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Hyperargininemia: Effect of ornithine and lysine supplementation
Volume 103 Number 5
genital myotonic dystrophy. Four of the 10 were delivered after pregnancies complicated by hydramnios; three had talipes, one together with reduced fetal movements, one with respiratory distress at term, and one with a positive diagnosis on postmortem examination. Two of the remaining three patients had extreme floppiness, one together with diaphragmatic hernia and one with respiratory distress at 38 weeks' gestation. The final patient had atelectasis and respiratory distress at term. Propositus status was assigned to 32 individuals. There were thus 31 (46 + 7 + 10 - 32) nonpropositus heterozygotes among a total of 57 nonpropositus siblings at risk. We have, therefore, already observed an excessive proportion of heterozygotes (54%). Of the 33 individuals who were normal at birth, onset occurred during childhood in seven, two at age 5 years, three at age8 years, and one each at age 15 and 16 years. Thus a risk of 7/33 (21%) is suggested for a normal sibling at birth. The clinical risk at age 16 years seems negligible. However, based on a truncated binomial distribution, n = 57, P = 0.5, a further 7.3% of the remaining 26 (1.9/26) might be expected to develop the disease. The corresponding risk at birth would then be 27%. DISCUSSION Because congenital myotonic dystrophy has only relatively recently been described,4 a risk table based on a lifetime follow-up of normal siblings will not be available for many years. At present, the best estimate can be provided by combining statistical and clinical observations; interpretation of these allows us to suggest that the risk to
Clinical and laboratory observations
763
a normal sibling at age 16 years lies somewhere between zero (clinical observation) and 7% (statistical calculation). Similarly, the risk to a normal sibling at birth lies between 21% and 27%. Our findings are supported by the work of Bundey and Carter, 5 who found that five of nine siblings of index cases with congenital myotonic dystrophy were affected. Our risk figures represent an overall risk, which may be modified somewhat both by the birth order and by the sex of the individual. Of the 53 patients, 26 were male, and only one first developed evidence of the disease beyond the early months of life, in contrast with six of 27 females (P = 0.11). Further, five of seven patients with later onset of myotonic dystrophy were born prior to the birth of infants with severe congenital disease. The risk of later developing myotonic dystrophy may therefore be slightly higher than the overall risk for females and for siblings born prior to the birth of congenitally affected infants. REFERENCES 1. Harper PS, Dyken PR: Early onset dystrophia myotonica: Evidence supporting a maternal environmental factor. Lancet 2:53, 1972. 2. O'Brien T, Harper PS: Reproductive problems and neonatal loss in women with myotonic dystrophy. J Obstet Gynecol (In press.) 3. O'Brien T, Harper PS: The course, prognosis and complications of childhood onset myotonic dystrophy. Dev Med Child Neurol (In press.) 4. Vanier TM: Dystrophia myotonica in childhood. Br Med J 2:1284, 1960. 5. BundeyS, Carter CO: Genetic heterogeneity for dystrophia myotonica. J Med Genet 9:311, 1972.
Hyperargininemia." Effect of ornithine and lysine supplementation Soo-Sang Kang, M.D., Ph.D., Paul W. K. Wong, M.D., M.Sc., and Michelle A. Melyn, M.D. Chicago, Ill.
HYPERARGIN1NEMIA resulting from arginase deficiency is characterized by recurrent vomiting, seizures, spastic From the Section of Genetics, Department of Pediatrics, Rush Medical College and Rush-Presbyterian-St. Luke's Medical Center. Supported by a grant from the March of Dimes/Birth Defects Foundation. Reprint requests: Soo-Sang Kang, M.D., Section of Genetics, Department of Pediatrics, Rush-Presbyterian-St. Luke's Medical Center, 1753 W. Congress Pkwy., Chicago, 1L 60612.
