NEUROLOGICAL RARITIES Pract Neurol: first published as 10.1136/practneurol-2014-000916 on 14 August 2014. Downloaded from Urea cycle disorders: a life-threatening yet treatable cause of metabolic encephalopathy in adults Nicholas F Blair,1 Philip D Cremer,1 Michel C Tchan2 1Department of Neurology, Royal ABSTRACT postoperative pain. She had no previous North Shore Hospital, Sydney, Urea cycle disorders are inborn errors of mood disorder or other psychiatric condi- Australia 2Adult Genetic Metabolic metabolism that, in rare cases, can present for tion. There was no recent alcohol intake Disorders Service, Westmead the first time in adulthood. We report a or history of substance abuse. Hospital, Sydney, Australia perplexing presentation in a woman 4 days Her initial blood results showed mul- postpartum of bizarre and out-of-character Correspondence to tiple mild abnormalities (table 1), many Dr Michel C Tchan, Department behaviour interspersed with periods of complete of which could be explained by recent of Genetic Medicine, Westmead normality. Without any focal neurological signs pregnancy; in particular, there was no Hospital, Hawkesbury Road, or abnormality on initial investigations, the renal or hepatic dysfunction, other than Westmead NSW 2145, Australia; [email protected] diagnosis became clear with the finding of a mildly elevated serum alkaline phosphat- significantly elevated plasma ammonia level, just ase, which may have been due to placen- Accepted 24 June 2014 as she began to deteriorate rapidly. She tal production. Her CT scan of head was Published Online First improved following intravenous dextrose and normal. CSF protein was mildly elevated 14 August 2014 lipid emulsion, together with sodium benzoate, at 0.58 g/L (0.15–0.45) with normal CSF arginine and a protein-restricted diet. She glucose and cell counts; Gram stain was remains well 12 months later with no permanent negative. sequelae. Whilst this is a rare presentation of an By the next morning, her clinical status uncommon disease, it is a treatable disorder and had completely normalised. Detailed its early diagnosis can prevent a fatal outcome. neurological and psychiatric assessments were normal. In the absence of any alter- CASE REPORT native explanation, a provisional diagno- A 38-year-old woman presented 5 days sis of post-partum psychosis was made, http://pn.bmj.com/ postpartum with an acute onset behav- although further investigations were ioural disturbance. She had been primi- awaited. Later that evening, her behav- gravid with an uncomplicated antenatal ioural state relapsed. She became disor- period other than breech presentation, ientated with fluctuating responses to requiring delivery by caesarean section. cognitive tasks and profound amnesia for She had vomited twice the day before, recent events. She had marked verbal and on September 29, 2021 by guest. Protected copyright. but was otherwise well. During the night motor perseveration. On asking her to her husband woke to find her confused. stand from a chair, for example, she per- She asked how he had entered the house formed this task repetitively until and repeatedly told him to get out. She stopped. The remaining examination was appeared to mistake her husband for his normal, apart from subtle asterixis. brother, and could not recall her recent Her MR scan of brain was normal. Her childbirth. She became uncharacteristic- EEG showed generalised delta slowing ally aggressive and violent, and an ambu- but no specific abnormality. Her plasma lance was called. ammonia was significantly elevated at On arrival in hospital, she was disorien- 292 μmol/L (normal 10–50). Shortly tated, markedly agitated and unable to thereafter, she markedly deteriorated, follow commands. There was no menin- requiring admission to the intensive care gism or focal neurological signs. She was unit, with progressively declining respon- afebrile and the remainder of examination siveness and prominent asterixis. To cite: Blair NF, Cremer PD, was normal. There was no significant past Arterial blood gas results demonstrated a Tchan MC. Pract Neurol medical history. She was taking no regular respiratory alkalosis with pH 7.52 (RR 2015;15:45–48. medications other than analgesics for 7.35–7.45), pCO2 29 mmHg (RR 32–45 Blair NF, et al. Pract Neurol 2015;15:45–48. doi:10.1136/practneurol-2014-000916 45 NEUROLOGICAL RARITIES Pract Neurol: first published as 10.1136/practneurol-2014-000916 on 14 August 2014. Downloaded from Table 1 Initial blood test results before confirmatory results were available. She was Normal Range in given 10% dextrose and 20% lipid emulsion (Intralipid) Test Result range pregnancy infusions intravenously. Treatment with sodium benzo- ate and arginine was also commenced and her diet was Haemoglobin (g/L) 108 ↓ 115–160 110–150 restricted to < 5g/day of protein. White cell count (×109/L) 5.0 4.0–11.0 She improved over the next 24 h and, by 48 h, was Platelet count (×109/L) 312 150–400 alert and orientated with a serum ammonia concentra- ↑ – – Serum sodium (mmol/L) 146 134 145 132 