Mild Phenotypes of Gyrate Atrophy in a Heterozygous Carrier with One Variant Allele of OAT.

This study aimed to identify whether gyrate atrophy of the choroid and retina (GACR) heterozygous individuals have possible clinical manifestations and to explore the potential pathogenic mechanism. In this retrospective study, we surveyed a two-generation pedigree of an individual diagnosed with GACR. Two family members underwent ophthalmological, hematologic, and genetic tests. An arginine-restricted diet with vitamin B6 supplementation was implemented; clinical assessments were repeated every 3 months during follow-up. The relative OAT mRNA expression was determined using a real-time quantitative polymerase chain reaction. The 19-year-old compound heterozygous daughter (OAT: c.1186C>T; c.748C>T) had bilateral pathologic myopia, posterior staphyloma, chorioretinal atrophy, macular abnormalities, and elevated hematologic ornithine. The 54-year-old heterozygous mother (OAT: c.1186C>T) presented with bilateral pathologic myopia, asymmetric posterior staphyloma, retina and choroidal capillary layer atrophy, retinal pigment epithelium abnormalities, and mildly elevated hematologic ornithine. Compared to normal individuals, the daughter and mother had 29% and 46% relative OAT mRNA expression, respectively (p < 0.001). We believe that this is the first report of a carrier of one OAT variant allele exhibiting a mild phenotype, suggesting that family members should be aware of the possibility of clinical involvement in carriers with some autosomal recessive conditions. Additional data suggest that nonsense-mediated, decay-initiated mRNA degradation may cause GACR.

Extending diagnostic practices in gyrate atrophy: Enzymatic characterization and the development of an in vitro pyridoxine responsiveness assay.

Gyrate atrophy of the choroid and retina (GACR) is caused by pathogenic biallelic variants in the gene encoding ornithine-δ-aminotransferase (OAT), and is characterized by progressive vision loss leading to blindness. OAT is a pyridoxal-5'-phosphate (PLP) dependent enzyme that is mainly involved in ornithine catabolism, and patients with a deficiency develop profound hyperornithinemia. Therapy is aimed at lowering ornithine levels through dietary arginine restriction and, in some cases, through enhancement of OAT activity via supraphysiological dosages of pyridoxine. In this study, we aimed to extend diagnostic practices in GACR by extensively characterizing the consequences of pathogenic variants on the enzymatic function of OAT, both at the level of the enzyme itself as well as the flux through the ornithine degradative pathway. In addition, we developed an in vitro pyridoxine responsiveness assay. We identified 14 different pathogenic variants, of which one variant was present in all patients of Dutch ancestry (p.(Gly353Asp)). In most patients the enzymatic activity of OAT as well as the rate of [14C]-ornithine flux was below the limit of quantification (LOQ). Apart from our positive control, only one patient cell line showed responsiveness to pyridoxine in vitro, which is in line with the reported in vivo pyridoxine responsiveness in this patient. None of the patients harboring the p.(Gly353Asp) substitution were responsive to pyridoxine in vivo or in vitro. In silico analysis and small-scale expression experiments showed that this variant causes a folding defect, leading to increased aggregation properties that could not be rescued by PLP. Using these results, we developed a diagnostic pipeline for new patients suspected of having GACR. Adding OAT enzymatic analyses and in vitro pyridoxine responsiveness to diagnostic practices will not only increase knowledge on the consequences of pathogenic variants in OAT, but will also enable expectation management for therapeutic modalities, thus eventually improving clinical care.

Hyperreflective Ganglion Cell Layer Band in Gyrate Atrophy.

We have described the hyperreflective ganglion cell layer band (HGCB) in a series of cases of gyrate atrophy. Clinical fundus examination and multimodal imaging which included optical coherence tomography (OCT) was done in all cases. Four patients (one male, three female) were studied. In all four cases, a hyperreflective band was noted in the ganglion cell layer. In three patients, the band was continuous, and in one patient, the band was patchy. To conclude, HGCB is a novel OCT sign in gyrate atrophy and can be valuable in prognostication of disease. [Ophthalmic Surg Lasers Imaging Retina 2024;55:598-602.].

Biochemical Studies on Human Ornithine Aminotransferase Support a Cell-Based Enzyme Replacement Therapy in the Gyrate Atrophy of the Choroid and Retina.

