Systemic Manifestations of Gyrate Atrophy of the Choroid and Retina

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.     

Gyrate Atrophy of the Choroid and Retina: Biochemical Considerations and Experience with an Arginine-Restricted Diet

Ornithine-δ-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 argininerestricted diet. Plasma ornithine decreased by 50 to 85% within one month. Orally administered, a-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-δ-aminotransferase activity.     

Clinical Trial of Vitamin B6 for Gyrate Atrophy of the Choroid and Retina

Seven patients with gyrate atrophy and deficiency of ornithine-8-aminotransferase were studied for in vivo pyridoxine responsiveness; three responded to oral vitamin B₆ with over 50% reduction of serum ornithine levels and return to normal of serum lysine levels. Electrophysiologic studies were performed on two B₆-responsive patients and one B₆-non responder over various time periods with and without pyridoxine supplementation. Electroretinogram (ERG) amplitudes improved 100% in one patient when initially given high doses of vitamin B₆. Electro-oculogram light-to-dark ratio also improved for this patient. Withdrawal followed by resumption of B₆ supplementation was associated with mild worsening followed by improvement of ERG responses respectively in both patients. Long-term follow-up will be needed to assess whether pyridoxine treatment will slow or halt the progression of the disease.     

Experimental Model of Gyrate Atrophy in Animals

Intravitreal injection of L-ornithine hydrochloride in physiologic saline solution caused marked edema specifically in the pigment epithelium of Sprague-Dawley strain albino and Evans black hooded rats and rhesus and cynomologus monkeys. Swelling of the pigment epithelial cells, which was most prominent four hours after the injection, disappeared by 24 hours. However, many pigment epithelial cells gradually degenerated resulting in patches of denuded areas. The photoreceptor cells overlying the damaged pigment epithelium degenerated secondarily.     

Gyrate atrophy of the retina and choroid

We report two methods for potential prenatal diagnosis of gyrate atrophy of the retina and choroid caused by an inborn error of ornithine aminotransferase activity. A high pressure liquid chromatography assay measures ornithine aminotransferase accurately and directly in cultured amniotic fluid cells. The differential incorporation of ¹⁴C-ornithine and ³H-leucine into cell protein measures OAT directly but rapidly and simply.This work was supported by National Eye Institute Grants EY-02706 and EY-02162 and by a Basil O' Connor Award from the National Foundation - March of Dimes to Dr. O'Donnell     

Ocular Findings in Patients with Gyrate Atrophy On Pyridoxine and Low-Protein,Low-Arginine Diets

Five patients, ages 12 to 30, with gyrate atrophy have shown substantial (60% or greater) decreases in plasma ornithine concentrations within four to eight weeks when placed on a therapeutic trial of low-protein (10–15 g/day), low-arginine diets supplemented with essential amino acids (EAA) and pyridoxine hydrochloride. Four of five patients have continued on modified protein restriction (20–35 g/day) and one on pyridoxine (300 mg/day) alone with maintenance of plasma ornithine in the range of 30 to 60% below pretherapeutic trial levels. After one year, four of five patients have shown no significant improvement in visual acuity, fields, final dark-adapted thresholds, electroretinograms, or fundus appearance. One patient with the poorest control of plasma ornithine has developed a decrease in ERG amplitudes and a new area of chorioretinal atrophy. These patients continue in this trial to determine whether or not any reductions in hyperornithinemia will modify the course of the ocular disease.     

Gyrate atrophy of the choroid and retina

Gyrate atrophy of the choroid and retina is caused by deficient activity of ornithine ketoacid aminotransferase, a pyridoxal phosphate dependent enzyme. Besides the typical eye findings, abnormalities have been found on muscle biopsy, electro-encephalography, electromyography and electrocardiography, establishing this as a generalized disorder. Ornithine is markedly elevated in plasma and other body fluids. Plasma lysine, glutamate, glutamine and creatine are reduced. The possible contributions of these biochemical disturbances to the pathogenesis of gyrate atrophy are discussed. The disease is one of the few examples of an inherited chorioretinal dystrophy whose underlying biochemical defect is known. It therefore offers a unique opportunity to develop and test rational approaches to therapy. These include lowering of the abnormally high ornithine by dietary restriction of its precursor arginine, facilitation of ornithine excretion by administation of -aminoisobutyric acid, replacement of deficient products such as lysine or creatine, or increasing residual enzyme activity by high levels of cofactor (vitamin B₆). The results of several studies employing such approaches to therapy are presented as well as preliminary indications of possible benefit in a few patients.     

