Gyrate Atrophy of the Choroid and Retina: A Review

Gyrate atrophy (GA) of the choroid and retina is a rare autosomal recessive genetic condition characterized by elevation of the plasma level of the amino acid ornithine due to deficiency of the enzyme ornithine ketoacid aminotransferase. Accumulation of ornithine occurs in various body tissues but leads primarily to characteristic ophthalmic manifestations including myopia, cataract, progressive chorioretinal atrophy, and macular changes. Patients usually present with night blindness that starts in the first decade of life followed by visual field constriction and eventually diminution of the central visual acuity and blindness. The condition has been reported worldwide and its differential diagnosis is broad and includes choroideremia and retinitis pigmentosa. Treatment currently depends on life-long dietary modifications including restriction of the amino acid arginine in diet. This article describes in detail the pathogenesis, clinical features, multimodal imaging findings, and treatment options for GA of the choroid and retina and its complications.

Atypical Presentation and Delayed Diagnosis of Gyrate Atrophy: Case Reports of Two Siblings

Gyrate atrophy is a hereditary condition characterized by ornithine amino transferase deficiency related large areas of retinal pigment epithelium and choriocapillaris lobular shaped atrophy in the peripherial retina. In this report, we present a case of atypical presentation of gyrate atrophy. The aim of this report is to present two siblings, one of which was associated with lamellar macular hole and with a history of previous diagnosis of retinitis pigmentosa. The delayed diagnosis of gyrate atrophy was made only after her brother, who was 5 years younger than her was diagnosed with gyrate atrophy. In addition, in this report, we evaluated gyrate atrophy in terms of multimodal imaging findings, differential diagnosis and treatment of macular complications.

Ultrawide field imaging to document the progression of gyrate atrophy of the choroid and retina over 5 years

A family of three siblings affected with gyrate atrophy of the choroid and retina is presented. Ultrawide field fundus imaging was used to monitor the progression of the disease objectively over 5 years.

Molecular and Cellular Studies Reveal Folding Defects of Human Ornithine Aminotransferase Variants Associated With Gyrate Atrophy of the Choroid and Retina

The deficit of human ornithine aminotransferase (hOAT) is responsible for gyrate atrophy (GA), a rare recessive inherited disorder. Although more than 60 disease-associated mutations have been identified to date, the molecular mechanisms explaining how each mutation leads to the deficit of OAT are mostly unknown. To fill this gap, we considered six representative missense mutations present in homozygous patients concerning residues spread over the hOAT structure. E. coli expression, spectroscopic, kinetic and bioinformatic analyses, reveal that the R154L and G237D mutations induce a catalytic more than a folding defect, the Q90E and R271K mutations mainly impact folding efficiency, while the E318K and C394Y mutations give rise to both folding and catalytic defects. In a human cellular model of disease folding-defective variants, although at a different extent, display reduced protein levels and/or specific activity, due to increased aggregation and/or degradation propensity. The supplementation with Vitamin B6, to mimic a treatment strategy available for GA patients, does not significantly improve the expression/activity of folding-defective variants, in contrast with the clinical responsiveness of patients bearing the E318K mutation. Thus, we speculate that the action of vitamin B6 could be also independent of hOAT. Overall, these data represent a further effort toward a comprehensive analysis of GA pathogenesis at molecular and cellular level, with important relapses for the improvement of genotype/phenotype correlations and the development of novel treatments.

Gyrate Atrophy

Gyrate Atrophy is an autosomal recessively inherited rare disease of the choroid and retina. Deficiency of ornithine aminotransferase enzyme (OAT) leads to 10 to 20 times ornithine levels in plasma which is thought to be the cause for the ocular findings. OAT gene is located on the tenth chromosome and when a mutation occurs OAT enzyme activity is decreased in the body. In the first decade, areas of chorioretinal atrophy are seen in the mid-peripheral retinal areas. In the progressing years, the macula may be involved and myopia is an accompanying feature]. Patients initially describe night vision problems and progressive visual field defects leading to central vision loss and blindness later on in the disease. Diagnosis is evident with clinical findings and elevated ornithine levels in plasma and is confirmed with OAT enzyme immune assay. Treatment is dietary modification and treatment of complications that may develop in the retina. GA is reported in diverse ethnic populations and in many sites around the World. Finland is the most reported country (1/50,000). It is very rare in Turkey.

Autosomal Dominant Gyrate Atrophy-Like Choroidal Dystrophy Revisited: 45 Years Follow-Up and Association with a Novel C1QTNF5 Missense Variant

We present a long-term follow-up in autosomal dominant gyrate atrophy-like choroidal dystrophy (adGALCD) and propose a possible genotype/phenotype correlation. Ophthalmic examination of six patients from two families revealed confluent areas of choroidal atrophy resembling gyrate atrophy, starting in the second decade of life. Progression continued centrally, reaching the fovea at about 60 years of age. Subretinal deposits, retinal pigmentation or choroidal neovascularization as seen in late-onset retinal degeneration (LORD) were not observed. Whole genome sequencing revealed a novel missense variant in the C1QTNF5 gene (p.(Q180E)) which was found in heterozygous state in all affected subjects. Haplotype analysis showed that this variant found in both families is identical by descent. Three-dimensional modeling of the possible supramolecular assemblies of C1QTNF5 revealed that the p.(Q180E) variant led to the destabilization of protein tertiary and quaternary structures, affecting both the stability of the single protomer and the entire globular head, thus exerting detrimental effects on the formation of C1QTNF5 trimeric globular domains and their interaction. In conclusion, we propose that the p.(Q180E) variant causes a specific phenotype, adGALCD, that differs in multiple clinical aspects from LORD. Disruption of optimal cell-adhesion mechanisms is expected when analyzing the effects of the point mutation at the protein level.

Partial regression of foveoschisis following vitamin B6 supplementary therapy for gyrate atrophy in a Chinese girl

Background To report a case of genetically confirmed gyrate atrophy (GA) of choroid and retina, who showed partial regression of foveoschisis following vitamin B6 supplementary therapy. Case presentation A 6-year-old Chinese girl complained about night blindness and progressive decreased vision in both eyes. Her best corrected visual acuity (BCVA) was 20/63 OD and 20/100 OS. Fundus examination showed bilateral multiple, sharply demarcated, scallop-shaped chorioretinal atrophy areas in the midperipheral and peripheral of the fundus. Spectral domain optical coherence tomography (SD-OCT) showed increased central macular thickness (CMT) with multiple intraretinal cystic spaces in the both eyes. There was no leakage or staining in the macular area in late phase of fluorescein angiography (FA). Blood tests confirmed hyperornithinemia and genetic analysis revealed two heterozygous mutations on ornithine aminotransferase (OAT) gene. Based on clinical presentation and genetic test, the patient was diagnosed as GA of the choroid and retina and further treated with vitamin B6 supplementary for three weeks. Her serum ornithine levels did not change but CMT on SD-OCT declined with partial regression of intraretinal cystic spaces. Then, the patient discontinued the drug because of severe muscle pain, and foveoschisis increased to initial level a month later. Conclusions Foveoschisis is a rare complication of GA. Vitamin B6 supplementation may alleviate foveoschisis, but its effort for reducing serum ornithine level might be limited. Potential drug adverse effects should be noted in pediatric patients.