Original article Wbelb s. Speri' be$ D. n l a d a l 1 B. w e r m u t h 3 Metabolic Stroke in Carbarnyl Phosphate Synthetase Deficiency '~epartmentof Pediatrics. '~epartment of Magnetic Resonance. University of Innsbruck. Austria, 3~epartmentof Clinical Chemistry, University of Berne. Switzerland Abstract Stroke-like episodes w i t h hemiparesis have been described i n children w i t h different inherlted metabolic diseases. We report the novel observation of a severe stroke as the presenting sign i n an 18-month-old girl with carbamyi phosphate synthetase (CPS) deficiency. MRI revealed infarction within the territory of the right middle cerebral artery. Localized 'H-NMR spectroscopy showed elevation of glutamine {at 2.0-2.5 and 3.7 pprn) and lactate within the region of infarction. CPS activity in the liver was reduced (2.5 mUI m g protein, n = 12-35). On a protein-restricted diet including arginine supplementation, the child has developed well with moderate mental retardation: no neurologic relapses have been observed over a period of 4 years. Abbreviations: Table 1 Inherited metabolic diseases with stroke: carbamyl phosphate synthetase ornithne transcarbamylase MFU: magnetic resonance imaging 'H-NMR: proton nuclear magnetic resonance MELAS: mitochondria1 encephalopathy, lactic acidosis, strokelike episodes HSE: herpes simplex encephalitis NAA: n-acetyl aspartate CDG: carbohydrate-deficient glycoprotein A. Organic aciduriar Homocystinuria (4. R), propionic-(10). methylmalonic-(40) isovaleric acidernia (14). glutaric aciduria type I (1. 17, 18. 27). glutaric aciduria type II (41). 3-methylcrotonyl-CoA carboxylase deficiency (38). 3-hydroxy-3methylglutaryl-coenzyme A lyase deficiency (23) OTC: Key words: Stroke - Urea cycle defect phate synthethase - Carbamyl phos- B. Mitochondriopathles Mitochondria1myopathies (5). Leigh disease (33). M E W syndrome (34), COX deficiency (30) C Lysosomal storage disorders Fabry disease (19). cystinosis (42) Introduction Stroke-like episodes with hemiparesis and reversible or irreversible brain damage have been described in an increasing number of different inherited metabolic diseases which have been reviewed recently (25,26,28, 35,41) (Table 1).The pathogenetic mechanisms of stroke in these metabolic disorders are heterogeneous and often remain unclear. Fndothelial wall damage, platelet dysfunction, coagulation disturbances, perfusion abnormalities and accumulation of toxic metabolites have been considered as possible explanations for the neuronal dysfunction (20). Several patients with urea cycle defects and stroke-like episodes as the presenting symptom have been described. These cases include hemizygotic (7) and heterozygotic children (11) with ornithine transcarbamylase (OTC)deficiency and acute symptoms of hemiplegia (7, 9, 11, 31). We report on an 18-months-oldgirl with recurrent episodes of hemiparesis, hyperammonemia and mild lactic acidosis who had Received January 2 , 1997; revised, acceptedJune 17, 1997 Neuropediatrics 28 (1997) 229-234 O fippokrates Verlag Siuttgart D. Urea cycle defects OTC deficiency (7.1 I), CPS deficiency (this report). E. Other Sulfite oxidase deficiency (37). hyperlipoproteinemia (16), CDG syndrome (3), phosphoglycerate kinase deficiency (39) suffered infarchon of the right middle cerebral artery territory Elevated g l u t m e and lactate levels were detectable by 'HNMR-spectroscopy in the lnfarcled area. Enzymatic measurement of a liver specimen finally revealed CPS deficiency. Case report This girl was the fourth c u d of non-consanguineous Caucasian parents. Pregnancy, labour and the postnatal period were uneventful. Her oldest sister suffered from cystic fibmsis.The remaining family hstory was unremarkable. At the age of 17 months, the patient was first admitted to a local hospital because of an episode of apyretic somnolence. Psychomotor development had been moderately retarded, walking was possible with help, and muscular hypotonia had been observed. Herpes simplex encephalitis (HSE) was suspected