diplegia, psychomotor retardation, and delayed physical growth. It has been suggested that the accumulation of both arginine and ammonia is responsible for the development of these clinical manifestations. In some patients, hyperammonemia is not a constant finding. However, the consistent elevation of plasma and urinary orotic acid values indicates a disturbance of ammonia metabolism. 1 It has been reported by various investigators that the use of a low-protein diet lowers plasma arginine concentrations in these patients. 13 Treatment with supplements of essen-
7 64
Clinical and laboratory observations
The Journal of Pediatrics November 1983
TabLe. M e a n amino acids, ammonia, and orotic acid concentrations
No therapy Arginine 0zmol/L) Plasma CSF Plasma/CSF Lysine (#tool/L) Plasma CSF Plasma/CSF Ornithine (#mol/L) Plasma CSF Plasma/CSF Citrulline (#mol/L) Plasma CSF Plasma/CSF Ammonia (#g/d0 Plasma Orotic acid (ug/mg creatinine) Urine
Lysine therapy
Lysine and ornithine therapy
Normal value Mean
I
Range
478.0 (9) 64.5 (2) 7.4
699.0 (6) 74.2 (1) 9.4
724.0 (11) 74.0 (2) 9.8
62.8 20.0 3.1
23 6
to 115 to 29
35.0 (9) 2.1 (2) 16.7
168.0 (6) 17.3 (1) 9.7
163.0 (11) 9.5 (2) 17.2
161.6 19.0 8.5
82 13
to 236 to 42
40.0 (9) 1.0 (2) 40.0
40.0 (6) ND (1) --
62.0 (11) 3.3 (2) 18.8
58.9 5.7 10.3
32 3
to 88 to 8.5
17.0 (9) 1.9 (2) 8.9
24.0 (6) 2.1 (1) 11.4
26.0 (11) 3.5 (2) 7.4
23.0 1.9 15.3
16 to 49 0.5 to 3.5
132.0 (15)
96.5 (8)
52.5 (12)
49.0
15
to 80
72.0 (5)
30.9 (3)
3.3 (4)
5.2
2
to 15
Abnormal plasma/CSF ratios observed for dibasic amino acids. All experiments carried out while patient given 1.5 gm protein/kg/day; blood samples obtained for chemical tests three hours after breakfast. Numbers of samples analyzed in parenthesis. ND, Nondetectable. t i a l amino acids results in further improvement. 1,4 The success with dietary management of hyperargininemia has been variable. W e report our experience with lysine and ornithine supplementation in a patient with hyperarginihernia. CASE REPORT The patient was an 11-year-old girl, born of unrelated Hispanic parents. At the age of 8 months, she was hospitalized because of a seizure disorder. Recurrent episodes of seizures were treated with anticonvulsants. Poor appetite and periodic vomiting resulted in a low protein intake. She sat up at 8 months, walked at 16 months, and started to say simple words at 2 years of age. At 4 years, an abnormal gait was observed, and spastic diplegia was diagnosed. At age 7 years, the patient functioned at a 3-year level. Physical examination revealed severe retardation in physical and psychomotor development, spasticity, and hyperactive deeptendon reflexes. Electroencephalogram showed diffuse cerebral dysfunction with epileptiform activity. Biochemical studies revealed hyperammonemia, hyperoroticaciduria, and marked hyperargininemia (Table). Amino acid determinations in the CSF showed an increase of arginine and a decrease of lysine and ornithine concentrations. Urinary excretion of arginine and ornithine was increased, but excretion of lysine was within the normal range. All essential amino acid ~r~bentrations in the plasma, except methionine, were low. Arginase activity was not detectable in the erythrocytes from the patient, whereas the activity in the erythrocytes from the mother was 520 #mol urea/hr/gm hemoglobin (normal 640 to 1300 :zmol).
