Monoamine and Amino Acid Turnover in the Lesch-Nyhan Syndrome: Effects of L-5-Hydroxytryptophan (L-5-Htp)

Abstract

We have shown an interaction between ABO and placental alkaline phosphatase (PAP) polymorphisms (Am. J. Hum. Genet. 24. 495. 1972) suggesting that allele plfl of PAP partially protects fetuses of blood group B from the damaging effects of antibodies produced by ABO incompatible mothers. On the contrary. ABO compatible fetuses are at a disadvantage. since "som" maternal immunological reaction is necessary for the implantation and maintenance of the zygote in utero. Since XY zygotes are antigenlcally more dissimilar from their mothers than X X zygotes, we expected a high M/F ratio in newborn infants of group 8 compatible with their mothers. The study of a consecutive series of 2296 newborns showed a M/F ratio of 1.86 among group B compatible infants. This deviation of the sex ratio from that of the general population (1. 1.05) is highly significant (P <0.01) and further supports our hypothesis that PAP plays an important role in the maternal-fetal imunological relationship. DECREASED OUABAIN BINDING IN CYSTIC FIBROSIS FIBRO-488 BLASTS. J.L. Breslow and J. Epstein, (Spon. by P.S. Gerald), Harvard Medical School and the Children's Hospital Medical Center, Dept. of Medicine, Boston. We have compared the sensitivities of normal and cystic fibrosis (CF) skin fibroblasts to the cytotoxic effects of ouabain (OB), a cardiac glycoside known to inhibit the transport of ions across cell membranes. Cells from 9 unrelated CF patients when plated at low density for 24 hours in K+ deficient medium and then exposed for 24 hours to OB at concentrations from 1 X 10-lo to 1 X 10-6~. show an increased survival when compared to normal cells. In agreement with these observations, studies of 3H-OB binding show that CF cells bind less 08 than normal cells in medium lacking K+. At low drug concentrations (2-20 X ~O-~M), the first order rate constant for 3~-~~ binding in CF cells was approximately 70% of normal. Equilibrium binding experiments were performed in 3 sets of fibroblast strains from age-matched normal and CF individuals. In a Scatchard analysis the CF strains had 84 + 2%. 56 _+ 1%. and 88 f 2% (mean * S.E.M) of normal 3~-~~ binding sites per mg cell protein (for each strain the difference from normal is p < .001). Previous studies by others of OB resistant mammalian cells isolated in culture showed decreased OB binding as well as a decreased ability of OB to inhibit ion trans ort. We have studied ion flux in normal and CF cells using apttb, a potassium analogue, and have shown identical inhibition of ion transport by OB in both cell types. Thus CF cells appear different from other previously described 0B resistant cells. The relationship of these observations to the primary genetic defect in CF is not yet clear. The oral administration of L-5-HTP and carbidopa to children with the Lesch-Nyhan syndrome has been reported to reduce the rate of self-mutilative behavior. In experimental animals, drugs which decrease brain serotonin induce aggressive behavior which is reversed by serotonin's immediate precursor L-5-HTP. A 6 m. old ...