702 Case reports / Journal of Clinical Neuroscience 13 (2006) 702–706 Fig. 2. Axial T2-weighted ﬂuid attenuated inversion recovery images of the brain at the level of the midbrain (a), hypothalamus (b), and thalamus (c). Hyperintense signal change is indicated by white arrows: in (a), the right mesial temporal lobe; in (b), the posterior limb of the right internal capsule; in (c), the right lateral geniculate body. defect could increase the danger of driving, the risk of falls, and occupational hazards. Therefore, it may be recommended that, in all patients with image ﬁndings of AChA territory infarction, a formal visual ﬁeld assessment is necessary. References 1. Helgason C, Caplan LR, Goodwin J, Hedges T. Anterior choroidal artery-territory infarction. Report of cases and review. Arch Neurol 1986;43:681–6. 2. Decroix JP, Graveleau PH, Masson M, Cambier J. Infarction in the territory of the anterior choroidal artery. A clinical and computerized tomographic study of 16 cases. Brain 1986;109: 1071–85. 3. Han SW, Sohn YH, Lee PH, Suh BC, Choi IS. Pure homonymous hemianopia due to anterior choroidal artery territory infarction. Eur Neurol 2000;43:35–8. 4. Rhoton A, Fujii K, Fradd B. Microsurgical anatomy of the anterior choroidal artery. Surg Neurol 1979;12:171–87. 5. Paroni-Sterbini GLP, Agatiello LM, Stocchi A, Solivetti FM. CT of ischemic infarctions in the territory of the anterior choroidal artery: a review of 28 cases. AJNR Am J Neuroradial 1987;8:229–32. 6. Hupperts RM, Lodder J, Heuts-van Raak EP, Kessels F. Infarcts in the anterior choroidal artery territory. Anatomical distribution, clinical syndromes, presumed pathogenesis and early outcome. Brain 1994;117:825–34. 7. Frisen L. Quadruple sectoranopia and sectorial optic atrophy: a syndrome of the distal anterior choroidal artery. J Neurol Neurosurg Psychiatry 1979;42:590–4. 8. Luco C, Hoppe A, Schweiter M, Vicuna X, Fantin A. Visual ﬁeld defects in vascular lesions of the lateral geniculate body. J Neurol Neurosurg Psychiatry 1992;55:12–5. 9. Neau JP, Bogousslavsky J. The syndrome of posterior choroidal artery territory infarction. Ann Neurol 1996;39:779–88. 10. Gunderson CH, Hoyt WF. Geniculate hemianopsia: incongruous homonymous ﬁeld defect in two patients with partial lesion of the lateral geniculate nucleus. J Neurol Neurosurg Psychiatry 1971;34:1–6. 11. Fisher M, Lingley JF, Blumenfeld A, Felice K. Anterior choroidal artery territory infarction and small-vessel disease (letter; comment). Stroke 1989;20:1591–2. doi:10.1016/j.jocn.2005.07.015 Carbamyl phosphate synthase deﬁciency: Diagnosed during pregnancy in a 41-year-old G. Eather a, D. Coman b b,c , C. Lander a, J. McGill a Department of Neurology, The Royal Brisbane Hospital Department of Metabolic Medicine, The Royal Children’s Hospital, Herston Road, Herston, Brisbane 4029, Australia c Department of Paediatrics and Child Health, University of Queensland Received 19 January 2005; accepted 13 July 2005 * b,c,* Corresponding author. Tel.: +61 7 3636 8111; fax: +61 7 3636 1860. E-mail address: jim_mcgill@health.qld.gov.au (J. McGill). Case reports / Journal of Clinical Neuroscience 13 (2006) 702–706 703 Abstract Carbamyl phosphate synthase deﬁciency (CPS) is a rare urea cycle defect. We present a case of a 41-year-old woman diagnosed with CPS deﬁciency during pregnancy. She is the oldest CPS-deﬁcient patient, at diagnosis, reported to date and the ﬁrst to be diagnosed during pregnancy. This case highlights the need for consideration of inborn errors of metabolism in adults presenting with unusual neurological and psychiatric conditions. Crown Copyright 2006 Published by Elsevier Ltd. All rights reserved. Keywords: Urea cycle; Carbamyl phosphate synthase deﬁciency; Pregnancy; Hyperammonaemia 1. Introduction Carbamyl phosphate synthetase (CPS) deﬁciency is a rare