RESULTS Our patient had persistent hyperammonemia, hyperorotic aciduria (Table), recurrent vomiting, and poor weight gain during protein restriction and orally administered lactulose therapy. Hence, selective amino acid supplementation was provided while protein intake was maintained at 1.5 g m / k g / d a y . During a period of six months, when the lysine supplement (250 m g / k g / d a y ) was given, an increase of arginine in the plasma and C S F and a decrease of ornithine in the C S F were observed (Table). Plasma ammonia and urine orotic acid values decreased but remained abnormal. On the other hand, with improvement in her appetite, all essential amino acids in the plasma were within the normal range. When lysine (250 m g / k g / d a y ) and ornithine (100 m g / k g / d a y ) supplements were given simultaneously for a period of six months, an increase in plasma and C S F arginine values was observed, but plasma lysine, ornithine, and ammonia concentration returned to normal (Table). The most significant change in the laboratory data was found in orotic acid excretion. Prior to ornithine supplementation, urinary orotic acid excretion was two to five times normal, whereas orotic acid excretion decreased to low normal values during this experimental period (Table). In addition, the patient not only tolerated these amino acid supplements well, but also had good appetite and cessation of vomiting. Better weight gain and improvement in
Volume 103 Number 5
electroencephalographic findings with marked reduction of epileptiform activity were observed. During ornithine and lysine therapy, unrestricted protein intake varying from 1.5 to 2.0 gm/kg/day did not result in any abnormal increase of plasma ammonia or urine orotic acid concentrations. The patient remained well clinically. Discontinuation of the ornithine supplement, however, caused an abnormal increase of plasma ammonia and urine orotic acid concentrations within a week. DISCUSSION Based on the observation that arginine and lysine share a common transport system in the blood-brain barrier, Pardridge 5 proposed that lysine deficiency in the brain caused by inhibition of lysine transport by high blood arginine concentrations would result in brain damage in patients with hyperargininemia. Because a common transport system for dibasic amino acids was also found in the renal tubules, a lysine load could result in a reduction of plasma arginine and ornithine concentrations by competitive inhibition of renal reabsorption. Contrary to expectation, there was no decrease in plasma arginine values after a load of lysine, either in normal subjects or in patients with hyperargininemia.6'7 In addition, a reduction of plasma ornithine but not of arginine was observed following lysine loading in patients with hyperornithinemia,s Because a high concentration of arginine may cause damage in the central nervous system selectively, intracerebral amino acid levels may be more critical than amino acid concentrations in the blood or other tissues. The ratios of arginine to other basic amino acids may also be important factors in neurotoxicity. Even if the plasma concentration of lysine or ornithine is not low, intracellular availability may be reduced by an elevated plasma arginine concentration. Hence, it would appear valuable to determine whether a lysine load could reduce arginine and increase lysine in the brain. Bryla and Harris 9 reported that arginine interferes with transmitochondrial transport of ornithine in isolated liver mitochondria. Ornithine is carbamoylated to citrulline within the mitochondria, whereas subsequent reactions of the urea cycle are carried out in extramitochondrial systems. In addition, hyperammonemia in these patients is not associated with an elevation of citrulline or the appearance of argininosuccinic acid; thus, it is possible that decreased carbamoylation of ornithine is a significant consequence of hyperargininemia. Competitive inhibition of ornithine uptake by excessive cytoplasmic arginine may cause an intramitochondrial deficiency of ornithine, which is indispensable for the metabolism of ammonia. Alternatively, intramitochondrial ornithine deficiency may occur because of a lack of ornithine regeneration from arginine
Clinical and laboratory observations
76$
in the liver. 1~ However, there is no apparent plasma deficiency of ornithine in these patients. 2,3 Our data demonstrate that ornithine and lysine supplements produced a substantial reduction of plasma ammonia and urinary orotic acid to normal values in a subject with hyperargininemia. In contrast, Cederbaum et at. 4 did not observe a consistent reduction of urinary orotic acid and pyrimidine in two patients given ornithine for five days. However, their patients were different in other aspects; they had increased plasma citrulline and CSF ornithine concentrations. Multiple factors may be involved in the pathogenesis of neurotoxicity in these patients. Periodic hyperammonemia is a well-recognized cause of brain damage. In addition, marked increase of arginine and low concentrations of ornithine and lysine in the brain may also be important factors. However, normal lysine and significantly increased ornithine values (nine to 16 times normal) were found in the CSF of some patients.4 In our patient, treatment with lysine and ornithine supplements was able to maintain plasma lysine, plasma and CSF ornithine, plasma ammonia, and urinary orotic acid within normal limits and permitted satisfactory growth. The marked improvement in the EEG findings suggested that this treatment might also be beneficial neurologically. The untoward effects of hyperargininemia, if any, will have to be determined by future observations. REFERENCES 1. Snyderman SE, Sansaricq C, Chen WJ, Norton PM, Phansalkar SV: Argininemia. J PEDIATR90:563, 1977. 