Journal of Perinatology (2011) 31, 682–684 r 2011 Nature America, Inc. All rights reserved. 0743-8346/11 www.nature.com/jp PERINATAL/NEONATAL CASE PRESENTATION Hyperammonemic coma in an ornithine transcarbamylase mutation carrier following antepartum corticosteroids

S Lipskind1, S Loanzon2, E Simi3 and DW Ouyang3 1Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Evanston, IL, USA; 2Department of Obstetrics and Gynecology, Saint Francis Hospital, Evanston, IL, USA and 3Department of Obstetrics and Gynecology, NorthShore University HealthSystem, University of Chicago Pritzker School of Medicine, Evanston, IL, USA

analysis confirmed that he was hemizygous for the OTC c.482A>G Women who are carriers of the ornithine transcarbamylase (OTC) mutation (p.N161S) mutation. She had one brother, two sisters and one are at risk for developing hyperammonemia during the postpartum period and nephew who died in the neonatal period, but their mutation carrier at times of metabolic stress. We present a unique case of hyperammonemic statuses could not be verified. The patient had immigrated to the coma occurring in an OTC mutation carrier during the antepartum period. United States from India and was a vegetarian for cultural reasons Multiple factors, including the administration of antenatal corticosteroids, likely with no other history of dietary restrictions, developmental delay or precipitated this critical condition. Clinicians should be aware of this life- symptomatic episodes of hyperammonemia. During this pregnancy, threatening clinical presentation and be prepared to identify, treat, and prevent she had undergone chorionic villus sampling with molecular hyperammonemia in affected individuals. testing that demonstrated an unaffected male fetus. Journal of Perinatology (2011) 31, 682–684; doi:10.1038/jp.2011.23 At the outside hospital, the patient was suspected to be in Keywords: pregnancy; hyperammonemic coma; ornithine transcarba- preterm labor and was treated with terbutaline and betamethasone. mylase deficiency; corticosteroids; haloperidol; antenatal Over 4 days, her mental status progressively deteriorated. She was given intravenous haloperidol for agitation and subsequently became dystonic and unresponsive. The patient was transferred to Introduction our hospital in critical condition. Upon arrival, she was Inborn errors of metabolism are a rare cause of hyperammonemic unresponsive with agonal breathing and a Glasgow Coma Scale coma. Ornithine transcarbamylase (OTC) is an enzyme of the urea score of 3. She was intubated and transferred to the intensive care cycle, which converts the toxic ammonia molecule to non-toxic, unit. External monitoring showed uterine contractions every 4 to water-soluble urea.1,2 OTC deficiency is an X-linked disorder 5 min and minimal fetal heart rate variability. Her labor was that results in hyperammonemia and has been associated with augmented, and she rapidly delivered a 2240 g infant with APGAR cases of postpartum encephalopathy in carriers.1,3 Here we present scores of 7 at 1 min and 8 at 5 min. a unique case of hyperammonemic coma occurring during the Initial investigations sought to exclude an acute cerebrovascular antepartum period in an OTC mutation carrier. event as the cause of her coma, but both head computerized tomography and magnetic resonance imaging were normal. Her urine toxicology screen was negative. When the patient’s ammonia À1 Case level of 213 mmol l (7 to 35) returned, hyperammonemia due to her OTC carrier status was strongly suspected as the cause. A 26-year-old gravida 3 para 1010 presented to an outside hospital Confirmatory plasma and urine amino-acid levels were sent for at 33 weeks gestation with complaints of fever, nausea, vomiting analysis, demonstrating a plasma glutamine level of and contractions. She was a known heterozygous carrier for a 1118 mmol lÀ1 (205 to 756) and a urine orotic acid level of familial mutation of the OTC gene. She had one prior first 5.6 mmol molÀ1 creatinine (0.4 to 1.2). Her initial serum glucose trimester miscarriage and one term live-born male infant who died was 63 mg dlÀ1. Importantly, no underlying infectious source 7 days after birth due to complications from OTC deficiency. DNA could be found. Blood, urine, sputum and cerebrospinal fluid Correspondence: Dr DW Ouyang, Division of Maternal-Fetal Medicine, NorthShore University cultures were negative; PCR for influenza A and B was negative; HealthSystem, University of Chicago Pritzker School of Medicine, 2650 Ridge Avenue, and placental pathology revealed no evidence of chorioamnionitis. Evanston, IL 60201, USA. E-mail: [email protected] Treatment of our patient’s hyperammonemia began with Received 23 August 2010; revised 7 January 2011; accepted 10 January 2011 dextrose-containing IV fluids and lactulose, but her ammonia Hyperammonemic coma in an OTC mutation carrier S Lipskind et al 683 levels continued to rise. Continuous venovenous hemofiltration was increased nitrogen utilization by the uterus, placenta and fetus, initiated along with intravenous sodium benzoate, an ammonia and detoxification of maternal nitrogen by the fetus.1,3 scavenger. The patient was started on protein-free total parenteral Multiple factors, including infection, steroids and haloperidol, nutrition to meet caloric needs and to prevent endogenous protein may have contributed to hyperammonemia in our patient. Several