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X-LINKED TRANSMISSION OF ORNITHINE-TRANSCARBAMYLASE DEFICIENCY
1148 ponent of hxmostasis. It is significant that heparin administered before stress decreased the amount and degree of bleeding from stress in animals receiving indirect anticoagulants. These observations provide an explanation for the successful experience of de Takats in using subI certainly support cutaneous heparin before operation. his statement that " the bodily defence against thromboembolism can be most effectively bolstered by heparin, but the set dosage and the timing of administration may need modification to obtain even better results than have been reported ". Hemostasis-Thrombosis Research Unit, Department of Physiology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N 0WO, Canada.
LOUIS B.
JAQUES.
X-LINKED TRANSMISSION OF ORNITHINE-TRANSCARBAMYLASE DEFICIENCY SIR,-Dr. Campbell and his colleagues1 suggested that
complete ornithine transcarbamylase (o.T.c.) deficiency a cause of neonatal deaths and that the gene coding for this enzyme may be X-linked. This suggestion was compatible with their finding of complete o.T.c. deficiency in a boy who died at 3 days and with previous reports of hyperammonxmia in girls with partial o.T.c. activity.2-4 We have identified two large pedigrees with O.T.C. deficiency which support these proposals.
may be
Family A was identified at the University of Washington when newborn boy died at 2 days with symptoms suggesting hyperammonaemia. Assays of the urea-cycle enzymes obtained post mortem from the liver revealed complete deficiency of o.T.c. The activity of other enzymes of the urea cycle (carbamyl-
Family B was identified at the University of Colorado when a boy died during the newborn period with symptoms of hyperammonsemia. This child also had complete deficiency of o.T.c. activity in liver tissue obtained at necropsy. 8 other boys in three generations had died with similar symptoms in the newborn period. The pattern of inheritance in each pedigree is consistent with X linkage. A total of 15 males have died, and 10 females can be identified as obligate heterozygotes (see figure). These two pedigrees support the suggestion of Campbell et al.that the genetic information for the o.T.c. enzyme is probably located on the X chromosome. The clinical and enzyme data are compatable with the suggestion that complete deficiency of o.T.c. is a cause of neonatal deaths in boys and that some female heterozygotes may have sufficient enzyme deficiency to cause clinical symptoms later in childhood. The degree of manifestation in female heterozygotes would be determined by the proportion of X chromosomes coding for the normal o.T.c. enzyme which would have been inactivated during development by lyonisation. Further confirmation of X linkage for O.T.C. will have to await valid techniques for heterozygote detection and/or demonstration of o.T.c. linkage to other X chromosome markers. Unfortunately, the absence of measurable O.T.c. activity in normal fibroblasts precludes the use of skin cultures for establishing X linkage. Department of Pediatrics, University of Washington, Seattle, Washington 98195. Department of Pediatrics, University of Colorado Medical Center, Denver, Colorado 80220.
C. RONALD SCOTT CECILIA CHIANG TENG. STEPHAN I. GOODMAN ARNOLD GREENSHER JOHN W. MACE.
a
phosphate synthetase, argininosuccinate synthetase, argininosuccinase, and arginase) was normal. In two generations 5 boys had died with similar symptoms.
Campbell, A. G. M., Rosenberg, L. E., Snodgrass, P. J., Nazum, C. T. Lancet, 1971, ii, 217. 2. Russell, A., Levin, B., Oberholzer, V. G., Sinclair, L. ibid. 1962, ii, 699. 3. Levin, B., Abraham, J. M., Oberholzer, V. G., Burgess, E. A. Archs Dis. Childh. 1969, 44, 152. 4. Sunshine, P., Lindenbaum, J. E., Levy, H. L., Freeman, J. M. Pediatrics, Springfield, 1972, 50, 100. 1.
