101È111
`J. Inher. Metab. Dis. 21 (Suppl 1)
`(1998)
`(
`SSIEM and Kluwer Academic Publishers. Printed in the Netherlands
`
`Alternative pathway therapy for urea cycle
`disorders
`
`F. FEILLET and J. V. LEONARD*
`Biochemistry, Endocrine and Metabolic Unit, Institute of Child Health, 30 Guilford
`Street, L ondon W C1N 1EH, UK
`* Correspondence
`
`Summary:
`In man the major pathway for the disposal of waste nitrogen is the
`urea cycle; in inborn errors of this pathway, nitrogen Ñux is reduced. As a
`result there is accumulation of ammonia and glutamine with disordered metab-
`olism of other amino acids. Nitrogen homeostasis can be restored in these
`patients with a low-protein diet combined with compounds that create alterna-
`tive pathways for nitrogen excretion. The introduction of these compounds has
`been a major advance in the management of these inborn errors and as a result
`the outcome, particularly for those treated early, has improved.
`
`THE UREA CYCLE
`
`Surplus nitrogen cannot be stored and has to be excreted. In mammals the major
`pathway for the metabolism of waste nitrogen is the urea cycle. In children on a
`protein intake of 1.25 g/kg, about 50% of the urinary nitrogen is excreted as urea
`(Brusilow and Maestri 1996). Quantitatively, 1 g of protein contains approximately
`0.16 g of nitrogen which, if catabolized completely, will be converted to 5.7 mmol of
`urea.
`The net e†ect of the urea cycle is to convert two nitrogen atoms derived from
`ammonia and aspartate to urea. The biochemical steps in the cycle are shown in
`Figure 1. Ammonia is probably derived from several sources (Brusilow and Horwich
`1995) and is converted to carbamoyl phosphate by carbamoyl-phosphate synthase.
`This enzyme requires an allosteric activator N-acetylglutamate for full activity. The
`carbamoyl phosphate condenses with ornithine to form citrulline which then reacts
`with aspartate to form argininosuccinate. This compound is then hydrolysed to
`arginine and fumarate. The arginine is cleaved by arginase, releasing urea with orni-
`thine being reformed. Within the urea cycle, ornithine acts as a carrier, being neither
`formed nor lost.
`
`INBORN ERRORS OF THE UREA CYCLE
`
`Defects of each step have now been described and are listed in Figure 1. The presen-
`tation is highly variable: those presenting in the newborn period usually have an
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`overwhelming illness but it may be subtle in those who present later in childhood or
`adult life (Brusilow and Horwich 1995; Leonard 1995). As a result of the inborn
`error, the Ñux in the pathway is reduced and all the defects are associated with
`hyperammonaemia and increased concentrations of glutamine in plasma (Brusilow
`and Horwich 1995). The metabolism of other amino acids is disordered depending
`on the site of the metabolic block. The concentrations of amino acids in the
`pathway immediately proximal to the enzyme defect will be increased and of those
`beyond the block decreased (Figure 1). For many years the mainstay of treatment
`was a low-protein diet but the metabolic control was frequently not satisfactory.
`The development of compounds that increase the excretion of nitrogen by alterna-
`tive pathways has been an important breakthrough in the management of these
`disorders (Brusilow et al 1979).
`
`NEUROTOXICITY OF UREA CYCLE INTERMEDIATES
`Ammonia increases the transport of tryptophan across the bloodÈbrain barrier with
`consequent increase in the production and release of serotonin (Bachmann and
`Colombo 1983). Some of the symptoms of hyperammonaemia can be explained on
`this basis and restriction of dietary tryptophan reverses some symptoms, particu-
`larly anorexia,
`in patients with these disorders (Hyman et al 1987). Ammonia
`induces many other electrophysiological, vascular and biochemical changes in
`experimental models, but it is not known to what extent these are relevant to the
`problems of hyperammonaemia in man (Surtees and Leonard 1989).
`Glutamine can also be shown to accumulate at high concentrations both in
`experimental models (Brusilow and Horwich 1995) and also in man in vivo using
`proton nuclear magnetic resonance spectroscopy (Connelly et al 1993). The concen-
`trations are such that the increase in osmolality could be responsible for changes in
`the intracellular water content and cerebral oedema.
