Gyrate Atrophy of the Choroid and Retina (GA) : Toxic Effects of Ornithine and Long-Term Therapy with an Arginine-Restricted Diet
GA is characterized by progressive chorioretinal degeneration and hyperornithinemia and is due to an inherited deficiency of ornithine-δ-aminotransferase (OAT). We have examined the ramifications of this enzymatic deficiency at the cellular and clinical levels. Unlike normal cells, intact GA fibroblasts do not convert radiolabeled ornithine to proline and glutamate. Although GA cells grow normally in standard medium, addition of ornithine (20 mM) kills > 98 % of the GA cells, while control cells grow at nearly normal rates. Addition of proline or other neutral amino acids (5 mM) blocks the ornithine toxicity ; whereas inhibitors of polyamine synthesis, guanidinoacetate, creatine, and the dibasic amino acids have no effect. These results suggest that high orni-thine concentrations in association with OAT deficiency is detrimal to some cells and that reduction of ornithine may be beneficial in GA patients. We therefore placed 9 GA patients on an argininerestricted diet for from 2–36 months. Within 40 days there was a 2–6 fold reduction in plasma ornithine which has been maintained for from 4–36 months in 4 of the patients. None of the patients has had progression of their ophthalmologic abnormalities while on the diet and as recently reported (Science 210:1128, 1980), one has had some improvement. At all plasma ornithine concentrations, total urine losses of arginine-derived carbon skeletons is less than predicted by arginine intake. This suggests that significant amounts of arginine (+/o ornithine) are metabolized in GA patients by either residual OAT activity, ornithine decarboxylase or by an as yet unelucidated pathway.