The gyrate atrophy of the choroid and retina (GACR) is a rare genetic disease for which no definitive cure is available. GACR is due to the deficit of ornithine aminotransferase (hOAT), a pyridoxal 5'-phosphate-dependent enzyme responsible for ornithine catabolism. The hallmark of the disease is plasmatic ornithine accumulation, which damages retinal epithelium leading to progressive vision loss and blindness within the fifth decade. Here, we characterized the biochemical properties of tetrameric and dimeric hOAT and evaluated hOAT loaded in red blood cells (RBCs) as a possible enzyme replacement therapy (ERT) for GACR. Our results show that (i) hOAT has a relatively wide specificity for amino acceptors, with pyruvate being the most suitable candidate for ornithine catabolism within RBCs; (ii) both the tetrameric and dimeric enzyme can be loaded in RBC retaining their activity; and (iii) hOAT displays reduced stability in plasma, but is partly protected from inactivation upon incubation in a mixture mimicking the intracellular erythrocyte environment. Preliminary ex vivo experiments indicate that hOAT-loaded RBCs are able to metabolize extracellular ornithine at a concentration mimicking that found in patients, both in buffer and, although with lower efficiency, in plasma. Overall, our data provide a proof of concept that an RBC-mediated ERT is feasible and can be exploited as a new therapeutic approach in GACR.

Gyrate atrophy of the choroid and retina: Update on diagnosis and treatment.

Gyrate atrophy of the choroid and retina (GACR) is a rare autosomal recessive disease characterised by elevated plasma ornithine levels due to deficiency of the enzyme ornithine aminotransferase (OAT). The accumulation of this amino acid in plasma leads to the development of patches of chorioretinal atrophy in the peripheral retina extending into the macular area. Patients usually present with night blindness followed by constriction of the visual field and, finally, decreased central vision and blindness. The disease is diagnosed by the presence of the characteristic clinical picture, the presence of hyperornithinaemia in plasma and the detection of mutations in the OAT enzyme gene. There is currently no effective gene therapy and the most common therapeutic intervention mainly involves dietary modifications with arginine restriction. This article aims to summarise the pathogenesis, clinical and diagnostic findings and treatment options in patients with GACR.

Vision on gyrate atrophy: why treat the eye?

In the April issue of this Journal, Boffa and coworkers put forward a new therapeutic approach for Gyrate Atrophy of the Choroid and Retina (GACR; OMIM 258870) (Boffa et al, 2023). The authors propose to apply gene therapy to the liver for GACR, a metabolic disease primarily affecting eyesight due to retinal degeneration. Their vision is enthusiastically supported by a News and Views comment in the same issue (Seker Yilmaz and Gissen, 2023). However, based on disease pathology, patient's needs, ethical considerations, therapeutic developmental time lines, and current state of the art of gene therapy for liver and eye, we have a different view on this issue: We argue below that local treatment of the eye is the preferred option for GACR.

Clinical characteristics of gyrate atrophy compared with a gyrate atrophy-like retinal phenotype.

INTRODUCTION: Gyrate atrophy (GA) is a rare retinal dystrophy due to biallelic pathogenic variants in the ornithine aminotransferase (OAT) gene, causing a 10-fold increase in plasma ornithine levels. It is characterized by circular patches of chorioretinal atrophy. However, a GA-like retinal phenotype (GALRP) without elevated ornithine levels has also been reported. The aim of this study is to compare the clinical characteristics of GA and GALRP and to identify possible discriminators. METHODS: A multicenter, retrospective chart review was performed at three German referral centres on patient records between 01/01/2009 and 31/12/2021. Records were screened for patients affected by GA or GALRP. Only patients with examination results for plasma ornithine levels and / or genetic testing of the OAT gene were included. Further clinical data was gathered where available. RESULTS: Ten patients (5 female) were included in the analysis. Three suffered from GA, while seven had a GALRP. Mean age (± SD) at onset of symptoms was 12.3 (± 3.5) years for GA compared with 46.7 (± 14.0) years for GALRP patients (p = 0.002). Mean degree of myopia was higher in GA (-8.0 dpt. ± 3.6) compared to GALRP patients (-3.8 dpt. ± 4.8, p = 0.04). Interestingly, all GA patients showed macular oedema, while only one GALRP patient did. Only one patient with GALRP had a positive family history, while two were immunosuppressed. DISCUSSION: Age of onset, refraction and presence of macular cystoid cavities appear to be discriminators between GA and GALRP. GALRP may encompass both genetic and non-genetic subtypes.

Clinical, biochemical and molecular analysis in a cohort of individuals with gyrate atrophy.