`
`Figure 1 (opposite) Pathways for the disposal of waste nitrogen: The urea cycle and alterna-
`tive pathways of nitrogen excretion
`Enzymes
`1. Carbamoyl-phosphate synthase
`
`2. Ornithine transcarbamoylase
`3. Argininosuccinate synthetase
`4. Argininosuccinate lyase
`5. Arginase
`6. N-Acetylglutamate synthase
`
`Inborn error of metabolism
`Carbamoyl-phosphate synthase
`deÐciency
`Ornithine transcarbamoylase deÐciency
`Citrullinaemia
`Argininosuccinic aciduria
`Arginase deÐciency
`N-Acetylglutamate synthase deÐciency
`
`Benzoate and phenylbutyrate are activated, conjugated to glycine and glutamine respectively
`and excreted, thereby creating an alternative pathway for nitrogen excretion
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`The clinical problems of arginase deÐciency are distinct from other urea cycle
`disorders and it seems probable that
`the high arginine concentrations are
`neurotoxic, although the mechanism is unknown. Arginine deÐciency may also con-
`tribute to the same symptoms in other disorders (Kline et al 1981).
`
`TREATMENT
`
`The aim of treatment is to correct the biochemical abnormalities and yet at the
`same time ensure that all the nutritional needs are met. The strategies used are to
`reduce protein intake to reduce the nitrogen Ñux through the urea cycle; secondly to
`utilize alternative pathways of nitrogen excretion; and thirdly to replace nutrients
`that are deÐcient.
`
`Low-protein diet
`
`Most patients with urea cycle disorders require a low-protein diet. The exact quan-
`tity of protein will depend on the inborn error, the age of the patient and the sever-
`ity of the disorder. For some patients, particularly those with severe disorders and
`those with marked protein aversion, the diet may need to be supplemented with
`essential amino acids (Brusilow and Horwich 1995; Leonard 1995).
`
`Alternative pathways for nitrogen excretion
`
`In many patients diet alone is not sufficient to control the metabolic derangement,
`so that additional therapy is necessary. A major advance in this Ðeld has been the
`development of compounds that increase the removal of waste nitrogen (Brusilow et
`al 1979). By giving these substances, nitrogen is converted to compounds other than
`urea and is excreted. Hence the load on the urea cycle is reduced (Figure 1). The Ðrst
`compounds introduced were arginine and sodium benzoate. Later phenylacetate
`was used but this has now been superseded by phenylbutyrate.
`
`Sodium benzoate:
`Benzoate is conjugated with glycine to form hippurate
`(Tremblay and Qureshi 1993) which is rapidly excreted in the urine (Figure 1). The
`possibility that sodium benzoate could be used to increase waste nitrogen excretion
`was Ðrst recognized by Lewis early this century (Lewis 1914) and it is well suited for
`this because its renal clearance is Ðve times the glomerular Ðltration rate (Brusilow
`et al 1979). For each mole of benzoate given, 1 mole of nitrogen is removed. In practi-
`cal terms 1 g of benzoate would, if completely converted to hippurate and excreted,
`result in the removal of the equivalent of 0.6 g protein.
`Sodium benzoate is usually given in doses up to 250 mg/kg per day, but in acute
`emergencies this can be increased to 500 mg/kg per day. Following a dose of
`250 mg/kg, the nitrogen removed by sodium benzoate, if conjugation is complete,
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`will be equivalent 0.15 g/kg of protein. Plasma ammonia and glutamine concentra-
`tions decrease (Brusilow and Maestri 1996). This, combined with a low-protein diet,
`may be sufficient in those with mild defects and it has been used widely with beneÐ-
`cial e†ects (Batshaw 1983; Letarte et al 1985; Takeda et al 1983).
