepam (10 mg administered intravenously) stopped the seizures, but in the following 30 minutes, the patient remained unresponsive to verbal commands, hypotonic, and areflexic. Her parents did not report alcohol or drug abuse. However, they described a history of recurrent episodes of vomiting, mental confusion, and lethargy during the past 10 years. Her mother emphasized a spontaneous refusal of meat meals since childhood. These episodes occurred during the premenstrual period or associated with febrile illness and would last for several hours. The patient had been diagnosed with epilepsy and was treated occasionally with carbamazepine. She had also undergone psychiatric evaluation on several occasions. The parents described a high protein intake in the days preceding her current ED presentation. Initial laboratory investigations revealed the following: blood glucose level of 102 mg/dl, blood urea nitrogen level of 20 mg/dl, creatinine level of 1.1 mg/dl, and normal electrolytes. A CBC count showed a hemoglobin level of 14.8 g/dl, WBC count of 12,600/mm 3, and platelet count of 302,000/mm 3. Liver function tests and clotting profile were normal. The patient had an arterial ph of 7.49, a PaO 2 of 91.4 mm Hg, a PaCO 2 of 25.8 mm Hg, a bicarbonate level of 20.1 mmol/l (normal 22 to 27 mmol/l), a base excess level of 0.9 mmol/l (normal ±2), and a lactate level of 0.8 meq/l (normal 0.8 to 1.2 meq/l). Because of the patient s history and the uncertain cause of coma, the diagnosis of a metabolic disorder was considered, and a plasma ammonia level was measured. A nonhemolyzed, heparinized arterial sample placed in ice was rapidly processed. The plasma ammonia level was increased at 192 µmol/l (normal 11 to 44 µmol/l). An OTCD was suspected, and both plasma and urinary amino acids and urine orotate concentrations were evaluated. The patient was admitted to the neurology service, and anticonvulsant therapy with 8 mg/d of lorazepam administered intravenously was instituted. After several hours, she remained comatose, and an EEG revealed slow waves but no epileptiform activity. Hyperammonemia was treated with lactulose, 10% glucose infusion (4 mg/kg per minute), and discontinuation of protein intake. After 24 hours, she had generalized seizures followed by deep coma (Glasgow JANUARY :1 ANNALS OF EMERGENCY MEDICINE 105

3 Coma Scale score of 4), and mechanical ventilation was necessary. Head computed tomographic scanning showed diffuse brain swelling with mild compression on the third and lateral ventricles. Magnetic resonance imaging (MRI) was obtained by using a 0.5 T superconductive unit (MR Vectra, GE Medical System, Milwaukee, WI), with Spin-Echo and Fast-Spin-Echo conventional sequences before and after gadolinium diethylenetriaminepentaacetic acid intravenous injection. MRI also showed a diffuse acute swelling of the cortex of both cerebral hemispheres characterized by marked hyperintensity on proton density and T2- weighted images and isointensity on T1-weighted images, without any contrast enhancement after contrast medium injection. The gray matter and subcortical white matter of the insula and temporal lobe were prominently involved. In the frontal corona radiata and centrum semiovalis, multiple acute leukoencephalopathic foci were also evident bilaterally (Figure 1A). The patient was transferred to our ICU, where a further increase in ammonia levels was observed (576 µmol/l). She underwent continuous venovenous hemodiafiltration (Prisma-Hospal, Lyon, France) and received intravenous administration of sodium benzoate and L-arginine hydrogen chloride 10% solution. On the fifth day, the ammonia level decreased from 576 to 27 µmol/l, and continuous venovenous hemodiafiltration was suspended. The patient s level of consciousness improved, and on the seventh day, she was awake. On the tenth day, she was discharged from our ICU. During her ICU stay, metabolic screening revealed a high plasma glutamine level (1,100 µmol/l, normal 337 to 673 µmol/l) and reduced serum ornithine (18 µmol/l, normal 29 to 125 µmol/l), arginine (22 µmol/l, normal 54 to 130 