enzyme deﬁciency of the ﬁrst step in the urea cycle (Fig. 1).1,2 Its incidence has been estimated to be 1/800 000 to 1/100 000.3,4 Ammonia and bicarbonate molecules are incorporated into carbamyl phosphate by CPS.4 The CPSI gene located on chromosome 2q35 encodes CPS.5 CPS deﬁciency is inherited in an autosomal recessive fashion. Neonatal onset and late onset clinical phenotypes of CPS deﬁciency have been described. The neonatal form is characterised by severe hyperammonemic encephalopathy, with altered consciousness and sometimes seizures.3,4 The clinical presentation of hyperammonaemia is highly variable. Neonates usually have severe symptoms with vomiting, lethargy and coma.6 Early and chronic features of hyperammonaemia such as anorexia, headaches, learning diﬃculties, irritability and cylical vomiting are often considered as non-speciﬁc and a diagnosis is easily overlooked.6,7 Partial enzyme deﬁciencies can manifest with a late onset form and have a variable presentation.3 A history of a self-imposed low protein diet is indicative of a protein metabolism disorder, although this diagnostic clue may be gained only in retrospect. We present a 41-year-old woman who was diagnosed with CPS deﬁciency after developing an hyperammonaemic coma during pregnancy. She is the oldest reported Fig. 1. Ammonia arises from amino acid metabolism and its detoxiﬁcation to urea occurs mainly in the liver. Carbamylphosphate synthase 1 (CPS1) catalyses the condensation of ammonia and bicarbonate. CPS1 is activated by N-acetylgutamate, which is created by N-acetylgutamate synthase (NAGS). Carbamyl phosphate is bound to ornithine by ornithine transcarbamylase (OTC) to create citrulline, which is transported out of the mitochondria and bound to aspartate by argininosuccinate synthase (ASS) forming argininosuccinate. Argininosuccinate is split into arginine and fumerate by argininosuccinate lyase (ASL). Arginine is then hydrolysed into ornithine and urea by arginase. 704 Case reports / Journal of Clinical Neuroscience 13 (2006) 702–706 Fig. 2. T2-weighted axial MRI images demonstrating symmetrical areas of increased signal in the (a) deep white matter of the cerebellar hemispheres (dentate nuclei) and (b) basal ganglia (globus pallidi). CPS-deﬁcient patient at diagnosis and the ﬁrst to be diagnosed during pregnancy. 1.1. Case report This 41-year-old woman was referred to the neurology department 4 years ago with a history of recurrent episodes of global headache, confusion, reduced level of consciousness, ataxia and slurred speech. These episodes persisted for several days, with clinical resolution after intravenous ﬂuids were administrated. The patient had a history of mild learning diﬃculties and ‘strange behaviour’ since childhood, and had self-selected a low protein diet. Magnetic resonance imaging (MRI) of the brain identiﬁed symmetrical areas of increased signal in the cerebellum and basal ganglia on T2-weighted images (Fig. 2) and an EEG showed diﬀuse slow wave changes. The working diagnosis had been basilar migraine syndrome with ischaemia and associated epileptiform activity, although this did not fully explain the clinical or imaging abnormalities. A formal psychiatric diagnosis was considered given the unusual constellation of presenting features, the patient’s unusual aﬀect and the onset of symptoms coinciding with the death of her father. The patient had two sisters who were both alive and well. Her mother had nine pregnancies, three of which spontaneously aborted between 10 and 12 weeks, and three of which were stillbirths. There were no live male births. The patient’s father had died from a myocardial infarction. When 17 weeks pregnant, our patient presented to the local hospital with a severe episode of confusion, headache, drowsiness, ataxia and slurred speech. Over the next 4 days