`Pharmacokinetics: Studies of the pharmacokinetics have shown that benzoate is
`rapidly converted to hippurate which is then cleared more slowly (Kubota and Ishi-
`zaki 1991). In this study, the mean maximum rate of clearance was 23 mg/h per kg,
`which is close to the maximum dose used clinically. However, there is wide variation
`in the recovery of the benzoate reported, which may be as low as 41% (Barshop et
`al 1989). The reasons for this have not been investigated, although a small quantity
`may be excreted as the glucuronide, which will reduce its efficacy. Studies of patients
`on their regular medication conÐrm that sodium benzoate is rapidly converted to
`hippurate but cleared more slowly (Figure 2). It has been recommended that plasma
`concentrations should not exceed 4.5 mmol/L (Simell et al 1986). In the neonatal
`period, induction of hippurate synthesis may be delayed, so that plasma benzoate
`concentrations may reach potentially toxic concentrations and should therefore be
`monitored (C. Bachmann, personal communication).
`Adverse e†ects: In animal studies sodium benzoate induces a rise in plasma
`ammonia concentrations coupled to a decrease in ATP and acetyl-CoA (Palekar
`and Kalbag 1991). This was thought to be caused by competition for free CoA (Griffith
`et al 1989) and the e†ect could be reversed with N-carbamoyl glutamate or carnitine
`(OÏConnor et al 1987, 1989). In sparse-fur mouse benzoate impairs several mito-
`chondrial pathways including the urea cycle, fatty acid oxidation and the citric acid
`
`Figure 2 Late-onset ornithine transcarbamylase deÐciency in a boy (S.H.) treated with
`sodium benzoate (375 mg/kg per day). ProÐle of plasma benzoate and hippurate during
`routine therapy. Arrows indicate each dose of 125 mg/kg
`
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`cycle, probably mediated through a decrease in acetyl-CoA (Kalbag and Palekar
`1988; Ratnakumari et al 1993b). In rats the rate of glycine production may also be
`rate limiting (Gregus et al 1992) and benzoate therapy could deplete the hepatic
`glycine pool. In the urease-treated rats benzoate, but not hippurate, has been shown
`to increase the rate of uptake of tryptophan into the brain (Bachmann et al 1986).
`Despite the animal studies,
`few adverse e†ects have been described in man
`(Batshaw and Brusilow 1981). No evidence could be found that benzoate impaired
`ureagenesis (Kubota and Ishizaki 1993). However, availability of glycine may limit
`its efficacy (Barshop et al 1989). Decreased carnitine concentrations have been
`described and carnitine supplements are reported to improve metabolic control
`(Michalak et al 1990; Ohtani et al 1988; Ratnakumari et al 1993a), but carnitine
`supplements do not appear to be used widely. There are no systematic studies of
`adverse e†ects and it seems that the most common side-e†ects are nausea and
`vomiting. Tinnitus and visual disturbance have also been recorded (Kubota and
`Ishizaki 1993; Simell et al 1986). However, side-e†ects may be underrecognized as it
`can be difficult to distinguish those of benzoate toxicity and of hyperammonaemia
`since both may increase the uptake of tryptophan into the brain (Bachmann et al
`1986).
`
`Sodium phenylacetate and phenylbutyrate: The next compound introduced was
`phenylacetate but this has now been superseded by the congener phenylbutyrate,
`because the former has a peculiarly unpleasant, clinging odour. Phenylbutyrate is
`activated to the CoA ester, which is metabolized by b-oxidation in the liver to
`phenylacetyl-CoA, which is then conjugated with glutamine (Figure 1). The resulting
`phenylacetylglutamine is excreted in the urine and hence 2 moles of nitrogen are
`excreted for each mole of phenylbutyrate. In practical terms, the conversion and
`excretion of 1 g of phenylbutyrate to phenylacetylglutamine would mean the
`removal of the equivalent of 1 g of protein.
`Phenylbutyrate is usually given as the sodium salt in doses of 250 mg/kg per day
`but has been given in doses of up to 630 mg/kg per day (Brusilow 1991). It is usually
`thought that conjugation and excretion are almost complete, but recoveries appear
`to be variable (Piscitelli et al 1995) and further studies are warranted. If conjugation
`and excretion were complete, the nitrogen removed following 250 mg/kg and
`630 mg/kg would be equivalent to 0.24 g and 0.6 g of protein/kg, respectively.
