Pediat. Res. 14: 779 (1980)

Letter to the Editor: Lysine Intolerance in Methylmalonic Acidemia

ICHIRO MATSUDA,"" NORlYUKl NAGATA. ITSUKO UEHARA, AND TAKENORI TERASHIMA

Department of Pediarrics. Kumamoto Universi!,' Hospiral, 860 Kumamoto. Japan

There are two different metabolic pathways to synthesize urea; If lysine-urea cycle is intact in our patient, urinary homocitrul- (a) Krebs-Henselite urea cycle; and (b) lysine-homocitrulline- line and homoarginine might be elevated as blood ammonia homoarigine-urea cycle, although the latter is a minor pathway increased, like in citrullinemia (6, 8) and other Krebs-Henselite and supported by a few reports (5,7. 8, 10). The first two steps of urea cycle disorders (4). Observed results may suggest that elevated Krebs-Henselite cycle-carbamylphosphate synthesis and conver- blood methylmalonic acid or methymalonyl CoA has a toxic effect sion from ornithine to citrulline are located at mitochondria in on lysine and ammonia metabolism, possibly on the stage of the liver, where a step of lysine to homocitrulline is also thought mitochondrial function. to be located (2).. . The connections of hyperlysinemia and hyperammonemia in urea cvcle disorders was re~ortedin ornithine carbamvltransferase deficiency (4). citrullinemia (5, 8), hyperlysinemia (I), and hy- REFERENCES AND NOTES perornithinemia (2). In methylmalonic acidemia, hyperlysinemia and hyperammonemia were also noted (6, 9). In earlier report, we I. Colombo. J. P.. Pldrter~ch.R.. Donath. A,. Spahr. A,. and Rossi. E: Congenital lyslne intolerance with periodic ammonia ~ntoxicalion.Lancet. 1: 1014 (1964). used the lysine loading test in two patients with variant form of 2. Fell. V.. Pollitt. R. J.. Sampson. G. A,. and Wright. T.: Ornlthinemia. hyperam- citrullinemia, in whom a higher elevation was found in blood monemla and homocitmllinurla. Am. J. Dis. Child.. 127: 752 (1974). lysine, ammonia, and urinary lysine as well as in urinary homo- 3. Gruskay. J. A. and Rosenberg. L. E.: lnhibit~on of hepat~cmitochondrial citrulline and homoarginine (5). These observations prompt us to carbamyl phosphatase synthetase (CPS') by acyl CoA esterase: poss~ble mechanism of hyperammonemia in the organic acidemias. Pediatr. Res. (Ab- perform the same loading test in a patient with methylmalonic stract). 13: 475 (1979). acidemia. A patient diagnosed as having methylmalonyl CoA 4. Krieger. I.. Bachman. C.. Gronemeyer. W.. and Cejku. J.: Propion~cac~demia mutase deficiency in cultured lymphocytes and skin fibroblasts (5) and hyperlysinemla In a case with orn~thlnetranscarbarnylase (OCT) defi- was receiving lysine (100 mg/dl per 0s) at attack of the episode ciency. J. Clin. Endocrinol. Metab.. 43: 796 (1976). 5. Matsuda. I.. Arashima. S.. Iman~sh~.Y.. Yamamoto. J.. Akaboshi. I.. Shinoruka. and under dietary control, where blood methylmalonic acid was S.. and Nagata. N.: Lysine Intolerance In a variant form of citmllinemia. 250 and below 10 pg/ml, respectively. In the former condition, Pediatr. Res.. 1.1: 1134 (1979). serum lysine was elevated from 3.5 to 38.8 pmol/dl, blood am- 6. Matsuda. 1.. Terashlma, T., Yamamoto. J., Akaboshi. I.. Shinozuka. S., Hattori. monia was elevated from 184 to 290 pg/dl, and urine lysine was S.. Nagata. N.. and Oka, Y.: Methylmalonic acidemla. Eur. J. Pediatr.. 128: 1x1 (1978). elevated from 1 13 to 986 mole/g creatinine [these increments were 7. Ryan, W. L.. Bark. A. J., and Johnson. R. J.: Lysine, homocltmll~ne and higher than those in control in our laboratory (6)], but no elevation homoarginine metabolism by the isolated perfused rat lrver. Arch. Blochem. was found in urinary homocitrulline and homoarginine. On the Biophys.. 123: 294 (1968). contrary, in the latter condition, serum lysine (5.1 pmole/dl) and X. Scott-Emuakpor. A,. Hlggis. J. V.. and Kohrrnan. A. F.: Citmlllnemia; a new case. with lmplicatlons concerning adaptallon to defective urea synthesis. blood ammonia (1 I1 &dl) were essentially unchanged, and an Pediatr. Res.. 0: 626 ( 1972). increase in urine lysine from 120 to 540 mole/g creatine was 9. Shapiro. L. J.. Bocan. M. E.. Paoman. L., Cedemaurn. S. D.. and Shaw. K. N. F.: within control rangk. Methylmalonyl Co-A mutase deficiency assoc~atedwith severe neonatal hy- Loading test was repeated using a double amount of lysine at perammonemia: activity of urea cycle enzymes. J. Ped~atr..93: 986 (1978). 10. Sogawa. H.. Oyanag~,K.. and Nakao. T.: Period~chyperarnmonem~a. hyperly- another attack of episode; urinary homocitrulline and homoargine sinemla and homocitrull~nem~aassociated with decreased arg~minosuccinate were again not elevated. synthetase and argin~anseact~vit~es. Pediatr. Res.. 11. 949 (1979). Shapiro et al. (9) found decreased activities of all 5 enzymes in I I. This research was supported by a grant for sc~entiticresearch from the Mln~stry Krebs-Henselite urea cycle in an autopsied liver sample of meth- of Education. Sc~ence,and Culture of Japan. 12. Requests for reprints should be addressed to: lchlro Matsuda. Department of ylmalonic acidemia. In rat and human liver homogenate, meth- Pediatrics. Kumamoto University Hosp~tal.860 Kumamoto. Japan. ylmalonyl CoA but not methylmalonic acid inhibited carbamyl- 13. Recelved for publication January 3. 1980. phosphate synthetase 1 (3). 14. Accepted for publ~cat~onJanuary 7. 1980.

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