her conscious state deteriorated and she required intubation and ventilation for 2 days. Immediately before the institution of mechanical ventilation, the patient developed abnormal facial and limb twitching along with global hyperreﬂexia. A provisional diagnosis of status epilepticus was considered. Her conscious state continued to ﬂuctuate after discharge from ICU, prompting consideration of a metabolic diagnosis. A repeat MRI identiﬁed similar changes to those noted 4 years earlier. Mitochondrial point mutations, spinocerebellar ataxia and Friedrich’s ataxia DNA analysis, vitamin E levels, very long chain fatty acids, lysosomal enzymes, urine and red cell porphyrin levels were all within normal limits. A urea cycle defect was ﬁrst suspected when a plasma amino acid proﬁle, performed because of nutritional concerns, revealed elevated glutamine (800 lmol/L; normal, 420–700) and low citrulline (12 lmol/L; normal, 20–60). Arginine and ornithine levels were within the normal ranges. Plasma ammonium was 520 lmol/L (normal, <50). The absence of orotic acid in the urine suggested a diagnosis of CPS deﬁciency or N-acetyl glutamate synthase deﬁciency (NAGS) (Fig. 1). CPS was eventually conﬁrmed on liver biopsy with CPS activity being approximately 20% of the lower limit of normal. Sodium benzoate (250 mg/kg/day) and arginine hydrochloride (210 mg/kg/day) intravenous infusions were commenced prompting a rapid improvement in her clinical Case reports / Journal of Clinical Neuroscience 13 (2006) 702–706 state, mirrored by her ammonium falling to normal levels. After a review of the literature, oral sodium phenylbutyrate (250 mg/kg/day) was used instead of sodium benzoate because of the lack of published information regarding its safety in pregnancy. Citrulline (210 mg/kg/day), protein restriction (1 gm/kg/day) and a high calorie diet were also utilised. Ammonium levels were easily maintained in the normal range (<50 mmol/L). Premature labour started spontaneously at 22 weeks and a live male infant was delivered. He survived 48 hours, dying of severe hyaline membrane disease and pulmonary hypoplasia. Maternal pre- and post-puerperal management consisted of intravenous 10% dextrose, sodium benzoate and arginine hydrochloride infusions without any metabolic decompensation. The patient remains well and neurologically normal with the current management regimen of oral sodium benzoate (250 mg/kg/day), citrulline (210 mg/kg/day) and modest protein restriction of 1 gm/kg/day. 2. Discussion There are infrequent reports of late onset CPS deﬁciency in the literature. CPS deﬁciency was found to cause an episode of hyperammonaemic coma and death in a 26-yearold woman in the postpartum period.8 A 16-year-old man was subsequently found to have CPS deﬁciency when he developed an hyperammonaemic coma in the context of an intercurrent viral illness.9 CPS deﬁciency was also diagnosed in a 33-year-old woman who had experienced mild intermittent symptoms throughout life but never experienced severe encephalopathy.10 These mild intermittent features consisted of nausea, vomiting, gait ataxia, and somnolence, some of which lasted for several days and were triggered by eating large quantities of meat10 and are almost identical to the symptoms experienced by our patient. A 32-year-old woman was diagnosed with mild CPS deﬁciency when she developed an hyperammonaemic coma after starting sodium valproate.11 Neuropsychiatric symptoms are a component of almost all inborn errors of metabolism that aﬀect the central nervous system.12 Adults with late onset urea cycle defects are often misdiagnosed with psychiatric conditions, such as chronic behavioural problems, psychosis, lethargy or recurrent encephalopathy.13 The suspicion of an underlying psychiatric or behavioural disorder was entertained on several occasions