The Journal o f Pediatrics Volume 122, Number 3 Christodoulou et aL 423 Ornithine transcarbamylase deficiency presenting with strokelike episodes J. Christodoulou, MBBS,PhD, I. A. Qureshi, PhD, R. R. Mclnnes, MD, PhD, a n d J. T. R. Clarke, MD, PhD From the Division of Clinical Genetics, Hospital for Sick Children, Toronto, Ontario, and the Pediatric Research Centre, HSpital Sainte-Justine, Montreal, Quebec, Canada A girl with ornifhine transcarbamylase deficiency had a history of recurrent strokelike episodes. The differential diagnosis of unexplained stroke should include primary urea cycle defects. (J PEDIATR4993;122:423-5) O r n i t h i n e t r a n s c a r b a m y l a s e ( E C 2.1.3.3) deficiency, an X-linked inborn error of a m m o n i a metabolism, is the most c o m m o n urea cycle defect. I Affected hemizygous males usually have h y p e r a m m o n e m i c encephalopathy in the newborn period that is often fatal. I Rarely, affected males are seen later with a r a n g e of symptoms including anorexia, poor growth, protein avoidance, behavior changes t h a t can be mistaken for psychotic illness, a n d mental retardation. 2 T h e clinical phenotype in heterozygous females is broad, ranging from no symptoms to h y p e r a m m o n e m i c episodes as severe as those seen in males. 3, 4 W e report here the novel observation of recurrent strokelike episodes in a heterozygous OTC-deficient girl. no history of unexplained neonatal or childhood deaths, mental retardation, or protein aversion in the maternal line. Initial investigations showed normal values for hemoglobin, leukocyte count, erythrocyte sedimentation rate, coagulation, venous blood gases, electrolytes, glucose, creatinine, thyroxine, and thyrotropin. The plasma level of ammonium at admission was 339 /.tmol/L (normal, <50) but gradually fell to 167 ttmol/L with no specific treatment and during an unrestricted diet. The results of semiquantitative analyses of urinary amino and organic acids, acylglycines, and acylcarnitines were normal. Plasma levels of protein S, protein C, fibrinogen, D-dimer, heparin cofactor 2, antitbrombin 1II, and plasminogen were normal. Mixed leukocyte a-galactosidase activity was also normal. The results of other relevant tests are summarized in the Table. CASE REPORT This girl was the first child of nonconsanguineous Chinese parents. The pregnancy, labor, and postpartum period were uncomplicated. The child was developmentally normal and had enjoyed good health until the age of 2 years 8 months, when she came to medical attention because of recurrent episodes of transient hemiparesis. One month before admission to the hospital, she had several transient episodes of right-sided weakness. The girl's first admission to the hospital was because of the sudden onset of right-sided hemiplegia, with facial involvement and slurred speech. At that time her height (80 cm) was below the third percentile for age; her weight ( ! 3.2 kg) and head circumference (49 cm) were at the 50th percentile. She was alert and had no dysmorphic features, abnormal cardiorespiratory signs, or hepatosplenomegaly. She had patchy atopic dermatitis. Neurologic examination demonstrated right-sided upper motor neuron hemiplegia, with power being grade II/V in the upper extremity and grade IV/V in the lower. She had hyperreflexia on the right, and the plantar reflex was extensor on that side; power and reflexes were normal on the left. The family history was unremarkable. In particular, there was Submitted for publication June 25, 1992; accepted Oct. 16, 1992. Reprint requests: J. Christodoulou, MBBS, PhD, Department of Paediatrics and Child ttealth, Children's Hospital, Pyrmont Bridge Rd., Camperdown, New South Wales 2050, Australia. Copyright 9 1993 by Mosby-Year Book, Inc. 0022-3476/93/$1.00+ .10 9/22/43519 I OTC Ornithine transcarbamylase I An electroencephalogram showed a slow-wave abnormality over the left hemisphere. A computed tomography scan of the head demonstrated a marked