BACKGROUND: Gyrate atrophy of the choroid and retina is a rare autosomal recessive metabolic disorder caused by biallelic variants in the OAT gene, encoding the enzyme ornithine δ-aminotransferase. Impaired enzymatic activity leads to systemic hyperornithinaemia, which in turn underlies progressive chorioretinal degeneration. In this study, we describe the clinical and molecular findings in a cohort of individuals with gyrate atrophy. METHODS: Study participants were recruited through a tertiary UK clinical ophthalmic genetic service. All cases had a biochemical and molecular diagnosis of gyrate atrophy. Retrospective phenotypic and biochemical data were collected using electronic healthcare records. RESULTS: 18 affected individuals from 12 families (8 male, 10 female) met the study inclusion criteria. The median age at diagnosis was 8 years (range 10 months - 33 years) and all cases had hyperornithinaemia (median: 800 micromoles/L; range: 458-1244 micromoles/L). Common features at presentation included high myopia (10/18) and nyctalopia (5/18). Ophthalmic findings were present in all study participants who were above the age of 6 years. One third of patients had co-existing macular oedema and two thirds developed pre-senile cataracts. Compliance with dietary modifications was suboptimal in most cases. A subset of participants had extraocular features including a trend towards reduced fat-free mass and developmental delay. CONCLUSIONS: Our findings highlight the importance of multidisciplinary care in families with gyrate atrophy. Secondary ophthalmic complications such as macular oedema and cataract formation are common. Management of affected individuals remains challenging due to the highly restrictive nature of the recommended diet and the limited evidence-base for current strategies.

Foveoschisis associated with gyrate atrophy in ornithine aminotransferase deficiency: A case report.

Ornithine aminotransferase (OAT) deficiency is an autosomal recessive disease characterized by elevated serum ornithine levels caused by mutations in genes encoding for ornithine aminotransferase, a vitamin B6-dependent mitochondrial matrix enzyme. Gyrate atrophy (GA) is characteristic findings in OAT that characterized by sharply demarcated circular, pigmentary, brain-like areas of chorioretinal atrophy in the peripheral retina. This case report presents rare assosiation between OAT and GA and describes the characteristic imaging findings of this unique, not fully understood clinical entity. The coexistence of GA and foveoschisis is extremely rare in OAT deficiency. We report a case of foveoschisis in a patient with OAT, and we will discuss the possible mechanisms that lead to it. A 24-year-old male patient presented with complaints of decreased vision and nictalopia for 1 year. The patient, who was diagnosed with oat 6 years ago, had typical gyrate atrophy in his Fundus floresein angiography and foveoschisis in his Optical coherence tomography. He was diagnosed with gyrate atrophy and foveoschisis. GA caused by OAT deficiency may present with macular involvement in the form of foveoschisis causing central visual impairment. Ophthalmologists should not ignore detailed fundus examination in children and young patients with visual impairment and should be aware of possible systemic diseases.

Biochemical and Bioinformatic Studies of Mutations of Residues at the Monomer-Monomer Interface of Human Ornithine Aminotransferase Leading to Gyrate Atrophy of Choroid and Retina.

Deficit of human ornithine aminotransferase (hOAT), a mitochondrial tetrameric pyridoxal-5'-phosphate (PLP) enzyme, leads to gyrate atrophy of the choroid and retina (GA). Although 70 pathogenic mutations have been identified, only few enzymatic phenotypes are known. Here, we report biochemical and bioinformatic analyses of the G51D, G121D, R154L, Y158S, T181M, and P199Q pathogenic variants involving residues located at the monomer-monomer interface. All mutations cause a shift toward a dimeric structure, and changes in tertiary structure, thermal stability, and PLP microenvironment. The impact on these features is less pronounced for the mutations of Gly51 and Gly121 mapping to the N-terminal segment of the enzyme than those of Arg154, Tyr158, Thr181, and Pro199 belonging to the large domain. These data, together with the predicted ΔΔG values of monomer-monomer binding for the variants, suggest that the proper monomer-monomer interactions seem to be correlated with the thermal stability, the PLP binding site and the tetrameric structure of hOAT. The different impact of these mutations on the catalytic activity was also reported and discussed on the basis of the computational information. Together, these results allow the identification of the molecular defects of these variants, thus extending the knowledge of enzymatic phenotypes of GA patients.

Liver-directed gene therapy for ornithine aminotransferase deficiency.

Gyrate atrophy of choroid and retina (GACR) is a chorioretinal degeneration caused by pathogenic variants in the gene encoding ornithine aminotransferase (OAT), an enzyme mainly expressed in liver. Affected patients have increased ornithine concentrations in blood and other body fluids and develop progressive constriction of vision fields leading to blindness. Current therapies are unsatisfactory and better treatments are highly needed. In two mouse models of OAT deficiency that recapitulates biochemical and retinal changes of GACR, we investigated the efficacy of an intravenously injected serotype 8 adeno-associated (AAV8) vector expressing OAT under the control of a hepatocyte-specific promoter. Following injections, OAT-deficient mice showed reductions of ornithine concentrations in blood and eye cups compared with control mice injected with a vector expressing green fluorescent protein. AAV-injected mice showed improved electroretinogram response and partial restoration of retinal structure up to one-year post-injection. In summary, hepatic OAT expression by AAV8 vector was effective at correction of hyperornithinemia and improved function and structure of the retina. In conclusion, this study provides proof-of-concept of efficacy of liver-directed AAV-mediated gene therapy of GACR.