and treatment with acyclovir was started. Investigation of laboratory parameters, including cerebrospinal fluid, revealed nothing abnormal. After 4 days, the girl was transferred to our hospital. She recovered neurologically Downloaded by: University of Pennsylvania Libraries. Copyrighted material. CPS: CPS deficiency has t o be added t o the list of metabolic diseases that may lead t o stroke-like episodes. In every case of unclear hemiparesis i n childhood, urea cycle defects should be included in the differential diagnosis. W. Sped et a1 Neuropediatrics 28 (1997) Dexamethasone and rnannitol were given for brain edema during the acute episode. Because of the unexplicable hyperamrnonemia, a low-protein diet (1 glkg b.w./day) supplemented with UCD 2 (Milupa) and L-carnitine (100 mgkg b.w/day) was started. T h e child recovered within a few days and remained neurologically stable thereafter. The hemiparesis of the left arm improved significantly and the ataxia resolved. No neurological decompensation occurred over a period of 4 years. The child, now 6 years old, shows mild mental retardation (developmental score, Xnuftnan Assessment Battery for Children, SED 65, SGD 80, SF 74, estimated IQ 8W35). A needle liver biopsy was performed to measure urea cycle enzymes. The sample was frozen immediately in liquid nitrogen and sent to Beme on dry ice. - Fig. 1 The T2-weighted image (TR 2400 rns. TE = 90 ms) at the first presentation of the patient showed bilateral hyperintensities within the white matter and a focal signal-intense lesion in the border zone between the territories of the middle cerebral artery and the posterior cerebral artery. Methods Magnetic resonance imaging (MRI) and NMR spectroscopy MRI and N M R spectroscopy were performed on a 1.5 Tesla irnaging/spectroscopy system (Siemens, Erlangen, Germany) u ~ h ga circulat polarized head coil. For ~ a & g , TI-weighted laboratory investigations revealed only moderate, w e n t ele- (TR = 550 ms, TE = 15 ms, 4 mm shce thichess) and T ~ vations of lactate (2.2 -OM, n = < 1.8 -om) and ammonia weighted images (TR = 2400 ms, TE = 15/90 ms, 5 rnm slice (1 17 m o r n , n = < 50 w o r n ) . On MRI, first abnormalities were t h i h e s s ) were acwred. For. spectroscopy, we employed a Spectra were acobserved (Fig. I), characterized by & n o m d y hgh-signal inten- stimulated echo SWence (12, 15). qcllred after optirmzation of the local magnetic &ld and of the sities around the periventncular white matter. chemical hft selective water suppression pulse from cubic One month later, aRer a two-day upper respiratory tract infection, volumes of interest (2.5 x 2.5 x 2.5 cm) using a TR of 1500 the child was readmitted because of progressive left-sided hemi- ms and a TE of 270 ms. h total, 382 excitations were accumuparesis and repeated vomibg. During the hospital stay, the lated, resulting in an examination time of 9 minutes for a local hemiparesis worsened and generalized ataxia developed. On the spectrum. Spectra were corrected for eddy currents using an third day, the girl experienced a sudden crisis with somnolence unsaturated l o d m d Hz0 spectrum and 1st order phase correcand focal convulsions of the left extremities. MRI showed an tion. abnormal, hyperintense signal confined to the entire territory of the right middle cerebral artery (Fig. 2a). Doppler and Duplex Enzyme assws sonography and transfemoral angiography were normal. Clotting (0.5 &orders, inclubg protein C and S deficiencies,were excluded. Liver (10-20 mg) was h o m o s e m in the 5Oi()-fold ~ a b data ~ during ~ the ~ t revealed ~ ~ hyperammonemia 1ml) of ice-cold water. CPS activity was determined spectro(688 pmol/l) and elevations of lactate (3.6 mmoY1) and pyruvate ph~Wmetncal1y the smesis time (0.146 -OM, n < 0.064 rnmolfl) in blood. Ladate in CSF was ,mania, bicarbonate and ATP in the Presence of omithine 3.6 mmoM (n = < 2 mmoY1). Blood cell count, blood gas and ohthine transcarbamylase. The assay mixture contained in analysis, transaminases, coagulation