2. Cederbaum SD, Shaw KWF, Valente M: Hyperargininemia. J PEDIATR90:569, 1977. 3. Shih VE: Urea cycle disorders and other original hyperammonemic syndromes. In Stanbury JB, Wyngaaden JB, Fredrickson DS, editors: The metabolic basis of inherited disease. New York, 1979, McGraw-Hill, p 362. 4. Cederbaum SD, Moedijono SJ, Shaw KNF, Carter M, Naylor E, Walzer M: Treatment of hyperargininemia due to arginase deficiency with a chemically defined diet. J Inher Metab Dis 5:95, 1982. 5. Pardrldge WM: Lysine supplementation in hyperargininemia (Letter). J PEDIATR91:1032, 1977. 6. Snyderman EE, Sansaricq C, Chen WJ, Norton PM, Phansalkar SV: Lysine supplementation in hyperargininemia (Reply). J PEDIATR91:1032, 1977. 7. Michels VV, Beaudet AL: Arginine deficiency in multiple tissues in argininemia. Clin Genet 13:61, 1978. 8. Giordano C, Desanto NG, Pluvio M, Santinelli R, Stoppoloni G: Lysine in treatment of hyperornithinemia. Nephron 22:97, 1978. 9. Bryla J, Harris EJ: Accumulation of ornithine and citrulline in rat liver mitochondria in relation to citrulline formation. FEBS Lett 72:331, 1976. 10. Qureshi 1A, Letente J, Quellet R, Lelievre M, Laberge C: Ammonia metabolism in a family affected by hyperarginihernia. Diabete Metab 7:5, 1981.
genital myotonic dystrophy. Four of the 10 were delivered after pregnancies complicated by hydramnios; three had talipes, one together with reduced fetal movements, one with respiratory distress at term, and one with a positive diagnosis on postmortem examination. Two of the remaining three patients had extreme floppiness, one together with diaphragmatic hernia and one with respiratory distress at 38 weeks' gestation. The final patient had atelectasis and respiratory distress at term. Propositus status was assigned to 32 individuals. There were thus 31 (46 + 7 + 10 - 32) nonpropositus heterozygotes among a total of 57 nonpropositus siblings at risk. We have, therefore, already observed an excessive proportion of heterozygotes (54%). Of the 33 individuals who were normal at birth, onset occurred during childhood in seven, two at age 5 years, three at age8 years, and one each at age 15 and 16 years. Thus a risk of 7/33 (21%) is suggested for a normal sibling at birth. The clinical risk at age 16 years seems negligible. However, based on a truncated binomial distribution, n = 57, P = 0.5, a further 7.3% of the remaining 26 (1.9/26) might be expected to develop the disease. The corresponding risk at birth would then be 27%. DISCUSSION Because congenital myotonic dystrophy has only relatively recently been described,4 a risk table based on a lifetime follow-up of normal siblings will not be available for many years. At present, the best estimate can be provided by combining statistical and clinical observations; interpretation of these allows us to suggest that the risk to
Clinical and laboratory observations
763
a normal sibling at age 16 years lies somewhere between zero (clinical observation) and 7% (statistical calculation). Similarly, the risk to a normal sibling at birth lies between 21% and 27%. Our findings are supported by the work of Bundey and Carter, 5 who found that five of nine siblings of index cases with congenital myotonic dystrophy were affected. Our risk figures represent an overall risk, which may be modified somewhat both by the birth order and by the sex of the individual. Of the 53 patients, 26 were male, and only one first developed evidence of the disease beyond the early months of life, in contrast with six of 27 females (P = 0.11). Further, five of seven patients with later onset of myotonic dystrophy were born prior to the birth of infants with severe congenital disease. The risk of later developing myotonic dystrophy may therefore be slightly higher than the overall risk for females and for siblings born prior to the birth of congenitally affected infants. REFERENCES 1. Harper PS, Dyken PR: Early onset dystrophia myotonica: Evidence supporting a maternal environmental factor. Lancet 2:53, 1972. 2. O'Brien T, Harper PS: Reproductive problems and neonatal loss in women with myotonic dystrophy. J Obstet Gynecol (In press.) 3. O'Brien T, Harper PS: The course, prognosis and complications of childhood onset myotonic dystrophy. Dev Med Child Neurol (In press.) 4. Vanier TM: Dystrophia myotonica in childhood. Br Med J 2:1284, 1960. 5. BundeyS, Carter CO: Genetic heterogeneity for dystrophia myotonica. J Med Genet 9:311, 1972.