µmol/l), and citrulline (10 µmol/l, normal 12 to 55 µmol/l) levels. Urinary orotic acid (230 µmol/mmol creatinine normal 0 to 10 µmol/mmol creatinine) and orotidine (22 µmol/ mmol creatinine) levels were high. Lactate-pyruvate ratio was in the normal range. These results confirmed a diagnosis of OTCD. At 1 year of follow-up, she did not demonstrate neurologic deficits and was still on both protein restriction (0.5 to 0.7 g/kg per day) and regular citrulline supplements (100 to 150 mg/kg per day). Follow-up MRI was performed 1 year later and showed diffuse cortical and subcortical gliotic and atrophic chronic changes, with particular involvement of the insula and temporal lobe. Moreover, there was an enlargement of cerebrospinal fluid ventricular and extracerebral spaces (Figure 1B). Figure 1. A, Magnetic resonance images obtained during the acute phase of the encephalopathy. A diffuse swelling of both frontal and temporal lobes, insulae (arrowheads), and pallidal nuclei (arrows) characterized by a marked hyperintensity caused by the higher amount of water in the pathologic tissues is evident. The ventricular cavities are normal. B, Magnetic resonance images obtained 1 year after the beginning of the disease. MRI shows diffuse cortical and subcortical gliotic and atrophic changes associated with cerebrospinal fluid ventricular and extracerebral space enlargement. These alterations represent the chronic evolution of the previous episodes of hyperammonemia. A B 106 ANNALS OF EMERGENCY MEDICINE 41:1 JANUARY 2003

4 DISCUSSION OTCD is the most common urea cycle disorder inherited as an X-linked dominant disease. In heterozygous female patients, the clinical manifestations are variable according to random inactivation of X chromosomes, and most of them (66%) have late-onset disease. 5 Nausea, vomiting, protein intolerance, behavior changes, lethargy, ataxia, seizures, and coma are often present and can be precipitated by catabolic stress, infections, dehydration, protein load, surgery, childbirth, and gastrointestinal bleeding. 6,7 Frequently, when patients with late-onset OTCD are hospitalized, they are thought to have encephalitis, poisoning, psychotic illness, or epilepsy. Particular attention should be paid to the history of previous episodes and to factors that might predispose to neurologic abnormalities or a family history of similar symptoms. Our patient had always spontaneously refused meat meals since childhood. However, she had recently eaten a high quantity of meat on 2 consecutive occasions immediately before her ED presentation. Neurologic symptoms had also been observed during febrile illnesses and the premenstrual period. Although the latter has been observed by other authors, 8 no definitive conclusion confirms this relation. 4 The patient s history and the recent trigger event suggested the presence of an inborn error of metabolism predisposing to hyperammonemic encephalopathy, and seizures and measurement of plasma ammonia levels were the key to early diagnosis in the emergency setting. Ammonemia results from catabolism of exogenous and endogenous amino acids, and it is detoxified to urea in the liver through a series of reactions known as the urea cycle (Figure 2). In adult patients, hyperammonemia is usually encountered in the setting of acute and chronic liver failure (Figure 3). In our patient, laboratory findings revealed normal liver function test results, and no Figure 2. Schematic representation of the major sources of ammonemia. GI, Gastrointestinal; TIPS, total implantable portocaval shunt Protein Exogenous Endogenous NH3 Liver Hepatic metabolism via the urea cycle Acute or chronic liver failure Inherited defects of urea cycle Valproic acid GI bleed Portal circulation Urea Reye s syndrome Urinary diversion Urea-splitting gram-negative bacteria NH3 Excretion via the kidneys Organic acidemia Primary carnitine deficiency Parenteral nutrition Gut Portosystemic shunt: TIPS, hepatic vascular abnormality JANUARY :1 ANNALS OF EMERGENCY MEDICINE 107