`Pharmacokinetics: After an intravenous load, Piscitelli and colleagues (1995)
`showed that phenylbutyrate was quickly converted to phenylacetate with saturable
`nonlinear kinetics. The subsequent conjugation to phenylacetylglutamine was more
`rapid, so that the concentrations of phenylacetate remained low. The peak concen-
`tration of phenylacetate was between 1 and 2 h and that of phenylacetylglutamine
`after 1 to 3.5 h.
`When it was given orally (Brusilow and Maestri 1996) the phenylbutyrate peak
`concentration was between 1 and 2 h post dose and the concentrations of phenylace-
`tate and phenylacetylglutamine peaked simultaneously at 3 h. When repeated doses
`were given, the concentration of phenylacetate increased during the day (Brusilow
`and Maestri 1996 and Figure 3), only returning to baseline overnight.
`
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`107
`
`Figure 3 Late onset ornithine transcarbamylase deÐciency in a boy (B.H.) treated with
`sodium benzoate (200 mg/kg per day) and sodium phenylbutyrate (300 mg/kg per day). ProÐle
`of plasma phenylbutyrate, phenylacetate and benzoate concentrations during routine therapy.
`Arrows indicate each dose of sodium benzoate (67 mg/kg) and sodium phenylbutyrate
`(100 mg/kg)
`
`e†ects: Wiech and colleagues
`Adverse
`recently reported a
`(1997) have
`retrospective study of the side-e†ects of sodium phenylbutyrate, but it was not
`always easy to distinguish between the e†ects of the disease and of the medication.
`The most common was menstrual disturbance in 23% of females at risk. Other
`problems included anorexia and a number of biochemical abnormalities including
`acidosis and alkalosis, hypoalbuminaemia, and hyper- and hypophosphataemia.
`Fanconi syndrome has been reported in two patients on an inborn error network on
`the Internet (Metab-1). On the same network it has also been reported that patients
`who do not swallow sodium phenylbutyrate quickly may develop oral mucositis.
`
`Arginine and citrulline:
`In man arginine is normally a nonessential amino acid
`(Snyderman et al 1959) because it is synthesized within the urea cycle. However,
`where there is a block in the cycle it becomes essential or at least semi-essential. For
`this reason, all patients with urea cycle disorders except those with arginase deÐ-
`ciency are likely to need a supplement of arginine to replace that which is not
`synthesized (Brusilow 1984). Brusilow showed that in the patients with urea cycle
`defects withdrawal of oral arginine led to a rise in plasma ammonia and glutamine,
`one reason for which was that patients became arginine deÐcient with net protein
`breakdown.
`For deÐciencies of ornithine transcarbamylase (OTC) and carbamoyl-phosphate
`synthase (CPS) a dose of arginine of 100È150 mg/kg per day appears to be sufficient
`for most patients. However, in severe variants of OTC and CPS deÐciencies citrul-
`line may be substituted for arginine in doses up to 170 mg/kg per day as this will
`
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`
`Figure 4 Argininosuccinic aciduria. As a result of the metabolic block, ornithine is not recy-
`cled and this is replaced by supplements of arginine. Argininosuccinate is excreted in the
`urine, thereby creating an alternative pathway for nitrogen excretion
`
`utilize an additional molecule of nitrogen. In patients with citrullinaemia and argin-
`inosuccinic aciduria there is a break in the cycle and ornithine is not reformed
`(Figure 4). Giving arginine which is converted to ornithine replaces that which is
`lost. In citrullinaemia patients receiving arginine therapy, plasma and, more impor-
`tantly, urine citrulline concentrations rise markedly creating an alternative pathway
`for nitrogen excretion, but the overall nitrogen excretion remains relatively small
`(Brusilow et al 1979). Similarly, in argininosuccinic aciduria plasma concentrations
`of argininosuccinate increase, but, as the renal clearance of argininosuccinate is
`high, a more e†ective pathway for removing waste nitroten is created (Brusilow and
`Batshaw 1979). Doses of arginine of up to 700 mg/kg per day may be needed
`(Maestri et al 1991). The increased plasma concentrations of citrulline and arginino-
`succinic acid could be toxic, but any problems appear to be less important than
`those caused by the accumulation of ammonia and glutamine.