in the initial assessments of our patient. Psychiatric manifestations are described in ornithine transcarbamylase deﬁciency (OTC),14,15 N-acetylglutamate synthetase (NAGS) deﬁciency,6 argininosuccinic aciduria16 and CPS deﬁciency. An 18-year-old patient, who had a long preceding history of intermittent psychotic episodes with nausea and vomiting coinciding with menstrual periods, was diagnosed with CPS deﬁciency after developing a hyperammonaemic coma.17 The immediate family of our patient noted a marked improvement in her behaviour and social interactions after diagnosis and treatment. 705 The MRI pattern observed in our patient, with involvement of the basal ganglia and cerebellum, is often seen in cases of metabolic encephalopathy. Metabolic stroke-like events have been described in an increasing number of inherited metabolic disorders, with the brain imaging changes often symmetrical and disrespecting vascular boundaries. These metabolic stroke-like events have been reported in the organic acidurias (e.g. methylmalonic aciduria and propionic aciduria), the mitochondriopathies (e.g. MELAS syndrome, Leigh disease), the lysosomal storage disorders (e.g. Fabry disease and cystinosis), the urea cycle defects (e.g. OTC deﬁciency and CPS deﬁciency), and other metabolic disorders (e.g. homocystinuria, the congenital disorders of glycosylation, and sulphite oxidase deﬁciency).18 CPS deﬁciency has been reported to cause stroke-like episodes with hemiparesis in an 18-month-old child.18 The pathophysiological mechanisms that cause cerebral infarction in the urea cycle defects are unclear. Elevated ammonia, lack of arginine, disturbed energy metabolism, neurotransmitter imbalance, astrocyte swelling, alterations in cerebral blood ﬂow, elevated intracranial blood pressure, glutamine accumulation, altered vascular endothelial wall integrity, and platelet dysfunction have all been implicated in contributing to the development of a metabolic stroke.18,19 In retrospect, the MRI changes depicted in our patient were the result of injury caused by recurrent and untreated metabolic decompensation. An increasing number of women with inborn errors of metabolism are reaching child-bearing age, with disorders such as the urea cycle defects creating an increased risk of metabolic decompensation.20 Such decompensation can occur at any stage of the pregnancy. The catabolic stress imposed by pregnancy contributed to our patient’s decompensation. While only a small number of inborn errors of metabolism have been shown to be teratogenic, consideration must be given to the foetal implications of their treatment regimens.20 There is limited information on the safety of the ammonium-scavenging drugs in pregnancy. Sodium phenylbutyrate (PB) treatment can, in theory, mimic maternal phenylketonuria, because phenylalanine is a metabolite of PB.21 Animal models suggest that phenylalanine and its metabolites are teratogenic.22 We were aware of three OTC pregnancies in which PB had been used without any foetal detriment.21 Our patient was commenced on PB well into the second trimester. The eﬀect of PB on gene silencing23 and cell diﬀerentiation24 was a concern for its use during pregnancy; these concerns would have been much higher if used during the ﬁrst trimester. At the time we were unaware of any literature reports regarding the use of sodium benzoate in pregnancy. Inborn errors of metabolism, including the urea cycle defects should be considered as a possible diagnosis in any patient with unexplained neurologic disorders, even in adulthood, especially when associated with altered level of consciousness, behavioural changes, vomiting, anorexia, or a self-imposed protein-restricted diet.15 This case highlights 706 Case reports / Journal of Clinical Neuroscience 13 (2006) 702–706 the diﬃculties often encountered in diagnosing the late-onset urea cycle defects. References 1. Brusilow SW, Horwich AL. Urea Cycle enzymes. Eighth ed. In: Scriver CR, Beaudet AL, Sly WS, et al., editors. The Metabolic and Molecular Bases of Inherited Disease, Vol. 2. New York: McGrawHill; 2001. p. 1909–63. 