Gyrate Atrophy Research Articles

A mini-review on the international gyrate atrophy symposium 2023: More than meets the eye. Focus on outstanding research questions

A mini-review on the international gyrate atrophy symposium 2023: More than meets the eye. Focus on outstanding research questions

Widefield Retinal Imaging in Gyrate Atrophy: Correlation of Structural, Biochemical, and Functional Characteristics

ObjectivesTo profile a cohort of gyrate atrophy patients classified by widefield retinal imaging and correlate the structural, biochemical, and functional characteristics. DesignRetrospective observational cohort study. ParticipantsSixty-five patients (129 eyes) with gyrate atrophy. MethodsData of participants with a diagnosis of gyrate atrophy were retrieved from their electronic medical records (January 2015 to December 2023). Retinal involvement was classified into three zones using widefield retinal images. Zone 3 had atrophic patches in the area anterior to the equator; Zone 2 had involvement limited to the arcades but posterior to the equator; Zone 1 had involvement within the vascular arcades and/or peripapillary region, with or without any other zone involvement. Macular assessment was performed using swept-source OCT (n=104). Flash ERG was performed in 40 eyes. serum ornithine levels (n=35) were measured, and genetic analysis was conducted (n=18). Main Outcome MeasuresDemography, patient profile, zone of retina involved, macular features, and serum ornithine levels. ResultsThe average age at presentation was 26.4 (range: 5-67) years, majority were male. Nyctalopia (n=35, 53.8%) and blurred vision (n=29, 44.6%) were the most common symptoms. Positive family history was reported in 32.3% of patients. Most eyes were myopic (69.8%<-3 D). Posterior subcapsular cataracts were documented in 36.4% of eyes. The highest frequency of retinal area affected was Zone 1 (57.14%), followed by Zone 2 (33.33%) and Zone 3 (9.52%), correlating with age at presentation. Foveoschisis was observed in 57.7% of eyes, with a higher prevalence in eyes with Zone 1 disease. Elevated serum ornithine levels (>163 μmol/L) were found in 77.14% of patients. ERG showed non-recordable (n=32) or severely reduced (n=8) responses in scotopic and photopic phases. Genetic analysis of 18 patients identified mutations in the OAT gene, including a novel missense variant (c.290T>C). ConclusionsThis large cohort of patients with gyrate atrophy revealed symmetrical involvement, predominantly in Zone 1. Most patients presented between the first and third decades, experienced nyctalopia, vision reduction, early posterior subcapsular cataracts, and varying degrees of myopia. Zone 1 involvement was strongly associated with foveoschisis and visual compromise.

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.

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.

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.].

A cohort study of 19 patients with gyrate atrophy of the choroid and retina (GACR)

A cohort study of 19 patients with gyrate atrophy of the choroid and retina (GACR)

Gyrate atrophy of the choroid and retina with a variant of uncertain significance in ornithine aminotransferase: a case report

Gyrate atrophy of the choroid and retina with a variant of uncertain significance in ornithine aminotransferase: a case report

Three siblings with gyrate atrophy of the choroid and retina: a case report.

Three siblings with gyrate atrophy of the choroid and retina: a case report.

Unilateral retinal neovascularization associated with recurrent vitreous hemorrhage in a patient with gyrate atrophy.

To describe the first case of unilateral peripheral retinal neovasularization associated with recurrent vitreous hemorrhage and localised tractional retinal detachment in a patient with gyrate atrophy (GA). Interventional case report. A 23-year-old man with confirmed diagnosis of gyrate atrophy presented with vitreous hemorrhage and history of stable peripheral inferior tractional retinal detachment in the left eye. After three months, the vitreous hemorrhage partially reabsorbed and peripheral retinal vascular abnormalities with focal neovascularization were detected with associated tractional retinal detachment and confirmed on fluorescein angiography. Cryotherapy was performed to prevent any further bleeding. Twelve months later, the left eye remained stable and no further vitreous bleeding occurred. The combination of peripheral retinal neovascularization, localised tractional retinal detachment and recurrent vitreous hemorrhage can be a unilateral complication of gyrate atrophy. In similar cases, cryotherapy may represent a valuable therapeutic option to prevent recurrent bleeding.

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

BackgroundGyrate 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.MethodsStudy 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.Results18 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.ConclusionsOur 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.