hypodensity in the left frontoparietal region, loss of gray-white matter differentiation, a hypodensity in the right frontal region, and a mass effect with midline shift (Figure). These findings were consistent with left frontoparietal and right frontal infarction. A single-photon emission computed tomography cerebral perfusion scan showed a marked reduction of perfusion in the left hemisphere, especially in the frontal lobe. A muscle biopsy specimen showed no histologic, histochemical, or electron microscopic abnormalities. During the next few weeks, muscle strength progressively improved. She was readmitted to the hospital a few weeks later with a history of anorexia for 3 weeks, and increasing irritability, intermittent fever, and rhinorrhea for 3 days. Physical examination showed signs of an upper respiratory tract infection, an axillary temperature of 39.8 ~ C, nonpurulent pharyngitis, and a clear nasal discharge. There was no evidence of encephalopathy. General physical examination findings were otherwise unremarkable. Muscle tone was slightly increased in the right arm, but the remainder of the neurologic findings were normal. Relevant biochemical abnormalities at the second admission included elevated activity of plasma aspartate aminotransferase (84 U/L) and an elevated plasma ammonium level (131 ~umol/L). The plasma glutamine level was elevated (1277/amol/L), the arginine level was low (12 ~mol/L; normal, 23 to 86), and the 424 Christodoulou et al. The Journal o f Pediatrics March 1993 Figure. Computed tomography scan of the head taken during the first admission to the hospital. Left frontoparietal and right frontal infarcts are present, with mild midline shift to to the right. T a b l e . Relevant investigations performed at first admission Value Blood (~umol/L unless otherwise stated) Urea (mmol/L) 3.9 Aspartate aminotransferase (U/L) 117 Lactate* (mmol/L) 2.99 Ammonium 339 Alanine 420 Glutamine 1223 Lysine 200 Arginine ND Argininosuecinate ND Citrulline 16 Carnitine Free 38 Total 73 Urine Orotic acid (mmol/moI creatinine) 41 ND, Not detected. *Five subsequentmeasurements~ere normal. Normal 2.9-7.1 <45 <2.5 <50 99-313 <746 45-144 23-86 ND 0.5-47 24-63 35-84 6-12 citrulline level was normal (5 umol/L). Urinary amino acid quantitation was normal; no argininosuccinate was detected. The urinary orotic acid concentration on this occasion was again elevated at 29 mmol/mol creatinine. The blood chromosome analysis was normal (46,XX), with no visible deletion or X-autosome translocation on routine G banding of a prophase preparation. A provisional diagnosis of OTC deficiency was made and she was begun on a low protein diet (total protein intake of 1 gm/kg per day) supplemented with product 80056 (Mead Johnson, Evansville, Ind.), Polycose (Ross Laboratories, Columbus, Ohio), and Pediasure (Ross Laboratories). In addition, oral therapy with carnitine, 100 mg/kg per day, and citrulline, 240 mg/kg per day, was prescribed. Hepatic OTC activity was measured as previously described5 in a needle biopsy specimen. The sample was snap frozen in liquid nitrogen and stored for 2 weeks at - 8 0 ~ C before assay. A frozen sample obtained post mortem from a known OTC-deficient patient was used as a negative control, along with a sample from a normal child as a positive control. The OTC activity for the normal control sample was 28.8 ,umol/hr per milligram of protein (previous normal values 42.2 ___ 11.5), and for the negative control sample The Journal o f Pediatrics Volume 122, Number 3 was 0 ,umol/hr per milligram. In our patient the OTC activity was 1.72 t~mol/hr per milligram, only 6% of the control value. DISCUSSION Inherited metabolic diseases known to cause stroke include homocystinuria, Fabry disease, sulfite oxidase deficiency, Leigh disease, the M E L A S (mitochondrial myopathy, encephalopathy, lactic acidosis and strokelike episodes) syndrome, and organic acidopathies including methylmalonic acidemia, propionic acidemia, isovaleric acidemia, and glutaric aciduria type I. 6 The pathogenesis of stroke in these disorders is not certain but may include such mechanisms as alterations in vascular endothelial wall integrity, platelet dysfunction, or alterations in cerebral perfusion or metabolism caused by the accumulation of toxic metabolites. In addition, defects of coagulation such as protein C or S deficiency may also cause stroke in childhood. 