Hyperargininemia." Effect of ornithine and lysine supplementation Soo-Sang Kang, M.D., Ph.D., Paul W. K. Wong, M.D., M.Sc., and Michelle A. Melyn, M.D. Chicago, Ill.
HYPERARGIN1NEMIA resulting from arginase deficiency is characterized by recurrent vomiting, seizures, spastic From the Section of Genetics, Department of Pediatrics, Rush Medical College and Rush-Presbyterian-St. Luke's Medical Center. Supported by a grant from the March of Dimes/Birth Defects Foundation. Reprint requests: Soo-Sang Kang, M.D., Section of Genetics, Department of Pediatrics, Rush-Presbyterian-St. Luke's Medical Center, 1753 W. Congress Pkwy., Chicago, 1L 60612.
diplegia, psychomotor retardation, and delayed physical growth. It has been suggested that the accumulation of both arginine and ammonia is responsible for the development of these clinical manifestations. In some patients, hyperammonemia is not a constant finding. However, the consistent elevation of plasma and urinary orotic acid values indicates a disturbance of ammonia metabolism. 1 It has been reported by various investigators that the use of a low-protein diet lowers plasma arginine concentrations in these patients. 13 Treatment with supplements of essen-
7 64
Clinical and laboratory observations
The Journal of Pediatrics November 1983
TabLe. M e a n amino acids, ammonia, and orotic acid concentrations
No therapy Arginine 0zmol/L) Plasma CSF Plasma/CSF Lysine (#tool/L) Plasma CSF Plasma/CSF Ornithine (#mol/L) Plasma CSF Plasma/CSF Citrulline (#mol/L) Plasma CSF Plasma/CSF Ammonia (#g/d0 Plasma Orotic acid (ug/mg creatinine) Urine
Lysine therapy
Lysine and ornithine therapy
Normal value Mean
I
Range
478.0 (9) 64.5 (2) 7.4
699.0 (6) 74.2 (1) 9.4
724.0 (11) 74.0 (2) 9.8
62.8 20.0 3.1
23 6
to 115 to 29
35.0 (9) 2.1 (2) 16.7
168.0 (6) 17.3 (1) 9.7
163.0 (11) 9.5 (2) 17.2
161.6 19.0 8.5
82 13
to 236 to 42
40.0 (9) 1.0 (2) 40.0
40.0 (6) ND (1) --
62.0 (11) 3.3 (2) 18.8
58.9 5.7 10.3
32 3
to 88 to 8.5
17.0 (9) 1.9 (2) 8.9
24.0 (6) 2.1 (1) 11.4
26.0 (11) 3.5 (2) 7.4
23.0 1.9 15.3
16 to 49 0.5 to 3.5
132.0 (15)
96.5 (8)
52.5 (12)
49.0
15
to 80
72.0 (5)
30.9 (3)
3.3 (4)
5.2
2
to 15
Abnormal plasma/CSF ratios observed for dibasic amino acids. All experiments carried out while patient given 1.5 gm protein/kg/day; blood samples obtained for chemical tests three hours after breakfast. Numbers of samples analyzed in parenthesis. ND, Nondetectable. t i a l amino acids results in further improvement. 1,4 The success with dietary management of hyperargininemia has been variable. W e report our experience with lysine and ornithine supplementation in a patient with hyperarginihernia. CASE REPORT The patient was an 11-year-old girl, born of unrelated Hispanic parents. At the age of 8 months, she was hospitalized because of a seizure disorder. Recurrent episodes of seizures were treated with anticonvulsants. Poor appetite and periodic vomiting resulted in a low protein intake. She sat up at 8 months, walked at 16 months, and started to say simple words at 2 years of age. At 4 years, an abnormal gait was observed, and spastic diplegia was diagnosed. At age 7 years, the patient functioned at a 3-year level. Physical examination revealed severe retardation in physical and psychomotor development, spasticity, and hyperactive deeptendon reflexes. Electroencephalogram showed diffuse cerebral dysfunction with epileptiform activity. Biochemical studies revealed hyperammonemia, hyperoroticaciduria, and marked hyperargininemia (Table). Amino acid determinations in the CSF showed an increase of arginine and a decrease of lysine and ornithine concentrations. Urinary excretion of arginine and ornithine was increased, but excretion of lysine was within the normal range. All essential amino acid ~r~bentrations in the plasma, except methionine, were low. Arginase activity was not detectable in the erythrocytes from the patient, whereas the activity in the erythrocytes from the mother was 520 #mol urea/hr/gm hemoglobin (normal 640 to 1300 :zmol).
