Gyrate Atrophy Symposium

Summary CLEMENT McCULLOCH, MD

In this symposium, major points of our knowledge of gyrate atrophy of the choroid and retina, many of them new and exciting, have been presented.

Takki and Milton have described the striking ap­pearance of the fundi. The gyrate lesions slowly expand with time; loss of vision also is slow, but progressive. The various ophthalmic findings have been described by all members of the symposium. They include: loss of night vision, contraction of visual field, decrease of voltage in the electroretinogram, vitreous syneresis, and cataracts. Myopia of 5 to 10 diopters is character­istic, and a late decrease in visual acuity, even to the 6/60 level, is likely. The disease would appear to be­long to the group of retinal pigmentary degenerations. The appearance of Takki's montage of an advanced case is close to that of advanced choroideremia. For such reasons, the diagnosis on ophthalmic assessment is almost, but not absolutely, certain.

However, as all our participants have mentioned, these patients show grossly elevated levels of blood ornithine, levels from a normal in the 50 j.tM/liter region to levels of 500 to 1000 j.tM/liter. This, combined with the clinical picture, is diagnostic.

The disease is inherited in an autosomal recessive manner. Carriers have no clinical stigma but may show slight elevation of blood ornithine levels, clear or­nithine more slowly on loading tests, and have only 50% enzyme activity in cell cultures. Prenatal diagno­sis is theoretically possible.

As has particularly been described by Kaiser­Kupfer et ai, close study ofthe patients has shown that there are a number of systemic abnormalities; the dis­ease is not confined to the eyes. The major findings include: (1) minor decreases in intelligence; (2) changes in the electroencephalogram; (3) minor weak­ness of muscle; (4) changes in staining of type II mus­cle fibers; (5) tubular inclusions in muscle cells on electron microscopy; (6) fine, sparse, straight hair with microstructural changes; and (7) lengthening and en­largement of mitochondria in liver cells.

Understanding of the biochemical abnormalities in this disease is developing rapidly. Ornithine is pro­duced in excess by muscle, kidney, the splanchnic or­gans, and is in excess in the cerebrospinal fluid and in the aqueous. On giving arginine, the level of blood ornithine rises, on giving glucose, the level falls . J

The gross biochemical abnormality suggests a

From The Department of Ophthalmology, University of Toronto, To­ronto, Canada.

hereditary enzymatic defect and such has been found. The enzyme, ornithine ketoacid transaminase (OKT), is deficient in these cases, to the 0 to 8% level, repre­senting a block in the conversion of ornithine to glutamic acid.

From our biochemical knowledge, two forms of treatment are possible. Pyridoxine phosphate is a cofactor in the enzymatic degradation . Therapeutic doses of Vitamin B6 have, in selected cases, reduced the level of blood ornithine. These findings have been described by We leber, Kennaway, and Buist.

A second form of treatment involves modification of the diet. Ornithine is not an amino acid present in the normal diet. However, it is formed in the body from arginine, probably largely via the urea cycle enzyme, arginase. Withdrawing arginine would remove the source of ornithine and therefore stop the production of ornithine. Such has been found to be true and the benefits have been described by Kaiser-Kupfer, de Monasterio and Valle, and by Berson, Shih and Sulli­van, and have been found by ourselves.2 The decrease in blood ornithine is steady and dramatic (from 1000 to 100 mM/l) and expectation of clinical improvement is warranted. Moreover, ophthalmic improvement has been recorded in selected cases, using the parameters of visual acuity, visual fields, night vision, color vi­sion , and electroretinograms. If one accepts these data, the corollary to be tested is that normalization of blood ornithine will stop progression of the disease. That point will take years to demonstrate.

It is worth noting that the visual improvements de­scribed in this symposium occurred in areas of normally-appearing retina. There, a toxic situation must have been reversible as compared with the areas of gyrate atrophy where no recovery is possible.

The implication is that the high levels of ornithine are themselves toxic. This tends to be confirmed by the finding that high levels of ornithine in culture media are more toxic to muscle cells, as mentioned by Kaiser-Kupfer et ai, and to fibroblasts of gyrate pa­tients, than to cells from normals. Also, Kuwabara et al have pointed out that ornithine injected into the vit­reous of rats produces cystic swelling and then degen­eration of retinal pigment epithelium. It is hoped that long-term control of ornithine levels will allow devel­opment of undamaged cells across the body, with sys­temic as well as ocular improvement of the patient.

Low-arginine diet may not be without complication. Arginine is a substrate in the urea cycle. Withdrawing arginine can lead to decreased removal of ammonia

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OPHTHALMOLOGY. APRIL 1981 • VOLUME 88 • NUMBER 4

and hyperammonemia. This complication can rapidly be corrected by giving arginine and arginine should be on hand to meet such an emergency. 3

Finally, as has been implied by Valle et aI, the exact mode of the toxicity is not yet proven. Is ornithine itself the toxic substance? The enzyme OKT is located in the mitochondria where major activities in inter­mediary metabolism occur, such as ATP synthesis. Is some critical reaction blocked, resulting even in . cell death, particularly in highly specialized areas such as the retina?

In summary, ophthalmology has joined here with the broad field of medicine in the elucidation of a disease that has a specific biochemical cause and a specific form of treatment. Investigations, particularly in the areas of biochemistry and cell biology, should lead to

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further understanding. This breakthrough may become a guide to resolving the basic defects in some of the other pigmentary retinal degenerations.

REFERENCES

1. McCulloch C, Marliss EB. Gyrate atrophy of the choroid and retina: clinical, ophthalmologic, and biochemical consid­erations. Trans Am Ophthalmol Soc 1975; 73:153-71,

2. Mcinnes RR, Bell L, Arshinoff S. et al. Significant improvement of vision with treatment of hyperornithinemia (gyrate atrophy) with a low-arginine diet (abstract). Am J Hum Genet 1979; 31 (6):55A.

3. Mcinnes RR, Arshinoff SA, Mc9ulloch C. Treatment of gyrate atrophy of the choroid and retina with low arginine diet. Trans Am Ophthalmol Soc 1980; (in press).