paramelers, glucose, and a total volume of 0.35 ml 33 m o l W C O 3 9 6 ~ 0 A-1 d serologcal parameters for viral mfections in plasma and 3 ~ m 0 1N-acetyl-glutamate,2 m o l ofithine, 5 ~ m o M l ~SO~, 25 pl CPS-kee ornithine transcarbamylase (Mc Lean et al) (32) CSF were normal. and 50 4 liver hornogenate. After five minutes pre-incubationin Plasma amino acid analysis revealed elevations of glutamine (938 the absence of the liver homogenate, citsulline formation was pmoV1, n: 2C-600 pmoM), alanine (1014 pmoV1, n: 99-350 allowed to proceed for 15 min at 37°C. The reaction was stopped wol/l), a-arninobutyric acid (131 prnoY1, n: 0-25 pmol/l) and by the addition of 0.25 ml of 0.5%tungstophosphoric acid in 5% lysine (369 pmoV1, n: 4.5144 pmoY1). Citsulline was 26 pmoM trichloroacetic acid. After centrifugation, citrulline was deter(n: 5 2 4 pmoV1). In the course of the disease, glutamine levels mined in the supernatant by the diacetyl-monoxime-antipyrine increased to 1008 pmoM and alanine decreased to 458 pmoY1 as reaction a c c o h g to Cmiotti and Spandrio (6) using synthetic well as did lactate and pyruvate. GC/MS analysis of urine for c i W e as a standard. \~vlthina few days without the need for other m m e n t . F&er Downloaded by: University of Pennsylvania Libraries. Copyrighted material. organic acids chd not reveal any abnormalities. Follow-up of plasma amino acids over a period of 4 years showed glutamine levels remaining hgh (700-900 pnoLl), alanine becorning normal, although in the upper normal range, and cifruhne fallmg below the limit of detection. An allopurinol loading test was normal. Total plasma carnitme was 30 pmoM (n = 34-52 pmoV l), acyl-camitme 4 pmoVl (n = 1-7 pmoY1). Muscle biopsy revealed a slightly increased lipid content but mitochondnal structure was normal on hstologic examination. Ivlitochondnal DNA analysis for the known MELAS point mutations revealed no abnormahties. Corbomyl Phosphate Synthetase Deficiency and Stroke Neuropediatrics 28 (1997) right hemisphere Cln A Ch L I I 1 I I I I 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 Chemical shiftlpprn Fig. 2b Fig. 2a OTC activjty was determined in the same manner by following citrulline synthesis from L o r n i t h e (2.5 mM) and carbamyl I I I I 1 I I I 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 Chemical shiftlppm phosphate (5 rnM) in triethanolamine/HCl (270 mM, pH 7.7). Fig. 2c One unit OF CPS or OTC activity is defined as the amount of enzyme producing 1 pnol citrulline per minute. Protein was Fig. 2a t o c After acute onset of left-sided hemiparesis the T2-weighted determined by the method of Lmry (29) using bovine serum image (same parameters as Fig, 1) a t the level of the basal ganglia shows abnormal signal intensity within the entire territory of the rlght middle albumin as standard. cerebral artery (a). Localized 'H-NMR spectroscopy of 15.6 ml volumes of Results MRI and NMR spectroscopy findings At the first presentation (Fig. 1) the T2-weighted image showed bilateral abnormal high signal intensity of the white matter around the frontal horns and the posterior horns of the lated ventncles. In addition, there was a signal intense lesion extending horn the right posterior horn of the lateral ventricle into the subcortical white matter. interest (2.5 x 2.5x 2.5 cm VOI) was performed from the affected and the contralateral hemisphere. The localized spectrum of the affected hemisphere (TR = 1500 ms. TE = 270 rns 382 N U ) (b) yielded a marked increase in cerebral lactate. In addition, there were signals between 2 and 2.5 ppm as well as 3.7 ppm, that indicated elevated glutamine levels. In the contralateral hemisphere (c), there was a resonance at 3.7 pprn that also suggested elevation of glutamine. One year Jater (Fig. 3a, b) the T2-weighted images were unchanged, a partial resolution of the penventricular signal abnormalities was found (see also Figs.1 and 2). The proton spectrum of the mfarcted area ylelded still elevated lactate at 3.7 ppm, glutamine was elevated to