RESULTS Our patient had persistent hyperammonemia, hyperorotic aciduria (Table), recurrent vomiting, and poor weight gain during protein restriction and orally administered lactulose therapy. Hence, selective amino acid supplementation was provided while protein intake was maintained at 1.5 g m / k g / d a y . During a period of six months, when the lysine supplement (250 m g / k g / d a y ) was given, an increase of arginine in the plasma and C S F and a decrease of ornithine in the C S F were observed (Table). Plasma ammonia and urine orotic acid values decreased but remained abnormal. On the other hand, with improvement in her appetite, all essential amino acids in the plasma were within the normal range. When lysine (250 m g / k g / d a y ) and ornithine (100 m g / k g / d a y ) supplements were given simultaneously for a period of six months, an increase in plasma and C S F arginine values was observed, but plasma lysine, ornithine, and ammonia concentration returned to normal (Table). The most significant change in the laboratory data was found in orotic acid excretion. Prior to ornithine supplementation, urinary orotic acid excretion was two to five times normal, whereas orotic acid excretion decreased to low normal values during this experimental period (Table). In addition, the patient not only tolerated these amino acid supplements well, but also had good appetite and cessation of vomiting. Better weight gain and improvement in
Volume 103 Number 5
electroencephalographic findings with marked reduction of epileptiform activity were observed. During ornithine and lysine therapy, unrestricted protein intake varying from 1.5 to 2.0 gm/kg/day did not result in any abnormal increase of plasma ammonia or urine orotic acid concentrations. The patient remained well clinically. Discontinuation of the ornithine supplement, however, caused an abnormal increase of plasma ammonia and urine orotic acid concentrations within a week. DISCUSSION Based on the observation that arginine and lysine share a common transport system in the blood-brain barrier, Pardridge 5 proposed that lysine deficiency in the brain caused by inhibition of lysine transport by high blood arginine concentrations would result in brain damage in patients with hyperargininemia. Because a common transport system for dibasic amino acids was also found in the renal tubules, a lysine load could result in a reduction of plasma arginine and ornithine concentrations by competitive inhibition of renal reabsorption. Contrary to expectation, there was no decrease in plasma arginine values after a load of lysine, either in normal subjects or in patients with hyperargininemia.6'7 In addition, a reduction of plasma ornithine but not of arginine was observed following lysine loading in patients with hyperornithinemia,s Because a high concentration of arginine may cause damage in the central nervous system selectively, intracerebral amino acid levels may be more critical than amino acid concentrations in the blood or other tissues. The ratios of arginine to other basic amino acids may also be important factors in neurotoxicity. Even if the plasma concentration of lysine or ornithine is not low, intracellular availability may be reduced by an elevated plasma arginine concentration. Hence, it would appear valuable to determine whether a lysine load could reduce arginine and increase