Chapter 83

Abstract

1. Ornithine is a nonprotein amino acid that is the substrate or product of five enzymatic reactions and the ligand of a transmitochondrial transport protein. Two of these enzymes, ornithine-δ-aminotransferase (OAT) and ornithine decarboxylase, catalyze reactions that consume ornithine. The former catalyzes the major catabolic reaction for ornithine. The source of ornithine is arginine in dietary protein, although, under certain circumstances, de novo synthesis of ornithine occurs by reversal of the normal flux of the OAT reaction.

2. There are two distinct genetic disorders that result in hyperornithinemia: gyrate atrophy of the choroid andretina (MIM 258870) and the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome (MIM 238970).

3. Gyrate atrophy of the choroid and retina is a progressive chorioretinal degeneration that is inherited as an autosomal recessive trait. It is caused by a deficiency of OAT. We know of more than 150 biochemically documented cases, about one-third of which are Finnish. There is myopia, night blindness, and loss of peripheral vision starting late in the first decade, proceeding to tunnel vision and eventual blindness by the third and fourth decades. Posterior subcapsular cataracts are present in nearly all patients by the end of the second decade. The ocular fundus exhibits sharply demarcated circular areas of complete chorioretinal degeneration that start in the midperiphery and gradually extend to the posterior pole. Tubular aggregates are present in the type 2 fibers of skeletal muscle. Plasma ornithine values range from 400 to 1400 μM, and 0.5 to 10 mM of ornithine is excreted daily. Plasma glutamate, glutamine, lysine, creatine, and creatinine concentrations are modestly reduced. OAT activity in the cells and tissues of patients is from 0 to 6 percent that in control subjects, and obligate heterozygotes have intermediate values. Seven patients are known to have had in vitro and in vivo responses to pharmacologic doses of pyridoxal phosphate or pyridoxine. Additional therapeutic approaches have included an arginine-restricted diet, which in some patients has lowered plasma ornithine to normal values; administration of pharmacologic doses of L-lysine or α-aminoisobutyric acid to increase renal losses; and administration of proline or creatine. No form of therapy is unequivocally effective; however, sib pair studies with young, well-controlled patients strongly suggest that chronic reduction of plasma ornithine to values <200 μM with an arginine-restricted diet slows or stops the chorioretinal degeneration. Results in a mouse model of gyrate atrophy support this conclusion. Creatine administration has resulted in improvement of the histologic abnormalities in muscle.

4. Human, rat, mouse, plant, and yeast OAT cDNAs have been cloned and sequenced. The human OAT gene has been mapped to 10q26 and its structure determined. A cluster of apparently nonfunctional OAT-related sequences maps to Xp10-Xp21. In cultured fibroblasts, about 85 percent of gyrate atrophy patients express near normal amounts of normal-sized OAT mRNA, but only about 10 percent have normal amounts of normal-sized OAT protein. More than 60 mutations causing gyrate atrophy have been detected.

5. The HHH syndrome is an autosomal recessive inherited disorder described in more than 50 patients. The clinical symptoms are related to the hyperammonemia and resemble those of the urea cycle disorders. Visual problems or ocular fundus changes are not typical. Plasma ornithine concentrations range from 200 to 1020 μM on a self-restricted ...

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