5 stigmata of chronic liver failure was observed. Valproic acid, used for the treatment of seizures, can also precipitate an episode of hyperammonemia caused by its mitochondrial toxicity, 9 but our patient had never used this drug. Other diagnoses, including total parenteral nutrition (deficit of arginine), urinary diversion (bacteriogenic ureapoiesis, delayed colonic transit), and gastrointestinal bleeding, were also excluded. Hyperammonemia in the presence of acidosis can suggest either an organic acidemia or Reye s syndrome, but our patient presented with respiratory alkalosis. Typically, Reye s syndrome affects younger patients, and laboratory findings reveal increases in serum aminotransferases and prothrombin time, hypoglycemia, metabolic acidosis, and hyperammonemia. Moreover, a prodrome of febrile illness and aspirin ingestion are often reported. Measurements of plasma and urinary amino acid and urinary orotic acid are sensitive for the diagnosis of OTCD. The differences between OTCD and other urea cycle defects are that (1) a marked increase in urinary orotic acid differentiates OTCD from carbamylphosphate synthetase deficiency and (2) patients with deficiency of arginosuccinate synthetase or arginosuccinate lyase have a marked increase in the plasma levels of citrulline or arginosuccinic acid, respectively. Allopurinol loading can also be used to detect female carri- Figure 3. The most common causes of hyperammonemia in adult patients. 16 Acute or chronic liver failure Inherited defects of urea cycle Organic acidemia Drugs Valproic acid Urinary Urinary diversion Urinary tract infections Reye s syndrome Parenteral nutrition Gastrointestinal bleeding Portosystemic shunt without chronic liver failure (hepatic vascular abnormality) Other metabolic causes Primary carnitine deficiency Fatty acid oxidation defects ers and will produce a marked increase in urinary excretion of orotidine. However, the allopurinol test often produces an ambiguous answer, and in uncertain cases, enzymatic activity on liver biopsies is recommended. 10 During the diagnostic workup, general measures can be used to rapidly reduce hyperammonemia. Hemodialysis is the treatment of choice; in this case, we performed continuous venovenous hemodiafiltration because it maintains stable blood pressure and cerebral perfusion and does not induce oscillations of intracranial pressure. 11 Parenteral protein-free nutrition is used to reduce the nitrogen load, and intravenous carbohydrates (10% or 20% glucose solution) provide an effective source of calories and prevent catabolism. Lactulose was used to reduce ammonia production in the gut. Therapy with sodium benzoate administered intravenously and L-arginine hydrogen chloride administered intravenously were used to activate ammonemia removal by using an alternative pathway. 12 During the acute episode, computed tomographic and MRI examinations demonstrated cerebral swelling and parenchymal lesions, sparing brain stem and cerebellar hemispheres, symmetrically involved both cerebral hemispheres and pallidal nuclei, with specific involvement of the insula, frontal, and temporal lobes. The symmetric cortical and subcortical damage without hemorrhage in a patient with acute onset of symptoms and without cardiac disease or drug abuse history should primarily suggest the possibility of an ischemicanoxic infarct or an acute metabolic disease. Ischemic cerebral infarct is rarely bilateral and symmetric, and in our patient, the distribution of parenchymal damage was not consistent with a specific vascular territory. Nonocclusive cerebral infarction (cerebral hypoxemia, hypotension, anemia, hypoglycemia, and metabolic enzymatic deficiencies) often involves the gray matter, particularly the basal ganglia and vascular border zones. Pure anoxia or anemic hypoxia resulting in infarction is rare if not complicated by other diseases. In our patient, brain swelling was probably caused by acute hyperammonemia. 13 Ammonium ions penetrate the brain, where they form glutamine through the reaction with glutamate catalyzed by using an astroglia-specific 108 ANNALS OF EMERGENCY MEDICINE 41:1 JANUARY 2003