`
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`
`T reatment of acute hyperammonaemia: Both sodium benzoate and sodium phenyl-
`butyrate can used intravenously during episodes of acute hyperammonaemia. The
`doses are similar to those for chronic long-term treatment, but care must be taken in
`calculating all doses, particularly when given intravenously. Two patients have died
`in the United States when given the wrong doses of the combined solution of
`sodium benzoate/sodium phenylacetate (S. W. Brusilow 1993, Memorandum to all
`investigators using sodium benzoate/sodium phenylacetate, 21 January 1993).
`
`L ong-term management of patients with urea cycle disorders: The protein intake,
`growth rate and requirements of the patients vary widely. For example some
`patients have a marked aversion to protein with consequently a low intake, while
`others eat normally. Amino acid utilization will increase during phases of rapid
`growth and decrease after puberty when growth ceases. As a result of the many
`factors that a†ect nitrogen utilization, the waste nitrogen load varies and hence the
`dose of alternative pathway medicines will also vary. The aim should be to maintain
`good metabolic control with plasma ammonia concentrations less than 80 kmol/L
`(normal \ 50 kmol/L) and plasma glutamine ideally less than 800 kmol/L, though in
`practice less than 1000 kmol/L is probably more realistic, particularly for those
`more severely a†ected (Maestri et al 1992).
`
`L ong-term e†ects of alternative pathway therapy: No controlled trials have been
`done to test the e†ect of alternative pathway medication and it is doubtful that
`such a trial would now ever be ethically acceptable. It is necessary to rely on bio-
`chemical changes and historical comparisons. The introduction of arginine, sodium
`benzoate and phenylbutyrate has improved both biochemical control and neuro-
`logical outcome (Letarte et al 1985; Maestri et al 1991, 1995, 1996; Msall et al 1984;
`Wildham et al 1992).
`In a recent review of 28 patients (23 females, 5 males) with late-presenting OTC
`deÐciency, 12 patients are of normal cognitive ability (IQ [ 85) but all the others are
`handicapped, ranging from mild to severe (P. Nicolaides, R. A. Surtees, J. V.
`Leonard, unpublished data). Analysing the data further, the 5 girls treated prospec-
`tively are normal. Of 7 patients with normal cognitive ability who presented symp-
`tomatically, 2 are still pre-school age, 2 others have speciÐc learning difficulties and
`2 presented late at 8 years and 12 years respectively.
`
`CONCLUSIONS
`
`Alternative pathway therapy combined with diet has proved remarkably e†ective,
`restoring nitrogen homeostasis in patients with urea cycle disorders. The drugs
`appear to be safe, although information is limited. The outcome is less good and is
`particularly dependent on the neurological status at the time of diagnosis and the
`response to treatment. Patients treated prospectively do better, so that every e†ort
`needs to continue to be made to establish diagnoses early.
`
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`ACKNOWLEDGEMENTS
`
`Feillet and L eonard
`
`The
`authors thank Dr Anne Green, Mrs Mary-Anne Preece and Ian Sewell for the
`assays of benzoate and phenylbutyrate and Dr Paula Nicolaides and Dr Robert
`Surtees for the outcome data of the patients they have studied.
`
`REFERENCES
`Bachmann C, Colombo JP (1983) Incrased tryptophan uptake into the brain in hyper-
`ammonaemia. L ife Sci 33: 2417È2424.
`Bachmann C, LuŽ thi H, Gradwohl M, Colombo JP (1986) Brain uptake of tryptophan in
`urease-injected hyperammonaemic rats after treatment with benzoate or hippurate.
`Biochem Med Metab Biol 36: 214È219.
`Barshop BA, Breuer J, Holm J, Leslie J, Nyhan WL (1989) Excretion of hippuric acid during
`sodium benzoate therapy in patients with hyperglycinaemia or hyperammonaemia. J Inher
`Metab Dis 12: 72È79.
`Batshaw ML (1983) Sodium benzoate and arginine: alternative pathway therapy in inborn
`errors of urea synthesis. Prog Clin Biol Res 127: 69È83.
