Gyrate atrophy of the choroid and retina with hyperornithinemia

Abstract

We studied 21 patients with gyrate atrophy of the choroid and retina and hyperornithinemia. Although the patients were not weak, type 2 muscle fibers were almost universally atrophic and had tubular aggregates. Gyrate atrophy is the first disease in which females are shown to have tubular aggregates; the sexes were affected equally. In gyrate atrophy the number of type 2 fibers decreases with age. The muscle and eye changes are probably related to abnormal creatine synthesis, caused, in gyrate atrophy, by the increased body pool of ornithine; muscle abnormalities may also be present in other tapetoretinal dystrophies.

Gyrate atrophy of the choroid and retina with hyperornithinemia: characterization of mutant liver L-ornithine:2-oxoacid aminotransferase kinetics.

“…A micromodification ofa method previously described (13) was used. For measurement of the enzyme kinetics the assay system contained 0.5-1,000 mM Lornithine, 3.75 mM a-oxoglutarate, and 4 ,ug/ml pyridoxal 5'-phosphate in a total volume of 25 ,lI. 40 ug of GA and 1-10 ,g of control liver homogenate protein was used.…”

“…The circular patchy atrophic lesions begin in the peripheral retina, enlarge, and coalesce, leaving only small central area ofthe posterior retina unaffected. In skeletal muscle, type II fibers are atrophic and partly filled with tubular aggregates, and the mitochondria may be altered (4). Plasma ornithine is 10-20 times higher than normal (5).…”

Gyrate atrophy of the choroid and retina with hyperornithinemia. Deficient formation of guanidinoacetic acid from arginine.

“…The patients are otherwise healthy but rapid muscular performance may be subnormal for age. The number of type II muscle fibers is decreased, and parts of the remaining fibers contain atrophic areas, seen in electron microscopy to be filled with tubular aggregates (2). Among the tapetoretinal dystrophies gyrate atrophy is not uncommon, for numerous cases have been reported from several countries.…”

The Ligand-induced Structural Changes of Humanl-Arginine:Glycine Amidinotransferase

“…AT is regulated in a variety of ways, including product inhibition of its catalytic activity by ornithine (5), end product repression of its synthesis at a pretranslational level by creatine (6 -10), induction by growth hormone and thyroxine (9,11), and repression during embryogenic development (12)(13)(14). Deficiencies of L-ornithine:2-oxoacid aminotransferase (EC 2.6.1.13) result in hyperornithinemia (15), which is associated with type II muscle fiber atrophy and gyrate atrophy of the choroid and retina, a disease that progressively leads to blindness (16). Because ornithine is a strong competitive inhibitor of AT, its 10 -20-fold increased plasma concentration in hyperornithinemia results in inhibition of AT, suggesting impaired de novo creatine biosynthesis as the cause of the aforementioned pathogenesis of the eye and muscle (16,17).…”

“…Deficiencies of L-ornithine:2-oxoacid aminotransferase (EC 2.6.1.13) result in hyperornithinemia (15), which is associated with type II muscle fiber atrophy and gyrate atrophy of the choroid and retina, a disease that progressively leads to blindness (16). Because ornithine is a strong competitive inhibitor of AT, its 10 -20-fold increased plasma concentration in hyperornithinemia results in inhibition of AT, suggesting impaired de novo creatine biosynthesis as the cause of the aforementioned pathogenesis of the eye and muscle (16,17). AT exhibits a rather broad substrate specificity and can utilize a wide variety of amidino donors, such as L-canavanine, 4-guanidinobutyrate, 3-guanidinopropionate, and hydroxyguanidine, and amidino acceptors, such as L-canaline, 4-aminobutyrate, 3-aminopropionate, and hydroxylamine, in addition to the physiological substrates (1).…”