Gyrate atrophy of the choroid and retina. A five-year follow-up of creatine supplementation

Gyrate atrophy of the choroid and retina (GA) is an autosomal recessive chorioretinal degeneration with a 10-20-fold elevation of plasma ornithine due to deficient activity of ornithine aminotransferase. Type II fibres of the skeletal muscle are atrophic and contain tubular aggregates in electron microscopy. Deficient creatine and creatine phosphate formation have been postulated to be involved in the pathogenesis of GA. The five-year follow-up results of oral creatine supplementation in 13 patients are presented. Visual function tests and fundus photographs showed progression of GA during the treatment. The velocity of the progression varied considerably between individuals. Generally, the progression was rapid in the young patients and slow in the more advanced stages. Abnormalities in the skeletal muscle decreased or disappeared rapidly. They reappeared in the few patients who discontinued the medication. The difference in the therapeutic effect on the skeletal muscle and eye is discussed.     

Visual Results of a Long-Term Trial of a Low-Arginine Diet in Gyrate Atrophy of Choroid and Retina

Visual function has been serially assessed in two gyrate atrophy patients who have had long-term reduction of plasma ornithine concentrations by a low-arginine diet. One patient demonstrated subjective and objective improvement after 15 months of treatment. In addition to improvements in dark adaptation thresholds, enlargement of visual fields, and a more normal electroretinogram, there was marked improvement in cone function as measured by color vision. There has been no change noted in the second patient. These results suggest that reduction of plasma ornithine may be beneficial in gyrate atrophy patients and that the high ornithine concentrations characteristic of this disorder play some role in the pathophysiology.     

Gyrate atrophy of the choroid and retina. Early findings

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.     

回旋状脉络膜视网膜萎缩一家系的新型突变与临床观察

目的:探讨一个回旋状脉络膜视网膜萎缩(GA)中国家系各家庭成员OAT基因的致病性突变及临床表现。方法:对该家系中的6名家庭成员均进行详细的眼科检查,通过全外显子组测序、生物信息学分析及Sanger验证明确基因测序结果及致病性突变。结果:先证者因其临床表现及体征诊断为GA。全外显子组测序结果显示先证者OAT基因分别于第6外显子和第10外显子上发现致病突变c.722C>T(p.P241L)、c.1186C>T(p.R396X),该复合杂合性突变在家系中呈现共分离状态。先证者的父亲和哥哥均检出杂合型p.R396X致病变异,母亲检出杂合型p.P241L致病变异。除先证者外,其他家庭成员均无临床症状。结论:该家系的先证者为复合杂合性突变,其中p.P241L为首次报道的基因突变类型。这一研究结果扩大了OAT基因变异的范围,有利于在分子基础水平进一步理解GA的致病因素。新型突变类型的发现与证实也将有助于为GA的临床诊断和基因治疗提供新的依据。     

Effects of the Nd:YAG Laser on the Primate Retina and Choroid

The effects of the neodymium:YAG laser in the thermal mode on the subhuman primate retina were studied with ophthalmoscopy, intravenous fluorescein angiography, light microscopy, transmission electron microscopy, and scanning electron microscopy using a plastic injection-corrosion technique. Representative samples were examined at 24 hours, 14 days, and 28 days after treatment. The burns appeared to predominantly affect the outer half of the retina and the inner half of the choroid, although with higher energy levels the inner retinal layers were occasionally involved. In most instances Bruch's membrane was disrupted. The injured choriocapillaris underwent a reparative process during a four-week period in which the discrete lesions observed at 24 hours had disappeared.     