catabolism. Within 36 h of treatment, her ammonia levels case reports have implicated infections as catalysts for decreased substantially (range 56 to 125 mmol lÀ1). On hospital hyperammonemic episodes in otherwise asymptomatic individuals. day 4, she became arousable and was able to follow simple Gastroenteritis and intra-amniotic infection were two possible commands. She was transitioned to oral sodium phenylbutyrate triggers suggested by our patient’s clinical presentation, but no and placed on a protein-restricted diet. Her mental status steadily infectious source could be identified. Decreased oral intake and improved and she was discharged home on hospital day 18. inadequate intravenous replacement at the onset of her illness may Six weeks following her discharge, the patient was mentally and have increased her endogenous protein catabolism, further neurologically intact and her ammonia levels remained normal. contributing to hyperammonemia in this setting. We further hypothesize that the administration of betamethasone for fetal lung maturity may have induced protein catabolism, resulting in endogenous nitrogen release and Comment worsening hyperammonemia. There have been two reports of non- The urea cycle is a series of enzymatic reactions responsible for pregnant OTC mutation carriers who developed hyperammonemic detoxification of nitrogenous waste derived from protein crises following steroid administration. One was a 48-year-old catabolism. Defects in any portion of the urea cycle can result in female who received intravenous steroids for a severe asthma hyperammonemia and its clinical manifestations. OTC deficiency attack. She was incorrectly diagnosed with ‘steroid psychosis’ and is the most common of the urea cycle disorders with an estimated lapsed into coma before metabolic encephalopathy was suspected, incidence of approximately one in 14 000.4 The majority of women and her serum ammonia level was found to be markedly elevated.2 heterozygous for OTC mutations remain asymptomatic; however, Another was a 36-year-old male who was prescribed oral 10 to 15% of carriers will become symptomatic during their prednisone for an autoimmune disorder and subsequently lifetime. This phenotypic variation is thought to occur due to developed hyperammonemic encephalopathy.8 No cases have been random inactivation of X chromosomes bearing the mutant allele previously published describing hyperammonemia following the (lyonization), leading to differing levels of OTC activity among administration of antenatal corticosteroids. carriers and their tissues.1,4,5 Affected individuals often exhibit In addition, our patient’s initial mental status changes were symptoms ranging from dietary protein aversion to profound treated with haloperidol. Certain medications, including valproic neuropsychiatric manifestations, such as ataxia, seizures and acid and haloperidol, have been known to cause hyperammonemia hyperammonemic encephalopathy.5,6 in patients with urea cycle disorders. Valproate is thought to Various factors can trigger hyperammonemic crises in precipitate hyperammonemia by exerting direct toxic effects on individuals with urea cycle disorders, either by increasing the need hepatic mitochondria and inhibiting the urea cycle.6 Haloperidol is for nitrogen clearance or by impairing urea cycle enzyme activity thought to exert similar inhibitory effects on urea cycle enzyme in the liver. These stressors include high-protein intake either from activity and was reported to trigger hyperammonemia in a patient a dietary load or total parenteral nutrition (TPN); increased with argininosuccinate synthase deficiency.4 Thus, haloperidol may endogenous protein catabolism due to reduced nutritional intake, have exacerbated the hyperammonemia in our patient by infection, trauma or steroid administration; and hepatic toxicity impairing her already overwhelmed OTC activity. from chemotherapy and other medications, such as valproic acid The diagnosis of a urea cycle defect should be considered in and haloperidol.2,4,5,6 women with a history of protein aversion, episodic behavioral A number of reports have described hyperammonemic changes or psychosis and a strong personal or family history of encephalopathy in OTC mutation carriers in the immediate neonatal losses. In addition, clinicians must recognize that OTC postpartum period, when maternal nitrogen burden is increased by mutation carriers remain at risk for developing symptomatic collagen breakdown during uterine involution.1,3 In contrast, there hyperammonemia. Although our patient was a known carrier, her are few reports of women with urea cycle enzyme deficiencies neuropsychiatric symptoms were not recognized as manifestations developing hyperammonemic coma during pregnancy. In the only of hyperammonemia, which delayed appropriate treatment and reported death associated with OTC deficiency during pregnancy, a resulted in administration of medications that may have previously asymptomatic woman developed fatal hyperammonemic precipitated or exacerbated her coma. Unexplained coma in this encephalopathy 2 days after receiving amino-acid-containing TPN setting should prompt a metabolic work-up with measurement of at 14 weeks gestation for hyperemesis gravidarum.7 Pregnancy is serum ammonia levels, which are typically >150 mmol lÀ1 during thought to confer protection against hyperammonemia due to an acute episode.4

