Correction of ornithine accumulation prevents retinal degeneration in a mouse model of gyrate atrophy of the choroid and retina

Abstract

Deficiency of ornithine-␦-aminotransferase (OAT) in humans results in gyrate atrophy of the choroid and retina (GA), an autosomal recessive disorder characterized by ornithine accumulation and a progressive chorioretinal degeneration of unknown pathogenesis. To determine whether chronic, systemic reduction of ornithine can prevent this form of retinal degeneration, we used an argininerestricted diet to maintain long term reduction of ornithine in a mouse model of OAT-deficiency (Oat ؊͞؊ ) produced by gene targeting. We evaluated the mice over a 12-month period by measurement of plasma amino acids, electroretinograms, and retinal histologic and ultrastructural studies. We found that an argininerestricted diet substantially reduces plasma ornithine levels and completely prevents retinal degeneration in Oat ؊͞؊ . This result indicates that ornithine accumulation is a necessary factor in the pathophysiology of the retinal degeneration in GA and that restoration of OAT activity in retina is not required for effective treatment of GA.

Auxotrophy-Based Detection of Hyperornithinemia in Mouse Blood and Urine

“…[11][12][13] Dietary restriction of arginine has been shown to prevent (but not reverse) retinal degeneration in OAT-deficient mice. 14 In humans, the impacts of this treatment have been more varied, with results ranging from visual improvement, [15][16][17] marked delay of, [18][19][20][21] modest delay of, 22,23 to no discernable bearing on 24 the progression of ocular symptoms. Better outcomes in patients with GACR may correlate with earlier implementation of arginine restriction, more rigorous compliance with the dietary regimen, or both.…”

Effect of Long-Term Treatment of L-Ornithine on Visual Function and Retinal Histology in the Rats

“…In some GA patients, enlargement of the atrophic area was found without any increase in the plasma level of L-Orn. 13,[18][19][20] In addition, L-Orn-loaded GA relatives and patients of HHH syndrome did not develop retinal degeneration, although the plasma concentration of them were 600-1100 µM. 31) Thus, it is unlikely that only L-Orn accumulation in the plasma would be a direct cause of RPE degeneration in GA.…”

“…17,18) In other patients, enlargement of the atrophic area was found despite biochemical control of the plasma level of L-Orn. 13,19) Furthermore, cases of GA-like traits have been reported without any increase in the plasma level of L-Orn. 20,21) Thus, it has been unclear whether L-Orn accumulation in the plasma is a direct cause of RPE degeneration in GA.…”

“…They also showed that Oat −/− mice on a standard diet exhibited an increased plasma level of L-Orn (1300 µM), reduced electroretinogram (ERG) amplitude and severe retinal degeneration, whereas Oat −/− mice on an arginine-restricted diet had a decreased L-Orn level (100-200 µM), normal ERG amplitudes and no retinal degeneration. 13) However, another mouse model for GA by dosing with 5-fluoromethylornithine, a selective inhibitor of OAT, demonstrated normal visual function and no ophthalmic toxicity, although the L-Orn level in the eye rose ten times. 16) In some patients, a chronic reduction of the plasma level of L-Orn to near the normal level led to a modest improvement and subsequent stabilization of visual function.…”

Efficacy of Vigabatrin Intervention in a Mild Phenotypic Expression of Succinic Semialdehyde Dehydrogenase Deficiency

“…Recently, it has been suggested that increase of ornithine levels might be involved in vigabatrin-associated visual field defects (Roubertie et al 1998;Sorri et al 2010) as a result of ornithine-d-aminotransferase (OAT) impairment. In some patients with gyrate atrophy, vitamin B6 substitution has been successfully employed to prevent the loss of vision (Wang et al 2000;Ohkubo et al 2005;Sorri et al 2010). In line with this observation, and in order to prevent a worsening of the visual defect, we implemented a pyridoxine supplementation (300 mg/day) in conjunction with the same dosage of vigabatrin.…”