some extent. The spectrum of the normal hemisphere showed a normal relationship between NAA, choline and creatine. One month later, after onset of the left-sided hemiparesis MRI showed infarction of the entire right middle cerebral artery tenitory (Fig. 2a). Localized 'H-NMR of the affected hemisphere (Fig. 2b) yielded a marked increase in cerebral lactate, consistent with ischemic infarction. In addition, there were signals between The follow-up MRI three years later was unchanged. The proton 2 and 2.5 ppm as well as 3.7 ppm, that could be attributed to spectra showed reduced NAA and choline/creatine, but no elevated glutamine levels according to Connelly et a1 (9). In the indication of lactate and glutamine in the right hemisphere. contralateral hemisphere, there was a resonance at 3.7 ppm that The proton NMR spectrum of the left hemisphere was normal. also suggested some elevation of glutarnine (Fig. 2c). 7ho months later, atrophy of the infarcted hemisphere had developed and the right lateral ventricle dilatated. The proton NMR spectra at that time revealed no elevation of glutamine. In the region of the infarct, NAA was decreased. Lactate was still elevated. Enwmotk findings CPS activity was reduced in a liver biopsy with a residual activity of 2.5 mU/mg protein ( normal = 12-35). OTC activity was in the normal range (338 mU/mg protein; normal = 160-560). Downloaded by: University of Pennsylvania Libraries. Copyrighted material. left hemisphere Neuropediatrics 28 (7997) W. Sperl et ol Mtochondrial carbamyl phosphate synthetase (CPS I) (EC 6.3.4.16), the k t enzyme in ureagenesis, is located in the mitochondrial matnx compartment and is expressed in liver and epithelial cells of intestinal mucosa. Two distinct clinical patterns result from autosomal recessively inherited CPS I deficiency: a lethal neonatal type with a complete or virtually complete deficiency of CPS I, and a late-onset type with parbal enzyme deficiency Recently, a mutation has been elucidated for the f i t time in a patient with a lethal course. A one-base substitution in an exon of the CPS I gene caused a 9 bp deletion in the mRNA due to aberrant splicing (22). Fig. 3a In our patient, the onset of the disorder was delayed and the clinical course was in accordance with the relatively high residual right hemisphere activity in ljver tissue. Hyperamrnonemia and subsequenl stroke may have developed as a consequence of catabolic stress during infection. I I I 4.0 3.5 3.0 1 I I 2.5 2.0 1.5 Chemical shiftlppm I I 1.0 0.5 ng. 3a and b One year later, the T,-weighted (same parameters as in Figs. 1 and 2) images (a) revealed atrophy of the infarcted hemisphere and dilatation of the right lateral ventricle. The periventricular signal abnormallties showed partial resolution (see also Figs.1 and 2). The proton spectrum (for parameters see Figs. 1 and 2) of the normal hemisphere revealed a normal relationship between NAA. choline and creatine. In the infarcted area on the right (b), lactate was still elevated and glutamine (3.7 ppm) was still elevated to some extent. The pathophysiological mechanism that causes cerebral infarction in urea cycle defects remains unclear. Elevated levels of ammonia or a lack of arginine have been considered responsible for neurological deficits (28). Possible mechanisms resulting in encephalopathy may be altered energy metabolism, neurotransmitter imbalance, astrocyte swelling, changes in cerebral blood flow and intracranial pressure. Many of these phenomena could also be secondary to intracerebral glutamine accumulation (9, 13, 31). It is unclear why ddferent metabolic dsorden can lead to a smxlar neurological pattern of stroke-like episodes. One explanation might be that all of them affect mitochondrial metabolism as well at the levels of the neurons or endothelial cells or smooth muscular cells of arterial walls (11). A current concept for MELAS suggests an imbalance between energy requirements and availability (21). In methylmalonic acidemia, a combination of hypovolemia, acidemia