Journal of Perinatology Hyperammonemic coma in an OTC mutation carrier S Lipskind et al 684

For patients presenting with acute hyperammonemic crisis, OTC mutations, including high-risk obstetric care, medical hemodialysis is the treatment of choice for rapid reduction of genetics, genetic counseling and dietary consultations. ammonia levels. Lactulose may be given to decrease the production of ammonia by the gastrointestinal tract. The ammonia scavengers, sodium phenylbutyrate, sodium benzoate and Conflict of interest L-arginine, may be employed to stimulate further removal by The authors declare no conflict of interest. alternate pathways.1,2,5 Further management strategies include administration of intravenous fluids containing dextrose to decrease catabolism, serial serum ammonium evaluations and References proactive use of ammonia scavengers. Complete avoidance of 1 Peterson DE. Acute postpartum mental status change and coma caused by protein should not exceed 24 to 48 h, after which depletion of previously undiagnosed ornithine transcarbamylase deficiency. Obstet Gynecol 2003; essential amino acids results in a catabolic state and endogenous 102: 1212–1215. nitrogen production.3 2 Summar ML, Barr F, Dawling S, Smith W, Lee B, Singh RH et al. Unmasked adult-onset urea cycle disorders in the critical care setting. Crit Care Clin 2005; 21: S1–S8. Although previous reports have described postpartum 3 Cordero DR, Baker J, Dorinzi D, Toffle R. Ornithine transcarbamylase deficiency in hyperammonemic coma in women heterozygous for OTC pregnancy. J Inherit Metab Dis 2005; 28(2): 237–240. mutations, we report the first case of a carrier who presented with 4 Smith W, Kishnani PS, Lee B, Singh RH, Rhead WJ, King LS et al. Urea cycle disorders: coma in the antepartum period that was not precipitated by an clinical presentation outside the newborn period. Crit Care Clin 2005; 21: S9–17. exogenous protein load. Physicians should exercise caution with 5 Gaspari R, Arcangeli A, Mensi S, Wismayer DS, Tartaglione T, Antuzzi D et al. Late-onset presentation of ornithine transcarbamylase deficiency in a young woman with the use of corticosteroids and TPN in known OTC mutation carriers hyperammonemic coma. Ann Emerg Med 2003; 41: 104–109. and consider close monitoring of ammonia levels following their 6 Gordon N. Ornithine transcarbamylase deficiency: a urea cycle defect. Eur J Paediatr administration, as well as in the immediate postpartum period. Neurol 2003; 7: 115–121. Prompt diagnosis and treatment of infection, including routine 7 Schimanski U, Krieger D, Horn M, Stremmel W, Wermuth B, Theilmann L. A novel tow- screening for asymptomatic bacteriuria, may prevent significant nucleotide deletion in the ornithine transcarbamylase gene causing fatal hyper- hyperammonemia. Timely reduction of hyperammonemia is ammonemia in early pregnancy. Hepatology 1996; 24(6): 1413–1415. 8 Atiq M, Holt A, Safdar K, Weber F, Ravinuthala R, Jonas M et al. Adult onset urea cycle crucial to averting long-term neurologic morbidity and mortality. disorder in a patient with presumed hepatic encephalopathy. J Clin Gastroenterol 2008; We support a multidisciplinary approach in managing women with 42: 213–214.

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