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E d i t o r i a l correspondence

The Journal o f Pediatrics March 1992

REFERENCE

I. Mead J. Functional significance of the area of apposition of diaphragm to rib cage. Am Rev Respir Dis 1979;110:31-2.

4.

5.

Carnitine deficiency caused by

valproic acid To the Editor: We read with great interest Shapira and Gutman's recent article I on carnitine deficiency in the muscle of patients taking valproic acid (VPA). We were struck by the large drop in muscle carnitine concentration produced by long-term VPA treatment. We have studied the effects of VPA and other anticonvulsant agents on earnitine metabolism and the urea cycle in human beings and mice. 2-6 We found that most children treated with VPA had hypocarnitinemia, that 52.3% had hyperamonemia, and that amino acids involved in the urea cycle were also affected; these alterations were reversed by oral administration of L-carnitine 2, 3 and were unrelated to prolonged fasting.4 Subcutaneous administration of a single dose of VPA to mice caused serum alterations similar to those described above. Thirty minutes after administration, acylearnitine levels in the liver, heart, muscle, and kidney had all risen, but in 4 hours had fallen again in all these tissues except the kidney. Free and total carnitine levels fell in the liver during the first 2 hours (returning to normal after 4 hours) but remained normal in muscle.5 In mice given VPA intragastrically every 8 hours for 7 days, free and total carnitine were above control levels in liver, muscle, and kidney 8 hours after the last dose of VPA. Acylcarnitine levels did not differ from those of a control group, but urinary excretion of acylcarnitine increased by 58.8%.6 Our experimental mice did not have the drop in free and total muscle carnitine levels observed in human beings by Shapira and Gutman 1and in mice by Nishida et al. 7 Further research on human beings sbould take into account their nutritional state, for which carnitine is a recognized marker; children with serious eneephalopathy often have major nutritional problems. M. Castro-Gago, MD F. Camifia, PhD S. Rodriguez-Segade, PhD Departarnento de Pediatria Servicio de Laboratorio Central Hospital General de Galicia Santiago de Compostela, Spain

REFERENCES

1. Shapira Y, Gutman A. Muscle carnitine deficiency in patients using valproic acid. J PEDIATR 1991;118:646-9. 2. Castro-Gago M, Otero S, Novo I, Rodrigo E, Rozas I, Rodriguez-Segade S. Defieiencia de carnitina asociada a hiperamonemia en nifios a tratamiento con ficido valproico. Revista Espanola de Epilepsia 1988;3:169-72. 3. Castro-Gago M, Rodrigo E, Novo I, Camifia F, Rodriguez-

6.

7.

Segade S. Hyperaminoacidemia in epileptic children treated with valproic acid. Childs Nerv Syst 1990;6:434-6. Castrn-Gago M, Rodrigo E, Marwan K, et al. Repercusi6n de la administraci6n aguda de ficido valproieo sobre el metabolismo de la carnitina y del amonio sanguineo. Revista Espanola de Epilepsia 1990;5:86-90. Rozas I, Camifia F, Paz JM, Alonso C, Castro-Gago M, Rodriguez-Segade S. Effects of acute valproate administration on carnitine metabolism in mouse serum and tissues. Biochem Pharmacol 1990;39:181-5. Camifia MF, Rozas I, Castro-Gago M, Paz M, Alonso C, Rodriguez-Segade S. Alteration of renal carnitine metabolism by anticonvulsant treatment. Neurology 1991;41:1444-8. Nishida N, Sugimoto T, Araki A, Woo M, Kakane Y, Kobayashi Y. Carnitine metabolism in valproate treated rats: the effect of L-carnitine supplementation. Pediatr Res 1987; 22:500-3.

Low plasma citruliine concentrations during protein restriction in an unaffected infant at risk for ornithine

transcarbamylase deficiency To the Editor: We read with interest the report of Batshaw et al) regarding the use of citrulline as a diagnostic marker in the prospective treatment of urea cycle disorders. We have noted similar suppression of citrulline levels in an infant at risk for ornithine transcarbamylase deficiency, and wish to add our experience to that of Drs. Batshaw and Berry. Baby Boy A was the 3500 gm product of a 41-week gestation. He had a maternal grandmother and two aunts who were carriers of ornithine transcarbamylase deficiency that resulted in symptoms; four maternal uncles died in the first week of life. The mother's carrier status was uncertain at the time of delivery. Apgar scores were 7 at 1 minute, and 9 at 5 minutes. The infant was transferred to the intensive care nursery for expectant management of ornithine transearbamylase deficiency pending diagnostic testing. The initial serum ammonia level was 50 ~mol/L (normal range, 5 to 50 ~mol/L) Treatment with sodium benzoate, 250 mg/kg per day, sodium phenylacetate, 250 mg/kg per day, and intravenously administered glucose was begun. The subsequent arterial ammonia level was 20 #mol/L. Because of the infant's vigor, on day 2 he was given an oral diet of L-arginine, essential amino acids, Mead Johnson formula 80056, and 24-calorie-30 ml formula, to provide 0.7 gm of protein/kg per day, and 104 calories/kg per day. Blood urea nitrogen levels ranged from 1 to 2 mmol/L (normal range, 8 to 18 mmol/L). Serial measurements of plasma amino acids were obtained. Trace levels of plasma citrulline were detectable on days 1 through 6, consistent with ornithine transcarbamylase deficiency. When serum ammonia concentrations remained normal at I week of life, the infant's protein intake was increased to 1.5 gm of protein per kilo-