ANTITHROMBIN III AND THE ŒSTROGEN CONTENT OF COMBINED ŒSTRO-PROGESTAGEN CONTRACEPTIVES
SBR,—Oral contraceptives have been reported to increase the risk of thromboembolism, and there are many attempts to find abnormalities which might explain the observed accidents. The decrease in antithrombin III (A.T. III) was the most frequent finding. 5-10 In 1969 we reported 11 a low level of A.T. III in 11 out of 15 women studied under oral contraception and a normal level in 4 women only. At that time, as well as in our following study, 12 we did not distinguish between type of pill used and its oestrogen content.
Our present study concerns 73 women who were given combined oestro-progestagens: 19 received 75-150 .g. cestrogen per day, and 54 received 50 jg. of this hormone. The control group consisted of 67 healthy women, aged 20 to 45, who were not on the pill (or not yet). All women taking the pill were examined every 3 to 6 months, at the 22nd to 25th day of the menstrual cycle (17th to 20th day of the pill). The period of time on the pill varied from 3 months to 4 years. Serum-A.T.-III was measured by the method of von Kaulla.13
Pedigrees of deficiency.
two
families with ornithine-transearbamylase
5. Fagerhol, M. K., Abildgaard, U., Bergsjo, P., Jacobsen, J. H. Lancet, 1970, i, 1175. 6. Howie, P. W., Mallinson, A. C., Prentice, C. R. M., Horne, C. H. W., McNicol, G. P. ibid. p. 1329. 7. Peterson, R. A., Krull, P. E., Finley, P., Ettinger, M. G. Am. J. clin. Path. 1970, 53, 468. 8. Von Kaulla, E., Von Kaulla, K. N. Lancet, 1970, i, 36. 9. Von Kaulla, E., Droegemueller, W., Aoki, N., Von Kaulla, K. N. Am. J. Obstet. Gynec. 1971, 109, 868. 10. Zuck, T., Bergin, J., Raymond, J., Dwyre, W. Surgery Gynec. Obstet. 1971, 133, 609. 11. Conard, J., Doumenc, J., Prost, R. J., Rozenbaum, H., Salomon, Y., Samama, M., Soria, J. Concours Méd. 1969, 41, 7089. 12. Conard, J., Doumenc, J., Samama, M., Bousser, J. XIIIth International Congress of Hæmatology, Munich, 1960; abstract p. 246. 13. Von Kaulla, E., Von Kaulla, K. N. Am. J. clin. Path. 1967, 48, 69.
LOUIS B.
JAQUES.
X-LINKED TRANSMISSION OF ORNITHINE-TRANSCARBAMYLASE DEFICIENCY SIR,-Dr. Campbell and his colleagues1 suggested that
complete ornithine transcarbamylase (o.T.c.) deficiency a cause of neonatal deaths and that the gene coding for this enzyme may be X-linked. This suggestion was compatible with their finding of complete o.T.c. deficiency in a boy who died at 3 days and with previous reports of hyperammonxmia in girls with partial o.T.c. activity.2-4 We have identified two large pedigrees with O.T.C. deficiency which support these proposals.
may be
Family A was identified at the University of Washington when newborn boy died at 2 days with symptoms suggesting hyperammonaemia. Assays of the urea-cycle enzymes obtained post mortem from the liver revealed complete deficiency of o.T.c. The activity of other enzymes of the urea cycle (carbamyl-
Family B was identified at the University of Colorado when a boy died during the newborn period with symptoms of hyperammonsemia. This child also had complete deficiency of o.T.c. activity in liver tissue obtained at necropsy. 8 other boys in three generations had died with similar symptoms in the newborn period. The pattern of inheritance in each pedigree is consistent with X linkage. A total of 15 males have died, and 10 females can be identified as obligate heterozygotes (see figure). These two pedigrees support the suggestion of Campbell et al.that the genetic information for the o.T.c. enzyme is probably located on the X chromosome. The clinical and enzyme data are compatable with the suggestion that complete deficiency of o.T.c. is a cause of neonatal deaths in boys and that some female heterozygotes may have sufficient enzyme deficiency to cause clinical symptoms later in childhood. The degree of manifestation in female heterozygotes would be determined by the proportion of X chromosomes coding for the normal o.T.c. enzyme which would have been inactivated during development by lyonisation. Further confirmation of X linkage for O.T.C. will have to await valid techniques for heterozygote detection and/or demonstration of o.T.c. linkage to other X chromosome markers. Unfortunately, the absence of measurable O.T.c. activity in normal fibroblasts precludes the use of skin cultures for establishing X linkage. Department of Pediatrics, University of Washington, Seattle, Washington 98195. Department of Pediatrics, University of Colorado Medical Center, Denver, Colorado 80220.