140 tion of 50 μmol/L. We continued treatment with intra- ↓ – – Serum potassium (mmol/L) 3.3 3.5 5.0 3.2 4.6 venous calories, benzoate and arginine for 3 days, ↑ – – Serum chloride (mmol/L) 108 97 107 97 109 before changing to oral arginine. Her plasma amino ↓ – – Serum bicarbonate (mmol/L) 20 24 34 18 26 acids (taken prior to treatment) revealed a low arginine Serum urea (mmol/L) 2.7 ↓ 3.1–8.1 1.0–3.8 and citrulline, and her urine testing showed elevated Serum creatinine (mmol/L) 40 ↓ 49–90 40–80 orotate, consistent with a diagnosis of ornithine trans- Anion gap (mmol/L) 22 ↑ 7–17 11–18 carbamylase (OTC) deficiency. Following discharge, Serum albumin (g/L) 32 ↓ 35–46 24–31 she needed additional oral benzoate to maintain stable Serum bilirubin (mmol/L) 3 3–18 ammonia levels. She remains well 12 months later. Serum alkaline phosphatase 161 ↑ 41–119 125–250 Sequencing of all exons, including intron/exon (U/L) boundaries, of the OTC gene showed no pathogenic Serum γ glutamyl 95–65 mutation. This occurs in approximately 30% of bio- transferase (U/L) chemically confirmed OTC deficiency cases and is – Serum alanine 40 5 40 likely due to intronic or promoter mutations. The aminotransferase (U/L) patient has one sister who was well and there was no Serum aspartate 36 12–36 aminotransferase (U/L) family history of unexpected male deaths. A protein 1 References ranges for pregnancy are given for results that were outside of loading challenge showed that her sister was the routine reference ranges. unaffected. mmHg) and HCO3 24 mmol/L (24–32 mmHg). Her DISCUSSION repeat ammonium level was 382 μmol/L. A urea cycle Urea cycle disorders are inborn errors of metabolism disorder was considered likely and treatment was started where there is a genetic defect in one of the enzymes http://pn.bmj.com/ on September 29, 2021 by guest. Protected copyright. Figure 1 The urea cycle produces urea from the nitrogenous waste products of protein metabolism. The six enzymes of the pathway are numbered 1–6, with their associated gene in brackets. 46 Blair NF, et al. Pract Neurol 2015;15:45–48. doi:10.1136/practneurol-2014-000916 NEUROLOGICAL RARITIES Pract Neurol: first published as 10.1136/practneurol-2014-000916 on 14 August 2014. Downloaded from Table 2 Urea cycle disorders and expected investigation results Urea cycle disorder Gene Inheritance Plasma amino acids Urine organic acids Carbamoylphosphate synthetase I deficiency CPS1 Autosomal recessive ↓ Arginine ↓/Normal urinary orotic acid ↓ Citrulline Ornithine transcarbamylase deficiency OTC X linked ↓ Arginine ↑ Urinary orotic acid ↓ Citrulline Argininosuccinic acid synthase deficiency or ASS1 Autosomal recessive ↑ Arginine citrullineamia type I ↑ Citrulline Argininosuccinase acid lyase deficiency or ASL Autosomal recessive ↑ Arginine argininosucciniaciduria ↑ Citrulline Arginase deficiency ARG1 Autosomal recessive ↑↑ Arginine N-acetylglutamate synthase deficiency NAGS Autosomal recessive ↓ Arginine ↓/Normal urinary orotic acid ↓ Citrulline Plasma amino acid and urinary organic acid levels indicated as being low (↓) or high (↑) relative to the reference range. of the urea cycle, which is responsible for the metab- L-asparaginase may also precipitate a hyperammonae- olism of nitrogen waste from the breakdown of pro- mic crisis. As in this case, women with OTC deficiency teins (figure 1). In doing so, the cycle produces urea are at risk of decompensation during the post-partum from ammonia. The urea cycle is also the only period,7 due to the increased catabolic protein load fol- endogenous source of the amino acids arginine, orni- lowing involution of the uterus. thine and citrulline. In humans, this biochemical In an adult presenting with acute encephalopathy, pathway occurs primarily in the liver, but to a lesser there may be no other suggestion in the clinical assess- extent in the kidney. The incidence of urea cycle dis- ment that the condition might be related to a genetic orders is about 1:35 000 live births.2 metabolic disorder, highlighting the importance of Classically, urea cycle disorders present in the neo- plasma ammonia testing, even when there is no evi- natal period with vomiting, anorexia and lethargy that dence of hepatic or renal dysfunction. In adults, a rapidly progresses to encephalopathy, coma and death plasma ammonia >80 μmol/L, in the absence of renal if untreated. Plasma ammonia of greater than 1000 or hepatic dysfunction, should raise suspicion of a μmol/L may be found in these circumstances and urea cycle defect. Plasma amino acid and urine results from a severe deficiency or total absence of any organic acid tests are used to distinguish the different of the first four enzymes in the urea cycle (CPS1, OTC, urea cycle disorders (table 2). ASS, ASL) or the cofactor NAGS. In cases where there OTC deficiency is the most common form of urea is only a partial deficiency of these enzymes, or in argi- cycle disorder (55%).3 Unlike other urea cycle disor- nase deficiency, the symptoms may be mild or not ders, which are recessive, its inheritance is X linked.