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Hyperammonaemia: a Deficiency of Liver Ornithine Transcarbamylase Occurrence in Mother and Child B

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Hyperammonaemia: a Deficiency of Liver Ornithine Transcarbamylase Occurrence in Mother and Child B Arch Dis Child: first published as 10.1136/adc.44.234.152 on 1 April 1969. Downloaded from Arch. Dis. Childh., 1969, 44, 152 Hyperammonaemia: a Deficiency of Liver Ornithine Transcarbamylase Occurrence in Mother and Child B. LEVIN, J. M. ABRAHAM, V. G. OBERHOLZER, AND E. ANN BURGESS From Queen Elizabeth Hospital for Children, London The biosynthesis from ammonia of urea, the some diarrhoea and vomiting in the last 3 months. major end product of nitrogen metabolism in man, The birthweight was 3 * 24 kg., the length was 50 8 cm., involves five stages. Four of them comprise and the head circumference 37 * 4 cm. She was breast- the urea cycle proper (Fig. 1), and inherited fed for three weeks and then given dried cows' milk feed, three whereupon she began to vomit after each feed and was metabolic disorders involving of these steps therefore changed to a succession of proprietary cows' have recently been characterized by the demonstra- milk preparations, with no improvement. tion of a deficiency of the particular enzyme She was first seen in hospital at the age of 3 months concerned. The first to be described was arginino- for persistent vomiting. She appeared a well-nourished succinic aciduria, resulting from a congenital girl but weighed only 4 81 kg., i.e. on the 10th centile absence of liver argininosuccinase (Allan et al., (Fig. 2). A rash, thought to be that of exanthem subi- 1958; Levin, Mackay, and Oberholzer, 1961). tum, was noticed on the trunk and limbs. She was copyright. The second was citrullinuria, arising from a defi- taking feeds vigorously but would vomit 2-1 hour later. ciency of liver argininosuccinic acid synthetase Initial investigations excluded a local cause for the (McMurray et al., 1962, 1963, 1964). The third vomiting: barium meal showed only slight reflux and was a specific syndrome due there was no pyloric obstruction. hyperammonaemia, Renal tubular acidosis was suspected because the to a severe deficiency ofliver ornithine transcarbamy- plasma standard bicarbonate was initially 18 mEq/l. lase, found in two affected female first cousins, when the corresponding urine was pH 9, and an attempt and reported in a preliminary account (Russell was therefore made to determine the hydrogen ion http://adc.bmj.com/ et al., 1962; Levin and Russell, 1967). clearance index (Peonides, Levin, and Young, 1965). We here describe an infant with the characteristic She was given ammonium chloride (0 9 g.) orally in clinical and biochemical features of this inherited divided doses over 2 days, i.e. 1-5 g./sq.m. per day. metabolic disorder in its most severe form; and After the last dose the patient refused feeds, became her mother, who is asymptomatic, except for having gradually drowsy, hypotonic, and mildly dehydrated. had an aversion to protein-containing foods almost The liver enlarged to 4 cm. below the costal margin. from birth, and who has high plasma ammonia Blood pH 7 * 425, urinary pH 9, and the plasma standard bicarbonate 23-5 mEq/l. 12 hours later she collapsed an with abnormal on September 24, 2021 by guest. Protected levels after overnight fast, and became deeply comatose. Reflexes were exag- increases induced by protein ingestion. The diag- gerated and fundi clear. CSF was normal. Plasma nosis was confirmed in both by estimating the Na, K, and Cl levels were raised, and the blood urea activity of the enzymes of the urea cycle which was 25 mg./100 ml. Glucose saline solutions were revealed a gross deficiency of ornithine trans- given intravenously and an initial dose of 100 mg. carbamylase in the liver. hydrocortisone. She remained comatose for 2 days, after which twitchings of the face and gustatory move- ments with clonic convulsions of the limbs began, Case History with phases of apnoea. Though the mental state improved thereafter, twitching increased in severity Case 1. A girl, the only child of unrelated parents, and frequency, developing into a state of continuous was delivered on 6 October 1967, by forceps at 41 weeks' myoclonic jerks involving the whole body. EEG gestation, after a pregnancy which was uneventful showed multiple focal abnormalities suggestive of apart from hyperemesis during the first 3 months and widespread disturbances, most prominent in the right posterior frontal region. The convulsions were con- Received October 28, 1968. trolled with paraldehyde and primidone over the next 152 Arch Dis Child: first published as 10.1136/adc.44.234.152 on 1 April 1969. Downloaded from Hyperammonaemia 153 PATHWAY OF UREA FORMATION Ammonia + Bicarbonate + 2ATP Carbamyl phosphate synthetase Carb hhate + mg + + 2 D +P Acetylqiuta mate - --0- Carbamyl phosphate+Ornithine OrnithineTranscarbamylase Citrulline + Pi Citrulline + Aspartate + ATP ASA synthetase e Argininosuccinic acid + AMP + PP Argininosuccinic acid Arqininosuccinase.... Arqinine fumaric acid Pi =Inorganic phosphate ArginineArqinne+ water Mn++Arginase Urea + Ornithine |PP = Pyrophos phate l FIG. 1.