Girate atrophy: clinical and functional features

Gyrate atrophy is a rare genetic metabolic disease with an autosomal recessive inheritance that causes progressive chorioretinal atrophy, fundus manifestations, and decreased visual function. The prognosis of the disease largely depends on the development and progression of complications (macular changes and cataracts) as well as concomitant neurological and somatic pathology.&#x0D; AIM: To describe three clinical cases of hypertension.&#x0D; MATERIAL AND METHODS: We examined three children with gyrate atrophy at 4, 10, and 15 years old. All patients underwent a comprehensive ophthalmological examination, including modern diagnostics, visualization, and electrophysiological studies.&#x0D; RESULTS: Although older patients have more pronounced changes in the fundus with involvement of the macular zone in the pathological process, a 4-year-old child has pronounced functional retinal disorders detected during electroretinogram registration, indicating an earlier manifestation of the pathological process. Gyrate atrophy was combined with foveoschisis and ornithinemia in older patients (10 and 15 years old).&#x0D; The differential diagnosis of gyrate atrophy should be carried out with high myopia with areas of dystrophy of the cobblestone pavement type on the periphery of the fundus, resembling foci of chorioretinal changes in hypertension.&#x0D; CONCLUSION: Patients with gyrate atrophy require an interdisciplinary approach that includes not only ophthalmologists but also pediatricians, medical geneticists, and other specialists with comorbidities.

Gyrate atrophy

Gyrate atrophy

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

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

Ultrawide-field OCT in Gyrate Atrophy

Ultrawide-field OCT in Gyrate Atrophy

Diffuse Choroidal Dystrophies

Hereditary diffuse choroidal dystrophies are conditions with atrophy especially in choriocapillaris, retinal pigment epithelium, and outer retinal layers. Choroideremia transmitted by X recessive inheritance and autosomal recessive Gyrate atrophy is common choroidal dystrophies. In the first decades, these two groups of diseases, whose symptoms begin with a decrease in night vision, progress with a progressive decrease in vision in the advanced decades as the pigmentary changes in the peripheral retina are also affected by the central retina. In Gyrate atrophy, progressive vision decrease and ocular complications can be stopped with dietary changes. However, the development of gene therapy and stem cell therapies for choroideremia is promising.

CRISPR correction of the Finnish ornithine delta-aminotransferase mutation restores metabolic homeostasis in iPSC from patients with gyrate atrophy

Hyperornithinemia with gyrate atrophy of the choroid and retina (HOGA) is a severe recessive inherited disease, causing muscular degeneration and retinochoroidal atrophy that progresses to blindness. HOGA arises from mutations in the ornithine aminotransferase (OAT) gene, and nearly one-third of the known patients worldwide are homozygous for the Finnish founder mutation OAT c.1205 T > C p.(Leu402Pro). We have corrected this loss-of-function OAT mutation in patient-derived induced pluripotent stem cells (iPSCs) using CRISPR/Cas9. The correction restored OAT expression in stem cells and normalized the elevated ornithine levels in cell lysates and cell media. These results show an efficient recovery of OAT function in iPSC, encouraging the possibility of autologous cell therapy for the HOGA disease.

GYRATE ATROPHY: A RARE CASE REPORT

Background- Gyrate atrophy of the retina &amp; choroid is a rare autosomal recessive inherited disease, characterized by progressive chorioretinal atrophy that results in progressive deterioration of peripheral &amp; night vision leading to blindness. Case presentation- This report presents a 40 year old woman consulting for a progressive fall of visual acuity RE with defective night vision. Ocular fundoscopy showed regions of conuent rounded chorioretinal atrophy. Visual eld &amp; retinal angiography were altered. High levels of plasma ornithine 685 nmol/mL) was detected and a diagnosis of gyrate atrophy of retina &amp; choroid was made. The patient was treated with high dose pyridoxine supplement (300 mg/d for 6 months) &amp; ornithine level of her serum was successfully reduced. Conclusion- The exact mechanism of chorioretinal atrophy in hyperornithemia is not known and a small percentage of affected people respond to Vitamin B supplimentation

Double macular hole with gyrate atrophy: A long-term postoperative follow-up

A 55-year-old female presented with diminution of vision, night blindness, and gyrate atrophy with “double macular hole” in the left eye. Spectral-domain optical coherence tomography of the left eye showed coexisting full thickness and lamellar macular hole with both eyes intraretinal schisis and thin epiretinal membrane. After electroretinography and biochemical confirmation of gyrate atrophy, along with arginine-restricted diet, left eye surgery was advised. Postoperatively complete closure of double hole with the resolution of schisis was achieved. However, at subsequent follow-up visits, significant recurrence of intraretinal schisis was noted due to the continued toxic effect of hyperornithinemia on inner retinal layers and retinal pigment epithelium, highlighting the need for effective future treatment options.

The Curious Case of Night Blindness: A Rare Case Report

Introduction: Gyrate Atrophy of the choroid and the retina is a rare autosomal recessive disorder caused by a mutation in ornithine aminotransferase. Case Report: We present an interesting case of a 55-year-old male who presented to us with complaints of night blindness, increase in number of minus glasses, senile cataract in both eyes, constriction of peripheral visual field and chorioretinal atrophic lesions in both eyes. Blood investigation revealed raised plasma ornithine levels at 690 micromole/L (normal range 30-90 micromole/L). There is progressive night blindness and visual field constriction due to progressive chorioretinal degeneration. It has now progressed to diminution of central visual acuity due to progressive macular and glaucomatous changes and cataract formation. Conclusion: There is history of blindness in two out of 6 more siblings which indicates a hereditary pattern.

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.