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Objective: To determine whether the long-term reduction of plasma ornithine levels by way of an arginine-restricted diet in patients with gyrate atrophy will slow the progression of this chorioretinal degeneration., Design: Natural history study of 2 pairs of siblings with gyrate atrophy treated with an arginine-restricted diet., Main Outcome Measures: Fundus photography and electrophysical and psychophysical retinal function tests., Results: After 16 to 17 years of receiving an arginine-restricted diet, the younger sibling in each pair, who was prescribed the diet at an earlier age than the older sibling, demonstrated a slower progression of lesions compared with the older sibling., Conclusions: If started at an early age, long-term substantial reduction of plasma ornithine levels may appreciably slow the progression of the chorioretinal lesions and, to a lesser extent, the progressive loss of retinal function in patients with gyrate atrophy.

Gyrate atrophy of the choroid and retina is an autosomal recessive, chorioretinal dystrophy that begins in childhood and leads to blindness in the fourth to seventh decade of life. The primary defect is deficiency of ornithine-delta-amino-transferase, which results in accumulation of ornithine. We examined six pairs of affected siblings to determine if intrafamilial variability in the phenotype was less than interfamilial, and to determine if long-term (5- to 7-year) reduction of ornithine with an arginine-restricted diet had an effect on the progression of the chorioretinal degeneration. All but one set of siblings underwent periodic ophthalmologic examinations. The clinical diagnosis was confirmed with the demonstration of hyperornithinemia and deficiency of ornithine-delta-aminotransferase. The molecular defects in their ornithine-delta-amino-transferase genes also were determined. The two younger pairs of siblings were given an arginine-restricted diet and followed up for 5 to 7 years. We found strikingly similar phenotypes in affected members of the same pair of siblings. In the young patients receiving the diet, there was substantial reduction of ornithine levels. These children had only modest progression of their ocular disease during this period. Furthermore, a comparison of the outcome of the younger with their older siblings at an equivalent age showed that the younger siblings, who started receiving the diet at an earlier age, had much less ocular disease. We conclude that intrafamilial phenotypic variation in gyrate atrophy is less than interfamilial and, therefore, that genetic heterogeneity plays a role in the phenotypic variability of gyrate atrophy. Furthermore, we conclude that chronic reduction of ornithine with an arginine-restricted diet dramatically slows the progression of the chorioretinal dystrophy.

In ten patients with gyrate atrophy (GA) and hyperornithinemia, the head hair was fine, straight, and sparse. On microscopic examination, both scalp and pubic hair contained intermittent dark cores within the medullary zone, which was not a deposit, but appeared to be due to the unusual refractive properties of loosely formed macrofilaments amidst wide spaces containing a structureless electron lucent but compact substance, which was insoluble in both water and solvents. Seven of the ten patients had abnormal wave forms on electroencephalography. Three of the five patients who underwent muscle biopsy had tubular aggregates. Of particular interest was the toxicity of exogenous ornithine added to muscle cell culture from GA patients as compared with the lack of toxicity in muscle from control patients. What specific role the hyperornithinemia and absence of OAT is playing in the histopathology of hair and muscle and the EEG changes awaits further biochemical investigation.

Ornithine-delta-aminotransferase deficiency is the primary biochemical defect in gyrate atrophy of the choroid and retina and results in the characteristic accumulation of ornithine. An additional consequence of this inborn error is that arginine, the precursor of ornithine, becomes an essential amino acid. Therefore, to reduce the accumulated ornithine, we placed nine gyrate atrophy patients on an arginine-restricted diet. Plasma ornithine decreased by 50 to 85% within one month. Orally administered, alpha-aminoisobutyric acid facilitated the reduction in ornithine by augmenting renal losses. Over the long term, three patients have maintained near normal plasma ornithine concentrations from 4 to 32 months. Two patients have maintained less striking reductions in ornithine, and four have either been poorly controlled or have terminated the diet. Urinary losses of arginine and ornithine in gyrate atrophy patients with high or low plasma ornithine concentrations are less than 50% of the estimated arginine intake. This observation suggests that the bulk of ingested arginine is somehow metabolized despite the severe reduction in ornithine-delta-aminotransferase activity.

In a patient with gyrate atrophy of the choroid and retina, an arginine-deficient diet has reduced plasma ornithine concentration fivefold during the past 20 months. Subjective improvement in her visual function was noted approximately 15 months after institution of her diet. This has been documented by improvements in the electroretinogram, dark-adaptation, and color vision. The improvement involves rod and, to a lesser extent, cone function. The results, although preliminary and limited to a single patient, suggest that reduction of plasma ornithine with a low arginine diet is beneficial in this disease.

Two patients had milder variants of the usual form of gyrate atrophy. Although the appearance of the chorioretinal degeneration was identical, the progression of the clinical signs and symptoms were slower with night blindness, cataracts, and decreased vision occurring at an older age. Additionally, the level of hyperornithinemia, although still increased above normal, was lower than that usually found in such patients (between 448 and 676 microM). Additionally, one of our patients responded to high dosage vitamin B6 with a 27% reduction in plasma ornithine. The difference in the quantitation of the increase in plasma ornithine, the difference in responsiveness to vitamin B6, and the difference in the clinical consequences of this underlying biochemical abnormality, indicated a variant form of gyrate atrophy, suggesting the presence of genetic heterogeneity.

Examination of two sisters ages 2 years 10 months and 6 years four months with gyrate atrophy of the choroid and retina provided an opportunity for detailed clinical investigation. Although the chorioretinal lesions were confined to the peripheral retina in the older case and were quite minimal in the younger case, there was electroretinographic evidence of marked involvement of the cone and rod systems. These cases offer an opportunity to assess an arginine restricted diet in preventing the progress of the disease.