C. RONALD SCOTT CECILIA CHIANG TENG. STEPHAN I. GOODMAN ARNOLD GREENSHER JOHN W. MACE.
a
phosphate synthetase, argininosuccinate synthetase, argininosuccinase, and arginase) was normal. In two generations 5 boys had died with similar symptoms.
Campbell, A. G. M., Rosenberg, L. E., Snodgrass, P. J., Nazum, C. T. Lancet, 1971, ii, 217. 2. Russell, A., Levin, B., Oberholzer, V. G., Sinclair, L. ibid. 1962, ii, 699. 3. Levin, B., Abraham, J. M., Oberholzer, V. G., Burgess, E. A. Archs Dis. Childh. 1969, 44, 152. 4. Sunshine, P., Lindenbaum, J. E., Levy, H. L., Freeman, J. M. Pediatrics, Springfield, 1972, 50, 100. 1.
ANTITHROMBIN III AND THE ŒSTROGEN CONTENT OF COMBINED ŒSTRO-PROGESTAGEN CONTRACEPTIVES
SBR,—Oral contraceptives have been reported to increase the risk of thromboembolism, and there are many attempts to find abnormalities which might explain the observed accidents. The decrease in antithrombin III (A.T. III) was the most frequent finding. 5-10 In 1969 we reported 11 a low level of A.T. III in 11 out of 15 women studied under oral contraception and a normal level in 4 women only. At that time, as well as in our following study, 12 we did not distinguish between type of pill used and its oestrogen content.
Our present study concerns 73 women who were given combined oestro-progestagens: 19 received 75-150 .g. cestrogen per day, and 54 received 50 jg. of this hormone. The control group consisted of 67 healthy women, aged 20 to 45, who were not on the pill (or not yet). All women taking the pill were examined every 3 to 6 months, at the 22nd to 25th day of the menstrual cycle (17th to 20th day of the pill). The period of time on the pill varied from 3 months to 4 years. Serum-A.T.-III was measured by the method of von Kaulla.13
Pedigrees of deficiency.
two
families with ornithine-transearbamylase
5. Fagerhol, M. K., Abildgaard, U., Bergsjo, P., Jacobsen, J. H. Lancet, 1970, i, 1175. 6. Howie, P. W., Mallinson, A. C., Prentice, C. R. M., Horne, C. H. W., McNicol, G. P. ibid. p. 1329. 7. Peterson, R. A., Krull, P. E., Finley, P., Ettinger, M. G. Am. J. clin. Path. 1970, 53, 468. 8. Von Kaulla, E., Von Kaulla, K. N. Lancet, 1970, i, 36. 9. Von Kaulla, E., Droegemueller, W., Aoki, N., Von Kaulla, K. N. Am. J. Obstet. Gynec. 1971, 109, 868. 10. Zuck, T., Bergin, J., Raymond, J., Dwyre, W. Surgery Gynec. Obstet. 1971, 133, 609. 11. Conard, J., Doumenc, J., Prost, R. J., Rozenbaum, H., Salomon, Y., Samama, M., Soria, J. Concours Méd. 1969, 41, 7089. 12. Conard, J., Doumenc, J., Samama, M., Bousser, J. XIIIth International Congress of Hæmatology, Munich, 1960; abstract p. 246. 13. Von Kaulla, E., Von Kaulla, K. N. Am. J. clin. Path. 1967, 48, 69.