`Batshaw ML, Brusilow SW (1981) Evidence of lack of toxicity of sodium phenylacetate and
`sodium benzoate in treating urea cycle enzymopathies. J Inher Metab Dis 4: 231.
`Brusilow SW (1984) Arginine, an indispensable amino acid for patients with inborn errors of
`urea synthesis. J Clin Invest 74: 2144È2148.
`Brusilow SW (1991) Phenylacetylglutamine may replace urea as a vehicle for waste nitrogen
`excretion. Pediatr Res 29: 147È150.
`Brusilow SW, Batshaw ML (1979) Arginine treatment of argininosuccinase deÐciency. L ancet
`1: 124È126.
`Brusilow SW, Horwich AL (1995) Urea cycle enzymes. In. Scriver CR, Beaudet AL, Sly WS,
`Valle D, eds. T he Metabolic and Molecular Bases of Inherited Disease, 7th edn. New York:
`McGraw-Hill, 1187È1232.
`Brusilow SW, Maestri NE (1996) Urea cycle disorders: diagnosis, pathophysiology, and
`therapy. Adv Pediatr 43: 127È170.
`Brusilow SW, Valle DL, Batshaw M (1979) New pathways of nitrogen excretion in inborn
`errors of urea synthesis. L ancet 2: 452È454.
`Connelly A, Cross JH, Gadian DG, Hunter JV, Kirkham FJ, Leonard JV (1993) Magnetic
`resonance spectroscopy shows increased brain glutamine in ornithine carbamoyl trans-
`ferase deÐciency. Pediatr Res 33: 77È81.
`Gregus Z, Fekete T, Varga F, Klaassen CD (1992) Availability of glycine and coenzyme A
`limits glycine conjugation in vivo. Drug Metab Dispos 20: 234È240
`Griffith AD, Cyr DM, Egan SG, et al (1989) Inhibition of pyruvate carboxylase by seque-
`stration of coenzyme A with sodium benzoate. Arch Biochem Biophys 269: 201È207.
`Hyman SL, Porter CA, Page TJ, Iwata BA, Kissel R, Batshaw ML (1987) Behavior manage-
`ment of feeding disturbances in urea cycle and organic acid disorders. J Pediatr 111: 558È
`562.
`Kalbag SS, Palekar AG (1988) Soidum benzoate inhibits fatty acids oxidation in rat liver.
`E†ect on ammonia levels. Biochem Metab Biol 40: 133È142.
`Kline JJ, Hug G, Schubert WK, Berry H (1981) Arginine deÐciency syndrome. Am J Dis
`Child 135: 437È442.
`Kubota K, Ishizaki T (1991) Dose-dependent pharmacokinetics of benzoic acid following oral
`administration of sodium benzoate to humans. Eur J Clin Pharmacol 41: 363È368.
`Kubota K, Ishizaki T (1993) E†ect of single oral dose of sodium benzoate on ureagenesis in
`healthy men and two patients with late onset citrullinaemia. Eur J Clin Pharmacol 45:
`465È468.
`
`J. Inher. Metab. Dis. 21 (1998) Suppl. 1
`
`10 of 11
`
`

`

`Alternative pathway therapy
`
`111
`
`Leonard JV (1995) Urea cycle disorders. In Fernandes J, Saudubray JM, Van den Berghe G,
`eds. Inborn Metabolic Diseases: Diagnosis and T reatment, 2nd ed. Berlin: Springer-Verlag,
`167È176.
`Letarte J, Qureshi IA, Ouellet R, Godard M (1985) Chronic benzoate therapy in a boy with
`partial ornithine transcarbamylase deÐciency. J Pediatr 106: 794È797.
`Lewis HB (1914) Studies in the synthesis of hippuric acid in the animal organism. J Biol
`Chem 18: 225È231.
`Maestri NE, Hauser ER, Bartholomew D, Brusilow SW (1991) Prospective treatment of urea
`cycle disorders. J Pediatr 119: 923È928.
`Maestri NE, McGowan KD, Brusilow SW (1992) Plasma glutamine concentration: a guide
`to the management of urea cycle disorders. J Pediatr 121: 259È261.