-Pathway of urea formation. three days, and the liver decreased in size. Milk plasma ammonia, both fasting (865 pg.NH3-N/100 ml.), feeds were gradually reintroduced, but after 7 days and after oral ingestion of 5 g. protein as a milk feed when a full milk complement was achieved, a similar (1240 t&g.NH3-N/100 ml.) The level in CSF taken episode of drowsiness and hypotonia, followed by at the same time was also high (435 IAg.NH3-N/100 ml.). unconsciousness with convulsions, occurred. Again The patient, then aged 5 months, was transferred to the liver enlarged. A second EEG showed a marked Queen Elizabeth Hospital for Children for further inves- deterioration with generalized flattening indicating tigation. She was spastic, and lying in mild opisthotonos, gross diminution in cerebral activity. Milk feeds were with clenched fists. The pupils reacted sluggishlyto light, accordingly stopped and she was again treated with but the fundi were clear. Both plantar reactions were ex- copyright. parenteral fluids over the next 3 days. tensor. Vision and hearing were both impaired. EEG The sequence of unconsciousness and coma after showed an even more marked lack of cerebral activity administration of ammonium chloride or of full protein over almost all areas than before. Glucose electrolyte intake suggested an impairment of ammonia meta- therapy was continued by oral administration of the bolism. This was confirmed by the high levels of fluid through a gastric tube. Plasma ammonia fell to nearly normal levels over the next 14 days, with some clinical improvement and decrease in spasticity. A 8 50 biopsy of the liver was taken by open operation. http://adc.bmj.com/ Histologically, the liver appeared normal. Enzyme 3 assays confirmed the diagnosis of liver omithine trans- carbamylase deficiency. Protein as milk feeds was reintroduced initially to give a daily dose of 2 g., divided into 2-hourly feeds. As there was no rise in fasting plasma ammonia the protein intake was increased by 6 stages to 6 g. daily, on which the fasting level was about &i 60 pg.NH3-N/100 ml., i.e. slightly above the normal. Citric acid was found to be effective in reducing the on September 24, 2021 by guest. Protected post-prandial rise, and she was thereafter stabilized on *c; 6 g. protein and 3 g. citric acid daily, divided into 6 doses given just before the feed (Fig. 3). Her weight which had previously fallen now began to increase (Fig. 2). At the age of 8 months she showed some clinical improvement; she could follow light and cried for food. However, she still had some spasticity of the lower limbs, and lay in a mild opisthotonic position with clenched hands. There was EEG evidence of gross brain damage. At 0 operation for a biopsy, the Aqe (months) brain was seen to be greatly reduced in size. The biopsy was reported by Dr. L. Crome to show, 'virtual FIG. 2.-Case 1. Weight chart, with centiles. Note disintegration of the cerebral cortex, with proliferation improvement in weight on low protein diet. of astrocytes and lipophages' (Fig. 4). Growth was Arch Dis Child: first published as 10.1136/adc.44.234.152 on 1 April 1969. Downloaded from 154 Levin, Abraham, Oberholzer, and Burgess ;E 12g. Protein intake -6 6 day *Z § L no protein X- 1 1240e E 8 140 0- 130 120 0' 110l 0cr 100 a 90 c 80 .CX0 c 70 E0 60 50 40 aE Protein load 30 5a+2 . 2+ 0~ 5o..j 05q.1q.- 72- lq.'2 2q.- 2-5q.- 72 - 2-5q.-2 -2-5q.-J' 2-5q. a j72- l2i 1 4 . j - i, 13 19 25 31 6 12 18 24 30 6 12 18 March April May FIG. 3.-Case 1. Effect of variation of daily protein intake, of protein load, and of oral citric acid on plasma ammonia. Note decrease in level with decreased protein intake; increase after a protein load; and reduction of the post-prandial rise of plasma ammonia by oral citric acid. copyright. http://adc.bmj.com/ on September 24, 2021 by guest. Protected FIG. 4.-Case 1. Cerebral cortex. Note proliferation of astrocytes and lipophages. (H. and E.) Arch Dis Child: first published as 10.1136/adc.44.234.152 on 1 April 1969. Downloaded from Hyperammonaemia 155 still retarded and there had been little or no increase normal. The plasma standard bicarbonate was in height or head circumference since the 5th month also normal, except a slightly low initial level and of age, despite some weight gain. X-rays showed no one which was high (31 mEq/l.) because of alkali carpal cenitres of ossification. therapy. Blood pH was always near the upper limit of normal, and was on one occasion 7-59, Case 2. The mother of Case 1, age 23 years, was normal at birth, weighed 2-9 kg., and was completely i.e.
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