A possible ocular biomarker for response to hyperornithinemia in gyrate atrophy: the effect of pyridoxine, lysine, and arginine-restricted diet in a patient with advanced disease.

BACKGROUND: Loss of function variants in the ornithine aminotransferase (OAT) gene cause accumulation of ornithine levels, leading to gyrate atrophy. The benefit of ornithine-lowering therapies has been documented in a mouse model and young patients, however, the effect in adults with advanced disease has not been well described. MATERIALS AND METHODS: Case report of an adult patient with advanced gyrate atrophy, who underwent treatment with pyridoxine and an arginine-restricted diet for four years. RESULTS: A 51-year-old female with advanced chorioretinal degeneration presented with hyperornithinemia (961 vs. normal 18-135 µmol/L) and compound heterozygous pathogenic variants in OAT (p.Tyr299* and p.Ala270Pro). Treatment with pyridoxine and arginine-diet restriction yielded a maximal reduction in ornithine levels by 71% (275 µmol/L). Optical coherence tomography (OCT) showed a reduction in ellipsoid zone (EZ) thickness that correlated with lower ornithine levels and reversed with higher ornithine levels. While her best-corrected visual acuity remained unchanged, the progressive decline in her visual fields appeared to stabilize during a one-year period when ornithine levels were below 500 µmol/L. CONCLUSIONS: In this report, we demonstrate that chorioretinal degeneration appears to stabilize in an adult patient with gyrate atrophy in association with a partial reduction in ornithine levels. We also observed a correlation with reduced EZ thickness on OCT and propose this may be a novel biomarker for ornithine reduction therapies. Our case study characterizes the potential retinal structure-function benefits of ornithine-lowering treatments even in cases of advanced chorioretinal degeneration. Thus, we recommend a low threshold for treating all patients with gyrate atrophy.

Regression of treatment-resistant gyrate atrophy-associated intraretinal cystic spaces using long-term diet restriction: A case report.

PURPOSE: Gyrate atrophy of the choroid and retina (GA) is a rare genetic ophthalmologic condition which primarily manifests in childhood. It is characterized by hyperornithinemia and progressive chorioretinal atrophy. Patients may develop macular intraretinal cystic spaces (ICS) for which various treatment modalities have been reported. We report a patient who failed to demonstrate visual or anatomic improvement following multiple treatments for GA-associated ICS but showed improvement following prolonged dietary modification and vitamin supplementation. CASE DESCRIPTION: A 6-year-old male patient presented with previously undiagnosed GA associated with ICS. He received 6 consecutive monthly intravitreal bevacizumab injections as well as topical nepafenac and dorzolamide for treatment of ICS without significant change detected by optical coherence tomography (OCT) following treatment. He was also maintained on an arginine restricted diet with vitamin B6 supplementation. Over the course of the ensuing year, the patient was lost to follow-up due to the coronavirus disease 2019 pandemic. When he returned, his vision was stable, and OCT showed regression of the ICS. His mother reported that he had continued only on dietary restriction and vitamin B6 supplementation with no other medications or interventions. Plasma ornithine level measurement confirmed dietary compliance. Further follow-up showed continued stabilization of the condition. CONCLUSION: In addition to retarding progressive chorioretinal atrophy, prolonged dietary modifications may result in improvement of treatment-resistant GA-associated ICS. Parents' education on the value of dietary modifications for patients with GA is highly recommended.

[Gyrate atrophy of the choroid and retina with ornithinemia and foveoschisis (clinical observation)]. / Atrofiya girate khorioidei i setchatki s ornitinemiei i foveoshizisom (klinicheskoe nablyudenie).

Gyrate chorioretinal atrophy (GCA) is a rare hereditary disease with certain complications; one extremely rare complication of GCA is foveoschisis. For the first time in Russian ophthalmology, a 10-year-old female child has been described to have genetically verified GCA associated with the OAT gene in combination with ornithinemia and foveoschisis. The diagnosis was made on the basis of fundus examination, perimetry data, autofluorescence, optical coherence tomography, fluorescence angiography, electroretinography, mass spectrometry with confirmation by molecular genetic research. The presented clinical case illustrates the need for an interdisciplinary approach to the diagnosis of GCA with diagnostic algorithm involving various examination methods and doctors of different specialties.

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.

First reported case of pregnancy in a patient with ornithine aminotransferase deficiency.

Ornithine aminotransferase deficiency is a rare autosomalrecessive human inborn error of the metabolism resulting in hyperornithinemia and progressive chorioretinal degeneration (gyrate atrophy) with blindness. There are few reports in the literature and none, to our knowledge, that address this condition during pregnancy. We report on a novel case of ornithine aminotransferase deficiency during pregnancy that was managed actively with arginine and protein restriction with serial amino acid and fetal growth monitoring, resulting in an uncomplicated term live birth.