7 All these disorders were excluded in our patient on the basis of clinical, biochemical, or histologic studies. Acute hyperammonemia in OTC-deficient heterozygotes may develop as a consequence of the catabolic stress of infection, or after excessive protein intake. ~ More recently, hyperammonemia has been reported in otherwise healthy OTC-deficient heterozygous females in the postpartum period, 8 and after valproate therapy for suspected epilepsy. 9 Such patients have symptoms and signs of an acute encephalopathic process. The caloric intake of our patient before the first admission had been poor; the second admission was precipitated by an apparent intercurrent viral illness. Our patient had no evidence of diffuse encephalopathy during either illness. To our knowledge, there are no previous reports of OTC deficiency with an initial or subsequent presentation of recurrent strokelike episodes, although there is 9 one report of a child with carbamoyl-phosphate synthetase deficiency who had strokelike episodes, l~ The basis of this apparently rare complication in patients with urea cycle defects is unclear but could include several of the possibilities mentioned above. Alternatively, the strokelike episodes could be due to some other cause, although at present such a cause remains unknown. The diagnosis of O T C deficiency in our patient was ini- Christodoulou et al. 425 tially delayed because the clinical findings did not suggest a disorder of ammonia metabolism. However, the biochemical hallmarks of hyperammonemia, hyperglutaminemia, and orotic aciduria prompted us to assay O T C activity in the liver. In the light of our experience with this child, we recommend that the investigation of children with strokes or strokelike episodes, when there are no known predisposing factors, should include plasma and urinary amino acid quantitation, plasma lactate and ammonium measurements, and urinary organic acid analysis, including orotic acid quantitation. REFERENCES I. Brusilow SW, ttorwich AL. Urea cycle enzymes. In: Scriver CR, Beaudet AL, Sly WS, Valle D, cds. The metabolic basis of inherited disease. 6th ed. New York: McGraw-Hill Information Services, 1989:629-63. 2. Finkelstein JE, ttauser ER, Leonard CO, Brusilow SW. Lateonset ornithine transcarbamylase deficiency in male patients. J PEDIArR 1990;117:897-902. 3. Batshaw ML, Msall M, Beaudet AL, Trojak J. Risk of serious illness in heterozygotcs for ornithine transcarbamylasc deficiency. J PEDIATR 1986;108:236-41. 4. Nagata N, Matsuda I, Matsuura T, et al. Retrospective survey of urea cycle disorders. II. Neurological outcome in fortynine Japanese patients with urea cycle cnzymopathies. Am J Med Genet 1991;40:477-8 I. 5. Qureshi IA, Letartc J, Ouellet R. Study of enzyme defect in a case of ornithine transcarbamylase deficiency. Diabete Metab 1978;4:239-41. 6. Natowicz M, Kelley RI. Mendelian etiologies of stroke. Ann Neurol 1987;22:175-92. 7. Israels SJ, Seshia SS. Childhood stroke associated with protein C or S deficiency. J PEDIATR 1987;i11:562-4. 8. Hawks Arn P, Hauser ER, Thomas GH, Herman G, Hess D, Brusilow SW. Hyperammonemia in women with a mutation at the ornithine carbamoyltransferase locus. N Engl J Med 1990;322:1652-5. 9. Tokatli A, Coskun T, Cataltepe S, Ozalp I. Valproate-induced lethal hyperammonaemic coma in a carrier of ornithine carbamoyltransferase deficiency. J Inher Metab Dis 1991; 14:836-7. I0. Batshaw M, Brusilow S, Walser M. Treatment of carbamylphosphatc synthetasc deficiency with keto analogues of essential amino acids. N Engl J Med 1975;292:1085-90.