`Maestri NE, Clissold DB, Brusilow SW (1995) Long-term survival of patients with arginino-
`succinate synthetase deÐciency. J Pediatr 127: 929È935.
`Maestri NE, Brusilow SW, Clissold DB, Bassett SS (1996) Long-term treatment of girls with
`ornithine transcarbamylase deÐciency. N Engl J Med 335: 855È859.
`Michalak A, Lambert MA, Dallaire L, et al (1990) Hypocarnitinemie chez les patients atteints
`dÏun defaut primaire du metabolisme de lÏammoniaque traites avec le benzoate de sodium.
`Diabete Metab 16: 226È233.
`Msall M, Batshaw ML, Suss R, Brusilow SW, Mellits ED (1984) Neurologic outcome in
`children with inborn errors of urea synthesis. N Engl J Med 310: 1500È1505.
`OÏConnor JE, Costell M, Grisolia S (1987) The potentiation of ammonia toxicity by sodium
`benzoate is prevented by L-carnitine. Biochem Biophys Res Commun 145: 817È824.
`OÏConnor JE, Costell M, Grisolia S (1989) Carbamyl glutamate prevents the potentiation of
`ammonia toxicity by sodium benzoate. Eur J Pediatr 148: 540È542.
`Ohtani Y, Ohyagani K, Yamamoto S, Matsuda I (1988) Secondary carnitine deÐciency in
`hyperammonemic attacks of ornithine transcarbamylase deÐciency. J Pediatr 112: 409È414.
`Palekar AG, Kalbag SS (1991) Amino acids in the rat liver and plasma and some metabolites
`in the liver after sodium benzoate treatment. Biochem Med Metab Biol 46: 52È58.
`Piscitelli SC, Thibault A, Figg WD, et al (1995) Disposition of phenylbutyrate and its metab-
`olites, phenylacetate and phenylacetylglutamine. J Clin Pharmacol 35: 368È373.
`Ratnakumari L, Qureshi IA, Butterworth RF (1993a) E†ect of L-carnitine on cerebral and
`hepatic energy metabolites in congenitally hyperammonemic sparse-fur mice and its role
`during benzoate therapy. Metabolism 42: 1039È1046.
`Ratnakumari L, Qureshi IA, Butterworth RF (1993b) E†ect of sodium benzoate on cerebral
`and hepatic energy metabolites in spf mice with congenital hyperammonemia. Biochem
`Pharmacol 45: 137È146.
`Simell O, Sipila I, Rajantie J, Valle DL, Brusilow SW (1986) Waste nitrogen excretion via
`amino acid acylation: benzoate and phenylacetate in lysinuric protein intolerance. Pediatr
`Res 20: 1117È1121.
`Snyderman SE, Boyer A, Holt EL (1959) The arginine requirement of the infant Am J Dis
`Child 97: 192È195.
`Surtees RJ, Leonard JV (1989) Acute metabolic encephalopathy. J Inher Metab Dis 12
`(supplement 1): 42È54.
`Takeda E, Kuroda Y, Toshima K, Watanabe T, Naito E, Miyao M (1983) E†ect of long term
`administration of sodium benzoate to a patient with partial ornithine carbamoyl trans-
`ferase deÐciency. Clin Pediatr Phila 22: 206È208.
`Tremblay GC, Qureshi IA (1993) The biochemistry and toxicology of benzoic acid metabo-
`lism and its relationship to the elimination of waste nitrogen. Pharmac T her 60: 63È90.
`Wiech NL, Clissold DM, MacArthur RB (1997) Safety and efficacy of buphenyl (sodium
`phenylbutyrate) tablets and powder (Abstract). Advances in Inherited Urea Cycle Disorders,
`Satellite to the 7th International Congress for Inborn Errors of Metabolism, Vienna.
`Wildham K, Koch S, Scheibenreiter S, et al (1992) Long-term follow-up of 12 patients with
`late onset variant of argininosuccinic acid lysase deÐciency: no impairment of intellectual
`and psychomotor development during therapy. Pediatrics 89: 1182È1184.
`
`J. Inher. Metab. Dis. 21 (1998) Suppl. 1
`
`11 of 11
`
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