2. Online Mendelian Inheritance in Man (Online). 2003 Apr 12 (cited 2004 Nov 18); Available from: URL: http://www.ncbi.nlm.nih.gov/ entrez/query.fcgi?db=OMIM. 3. Hoshide R, Matsuura T, Haraguchi Y, et al. Carbamyl phosphate synthetase 1 deﬁciency: One base substitution in an exon of the CPS1 gene causes a 9-basepair deletion due to aberrant splicing. J Clin Invest 1993;91:1884–7. 4. Takeoka M, Soman TB, Shih VE, et al. Carbamyl phosphate synthetase 1 deﬁciency: A destructive encephalopathy. Pediatr Neurol 2001;24:193–9. 5. Summar ML, Hall LD, Hutcheson HB, et al. Characterization of genomic structure and polymorphisms in the human carbamyl phosphate synthetase 1 gene. Gene 2003;311:51–7. 6. Belanger-Quintana A, Martinez-Pardo M, Wermuth B, et al. Hyperammonaemia as a cause of psychosis in an adolescent. Eur J Pediatr 2003;162:773–5. 7. Summar M, Tuchman M. Proceedings of a consensus conference for the management of patients with urea cycle disorders. J Pediatr 2001;138:S6–S10. 8. Wong LC, Craigen WJ, O’Brien WE. Postpartum coma and death due to carbamyl-phosphate synthetase 1 deﬁciency. Ann Intern Med 1994;120:216–7. 9. Lo WD, Sloan HR, Sotos JF, et al. Late clinical presentation of partial carbamyl phosphate synthetase 1 deﬁciency. Am J Dis Child 1993;147:267–9. 10. Call G, Seay AR, Sherry R, et al. Clinical features of carbamyl phosphate synthetase-1 deﬁciency in an adult. Ann Neurol 1984;16: 90–3. doi:10.1016/j.jocn.2005.07.014 11. Verbiest HBC, Straver JS, Colombo JP, et al. Carbamyl phosphate synthetase-1 deﬁciency discovered after valproic acid-induced coma. Acta Neurol Scand 1992;86:275–9. 12. Estrov Y, Scaglia F, Bodamer OAF. Psychiatric symptoms of inherited metabolic disease. J Inher Metab Dis 2000;23:2–6. 13. Golomb M. Psychiatric symptoms in metabolic and other genetic disorders: Is our ‘‘organic’’ workup complete? Harvard Rev Psychiatry 2002;10:242–8. 14. Largilliere C. Psychiatric manifestations in girl with ornithine transcarbamylase deﬁciency. Lancet 1995;345:1113. 15. Legras A, Labarthe F, Maillot F, et al. Late diagnosis of ornithine transcarbamylase defect in three related female patients: Polymorphic presentations. Crit Care Med 2002;30:241–4. 16. Odent S, Roussey M, Journel H, et al. Argininosuccinic aciduria. A new case revealed by psychiatric disorders. J Genet Hum 1989;37:39–42. 17. Wakutani Y, Nakayasu H, Takeshima T, et al. A case of late-onset carbamyl phosphate synthetase 1 deﬁciency, presenting periodic psychotic episodes coinciding with menstrual periods. Rinsho Shinkeigaku 2001;41:780–5. 18. Sperl W, Felber S, Skadal D, et al. Metabolic stroke in carbamyl phosphate synthetase deﬁciency. Neuropediatrics 1997;28:229–34. 19. Christodoulou J, Quareshi A, McInnes R, et al. Ornithine transcarbamylase deﬁciency presenting with stroke like episodes. J Pediatr 1993;122:423–5. 20. Walter J. Inborn errors of metabolism and pregnancy. J Inherit Metab Dis 2000;23:229–36. 21. Batshaw ML, MacArthur RB, Tuchman M. Alternative pathway therapy for urea cycle disorders: Twenty years later. J Pediatr 2001;38: S46–54. 22. Denno KM, Sadler TW. Phenylalanine and its metabolites induce embryopathy’s in mouse embryos in culture. Teratology 1990;42: 565–70. 23. Lea MA, Randolph VM, Hodge SK. Induction of histone acetylation and growth regulation in erythroleukemia cells by 4-phenylbutyrate and structural analogs. Anticancer Res 1999;62:221–7. 24. Thibault A, Cooper MR, Figg WD, et al. A phase 1 and pharmacokinetic study of intravenous phenylacetate in patients with cancer. Cancer Res 1994;310:1630.