Late-onset presentation of ornithine transcarbamylase deficiency in a young woman with hyperammonemic coma☆

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/mm3, and platelet count of 302,000/mm3. 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 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).

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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.

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).

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).

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Figure 2. Schematic representation of the major sources of ammonemia. GI, Gastrointestinal; TIPS, total implantable portocaval shunt

In adult patients, hyperammonemia is usually encountered in the setting of acute and chronic liver failure (Figure 3).

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Figure 3. The most common causes of hyperammonemia in adult patients.16

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 carriers 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 ischemic-anoxic 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 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.