and accumulation of organic acids may be a possible cause of a severe local deficit in energy metabolism (20, 40). Strokes might thus result from an acute, relative deficiency of cellular ATP Focal seizure activity could also play an important role as a harbinger to stroke-like episodes. A focal seizure places Discussion extreme metabolic demand on brain tissue and may cause We report on the novel observation of a severe metabolic stroke reversible or irreversible metabolic exhaustion of the epileptic in the right middle cerebral artery territory in an 18-month-old zone. girl with carbarnyl phosphate synthetase deficiency. The initial clinical symptoms mimicked a cerebrovascular insult. MRI find- Lactate elevation in our patient was most probably secondary, as utgs lint suggested MELAS syndrome (24). Lactate, pyruvate it has also been observed in a patient with OTC deficiency, and plasma alanine levels were moderately elevated. Moreover, described by de Grauw et al ( l l ) , who had moderate lactate Downloaded by: University of Pennsylvania Libraries. Copyrighted material. an elevation of lactate was also observed in 'H-NMR spectroscopy. However, high levels of ammonia (approx. 700 pmoYI) in plasma during the crisis, constantly elevated Ievels of glutamine and rapid normalization of lactate levels thereafter did not fit into the clinical picture of MELAS syndrome. Muscle biopsy excluded all known point mutations of MELAS. Signals between 2 and 2.5 as well 3.7 ppm in 'H-NMR spectroscopy could be attributable to elevated glutamine. A similar finding was reported recently for a patient with OTC deficiency by Connelly et al (9). Therefore, a urea cycle defect, most probably 0°K deficiency, was suspected as the underlying h e in our patient. However, urine analysis of organic acids showed no omtic aciduria and the allopurinol loading test was also normal. Other urea cycle defects except CPS and NAGS deficiency were ruled out on the basis of the plasma amino acid pattern. Finally, enzyme measurement in a Liver biopsy specimen revealed CPS deficiency with a considerable residual activity. Neuropediatrics 28 (1997) Carbamyl Phosphate Synthetase Deficiency and Stroke In conclusion, it is important to be aware that acute hemiparesis in childhood mimicking a cerebrovascular insult may be due to a metabolic disturbance. We recommend to exclude urea cycle defects including OTC and CPS deficiency in all unknown causes of stroke or stroke-like episodes. These very rare urea cycle defects can easily be overlooked in selective screening, since only unspecific glutamine and alanine elevation is observed in the amino acid proNes and no organic aciduria is detectable. Acknowledgments We would like to thank Dr. Obermayer, Akad. Lehrhankenhaus Schwabing, Institute for Diabetes Research and Cliical Chemistry, Munich, for mtDNA-analysis and Chris Priestly for editorial assistance. 'Qrahm, I., H . Bruhn, M. L. Gyngell, K. D. Merboldl, W. Hiinicke, R. 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In: The Metabolic and Molecular Bases of Inherited hemorrhage complicating isovaleric acidemia: a case report. Neurology Disease.(C. R. S n i w , A. L. Beaudet, W . S. Sly, D. Valle, eds.) 7th Edition, 31 (1981)746748 McGrawHiU Inc, 34853511 methylmalonic and propionic acidemia. Arch. Neurol. 41 (1984)1293- " 1296 35 Riikonen, Downloaded by: University of Pennsylvania Libraries. Copyrighted material. elevation in plasma and CSE In our patient, the stroke occurred predominantly in the right middle cerebral artery territory, but there was also bilateral involvement of the deep white matter. This suggests metabolic distress of brain tissue in addition to vascular damage leading to underperfusion. Similar c h c a l reports have been made for children with OTC deficiency (7,9,11, 31). Batshaw et a1 also described focal deficits in a patient with CPS deficiency (2). Neuropediatrics 28 (1997) W. Sperl et ol Thompson, G. N., 1. Christodoulou, D. M . 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