Modelling the Natural History of Geographic Atrophy in Patients with Age-Related Macular Degeneration

Purpose: To model the natural course of geographic atrophy (GA) in patients with age-related macular degeneration (AMD). Methods: Data on the natural course of GA were collected in the multi-center, longitudinal, prospective observational FAM study. The size of GA was measured by autofluorescence scanning laser ophthalmoscopy. The natural course of GA is modelled by two different mixed effect models (MEM). Both models are compared with respect to the correctness of the model assumptions, goodness of fit, and predictive behavior. Results: The linear model results in better prediction, the non-linear model is more in agreement with the model assumptions. The non-linear model fits the data for small and large areas of GA better, while the linear model seems to be more adequate for the medial areas. More data will be needed to study the interplay of both models in more detail. Conclusions: The natural course of GA varies extremely between individuals. However, reliable factors for the explanation of this variability have so far not been established. MEM are useful for describing “inter-individual” as well as “intra-individual” influences without the need for precise knowledge of the influencing factors. Using MEM to evaluate data on the natural history of GA allows one to derive parameter estimates, which could be used to design interventional trials for modes of therapy with a potential to reduce or stop the progression of GA in patients with AMD.     

Bevacizumab for the treatment of intraretinal cystic spaces in a patient with gyrate atrophy of the choroid and retina

ABSTRACT

Background: Gyrate atrophy of the choroid and retina is a rare autosomal recessive condition characterized by chorioretinal atrophy due to deficiency of the enzyme ornithine aminotransferase that can be complicated by intraretinal cystic spaces.

Case report: A 15-year-old female complaining of gradually progressive diminution of vision in both eyes preceded by night blindness was found to have gyrate atrophy of the choroid and retina with intraretinal cystic spaces that was evaluated using multimodal imaging including fluorescein angiography, optical coherence tomography, and optical coherence tomography angiography. Functional and anatomical improvement of the intraretinal cystic spaces was achieved with monthly intravitreal bevacizumab injections.

Conclusion: Repeated intravitreal bevacizumab injections can result in anatomical and functional improvement of intraretinal cystic spaces in patients with gyrate atrophy of the choroid and retina.     

A Model for the Formation of Ring Mitochondria in Retinal Pigment Epithelium

Purpose:To investigate the mechanism and sequence of formation of ring-shaped mitochondria in retinal pigment epithelial cells of a chick model of gyrate atrophy.Methods: Electron microscopic analysis of the ultrastructure of retinal pigment epithelial (RPE) mitochondria was carried out in chicks injected intravitreally with formoguanamine regularly (every 4 days) over the first 2 weeks or 4 weeks post-hatching. Formoguanamine is a triazine drug which induces hyperor-nithinemic symptoms in the chick eye similar to those seen in human gyrate atrophy.Results: A large population of irregularly shaped mitochondria was observed in the RPE of both peripheral and central retina. They showed extensive morphological changes. At 2 wk,the mitochondria appeared enlarged and abnormal in shape with vacuolisation, partial loss of their double membrane and reduced mitochon-drial cristae. By 4 wk, the mitochondria had assumed a rounder, almost circular profile,many with central holes,so-called ring mitochondria.Conclusi     

The Natural History of Asymptomatic Retinal Breaks

A long-term prospective follow-up of 359 asymptomatic retinal breaks, involving 231 eyes of 196 patients, was carried out for from one to 18 years, without treatment. This group was drawn from a consecutive series of phakic eyes of patients who had not had retinal detachment. Fifty of the breaks were fractional tears with attached flaps. No case of clinical retinal detachment occurred. Eighteen separate small subclinical retinal detachments occurred, involving 17 eyes, but only three of these enlarged slightly. No case in the series was treated. The absence of clinical retinal detachment in this series argues strongly for the relative safety of asymptomatic retinal breaks in phakic, nonfellow eyes, even if they are tears with attached flap in superior locations. Prophylactic treatment is not justified for this type of break in this type of eye.