lysine in the brain. Bryla and Harris 9 reported that arginine interferes with transmitochondrial transport of ornithine in isolated liver mitochondria. Ornithine is carbamoylated to citrulline within the mitochondria, whereas subsequent reactions of the urea cycle are carried out in extramitochondrial systems. In addition, hyperammonemia in these patients is not associated with an elevation of citrulline or the appearance of argininosuccinic acid; thus, it is possible that decreased carbamoylation of ornithine is a significant consequence of hyperargininemia. Competitive inhibition of ornithine uptake by excessive cytoplasmic arginine may cause an intramitochondrial deficiency of ornithine, which is indispensable for the metabolism of ammonia. Alternatively, intramitochondrial ornithine deficiency may occur because of a lack of ornithine regeneration from arginine
Clinical and laboratory observations
76$
in the liver. 1~ However, there is no apparent plasma deficiency of ornithine in these patients. 2,3 Our data demonstrate that ornithine and lysine supplements produced a substantial reduction of plasma ammonia and urinary orotic acid to normal values in a subject with hyperargininemia. In contrast, Cederbaum et at. 4 did not observe a consistent reduction of urinary orotic acid and pyrimidine in two patients given ornithine for five days. However, their patients were different in other aspects; they had increased plasma citrulline and CSF ornithine concentrations. Multiple factors may be involved in the pathogenesis of neurotoxicity in these patients. Periodic hyperammonemia is a well-recognized cause of brain damage. In addition, marked increase of arginine and low concentrations of ornithine and lysine in the brain may also be important factors. However, normal lysine and significantly increased ornithine values (nine to 16 times normal) were found in the CSF of some patients.4 In our patient, treatment with lysine and ornithine supplements was able to maintain plasma lysine, plasma and CSF ornithine, plasma ammonia, and urinary orotic acid within normal limits and permitted satisfactory growth. The marked improvement in the EEG findings suggested that this treatment might also be beneficial neurologically. The untoward effects of hyperargininemia, if any, will have to be determined by future observations. REFERENCES 1. Snyderman SE, Sansaricq C, Chen WJ, Norton PM, Phansalkar SV: Argininemia. J PEDIATR90:563, 1977. 2. Cederbaum SD, Shaw KWF, Valente M: Hyperargininemia. J PEDIATR90:569, 1977. 3. Shih VE: Urea cycle disorders and other original hyperammonemic syndromes. In Stanbury JB, Wyngaaden JB, Fredrickson DS, editors: The metabolic basis of inherited disease. New York, 1979, McGraw-Hill, p 362. 4. Cederbaum SD, Moedijono SJ, Shaw KNF, Carter M, Naylor E, Walzer M: Treatment of hyperargininemia due to arginase deficiency with a chemically defined diet. J Inher Metab Dis 5:95, 1982. 5. Pardrldge WM: Lysine supplementation in hyperargininemia (Letter). J PEDIATR91:1032, 1977. 6. Snyderman EE, Sansaricq C, Chen WJ, Norton PM, Phansalkar SV: Lysine supplementation in hyperargininemia (Reply). J PEDIATR91:1032, 1977. 7. Michels VV, Beaudet AL: Arginine deficiency in multiple tissues in argininemia. Clin Genet 13:61, 1978. 8. Giordano C, Desanto NG, Pluvio M, Santinelli R, Stoppoloni G: Lysine in treatment of hyperornithinemia. Nephron 22:97, 1978. 9. Bryla J, Harris EJ: Accumulation of ornithine and citrulline in rat liver mitochondria in relation to citrulline formation. FEBS Lett 72:331, 1976. 10. Qureshi 1A, Letente J, Quellet R, Lelievre M, Laberge C: Ammonia metabolism in a family affected by hyperarginihernia. Diabete Metab 7:5, 1981.