6 enzyme, glutamine synthetase. The osmotic action of glutamine appears to be responsible for cerebral edema in OTCD and in other disorders associated with hyperammonemia. 14 Many authors have reported MRI findings in patients affected by OTCD during the chronic stage of the disease. 15 A common characteristic of all patients is the bilateral cerebral atrophy associated with multifocal leukoencephalopathy, which is often asymmetric. In our patient, we obtained a follow-up MRI examination 1 year after the acute encephalopathy. MRI showed diffuse cortical and subcortical gliotic and atrophic changes associated with cerebrospinal fluid ventricular and extracerebral space enlargement. Because of the lack of previous MRI, we cannot exclude that some alterations were already present at the time of acute presentation but hidden by the severe brain edema. Despite the radiologic abnormalities, she had no severe neurologic sequelae. Because the patient refused to undergo intellectual testing, more subtle deficits could not be detected. In conclusion, in patients of any age with altered consciousness, coma, or seizures with no clear anatomic or toxicologic cause, one should consider obtaining plasma ammonia levels. Hyperammonemia without evidence of hepatic failure suggests an amino acid cycle disorder of which OTCD is the most common. Early diagnosis and correct management might avoid cerebral edema and subsequent morbidity and mortality. 5. Brusilow SW, Maestri NE. Urea cycle disorders: diagnosis, pathophysiology and therapy. Adv Pediatr. 1996;43: Legras A, Labarthe F, Maillot F, et al. Late diagnosis of ornithine transcarbamylase defect in three related patients: polymorphic presentations. Crit Care Med. 2002;30: Trivedi M, Zafar S, Spalding MJ, et al. Ornithine transcarbamylase deficiency unmasked because of gastrointestinal bleeding. J Clin Gastroenterol. 2001;32: Perini M, Zarcone D, Corbetta C. Hyperammoniemic coma in an adolescent girl: an unusual case of ornithine transcarbamylase deficiency. Ital J Neurol Sci. 1993;14: Kay JD, Hilton-Jones D, Hyman N. Valproate toxicity and and ornithine transcarbamylase deficiency. Lancet. 1986;2: Hauser ER, Finelistein JE, Valle D, et al. Allopurinol-induced orotidinuria: a test for mutation at the ornithine transcarbamylase locus. N Engl J Med. 1990;322: Chen CY, Chen YC, Fang JT, et al. Continuous arteriovenous hemodiafiltration in the acute treatment of hyperammonaemia due to ornithine transcarbamylase deficiency. Ren Fail. 2000;22: Feillet F, Leonard JV. Alternative pathway therapy for urea cycle disorders. J Inherit Metab Dis. 1998;21: Kendall BE, Kingsgley DPE, Leonard JV, et al. Neuroradiological features and computed tomography of the brain in children with ornithine carbamoyl transferase deficiency. J Neurol Neurosurg Psychiatry. 1983;46: Butterworths RF. Effects of hyperammonaemia on brain function. J Inherit Metab Dis. 1998;21: Bajay SK, Kurlemann G, Schuierer G, et al. CT and MRI in a girl with late-onset ornithine transcarbamylase deficiency: case report. Neuroradiology. 1996;38: Hawkes ND, Thomas GA, Jurewicz OM, et al. Non-hepatic hyperammonaemia: an important, potentially reversible cause of encephalopathy. Postgrad Med J. 2001;77: Received for publication January 31, Revision received August 12, Accepted for publication August 21, Address for reprints: Rita Gaspari, MD, Department of Anaesthesiology and Intensive Care, Catholic University of Rome, L.go F. Vito 1, Rome, Italy; , fax ; atypga@tin.it. REFERENCES 1. Rowe PC, Newman SL, Brusilow SW. Natural history of symptomatic partial ornithine transcarbamylase deficiency. N Engl J Med. 1986;314: Finkelstein JE, Hauser ER, Leonard CO, et al. Late-onset OTC defiency in male patients. J Pediatr. 1990;117: Yorifuji T, Muroi J, Uematsu A, et al. X-inactivation pattern in the liver of a manifesting female with ornithine transcarbamylase (OTC) deficiency. Clin Genet. 1998;54: Maestri NE, Lord C, Glynn M, et al. The phenotype of ostensibly healthy women who are carriers ornithine transcarbamylase deficiency. Medicine. 1998;77: JANUARY :1 ANNALS OF EMERGENCY MEDICINE 109