RARE DISEASE
Gyrate atrophy of choroid and retina
Gyrate atrophy of choroid and retina
Gyrate atrophy of choroid and retina
Synonyms: HOGA, Hyperornithinemia, Hyperornithinemia-gyrate atrophy of choroid and retina syndrome, Ornithine aminotransferase deficiency
Synonyms: HOGA, Hyperornithinemia, Hyperornithinemia-gyrate atrophy of choroid and retina syndrome, Ornithine aminotransferase deficiency
Synonyms: HOGA, Hyperornithinemia, Hyperornithinemia-gyrate atrophy of choroid and retina syndrome, Ornithine aminotransferase deficiency
Drug discovery
0
drugs
With orphan designations
Overview
Gyrate atrophy of the choroid and retina (GACR) is a rare autosomal recessive disorder caused by mutations in the OAT gene, resulting in ornithine aminotransferase deficiency and systemic hyperornithinemia. It manifests as progressive chorioretinal degeneration, childhood-onset myopia, night blindness, and peripheral vision loss, typically progressing to legal blindness by age 50 [1][5][15]. While primarily ocular, some patients exhibit neurological abnormalities or creatine deficiency [1][4]. Current management focuses on slowing progression through dietary modifications and vitamin supplementation, though no curative therapies exist [4][7][12].
Burden
High morbidity: 100% develop severe visual impairment, with 38% showing macular involvement by adulthood [4][9]
Quality-of-life impact: Lifelong dietary restrictions and progressive disability requiring adaptive resources [4][7][16]
Economic burden: Costs associated with multidisciplinary care, dietary management, and advanced therapies [13][16]
Therapies
Dietary: Arginine-restricted/low-protein diets to reduce plasma ornithine (slows progression but rarely normalizes levels) [2][7][12]
Supplements: Pyridoxine (B6) for responsive mutations; creatine for secondary deficiency [4][7][16]
Ocular: Cataract surgery, low-vision aids, and experimental gene therapies targeting liver/retina in clinical trials [10][13][16]
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders
Research Papers
160 drug discovery papers about Gyrate atrophy of choroid and retina, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
160 drug discovery papers about Gyrate atrophy of choroid and retina, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-13 | Case report on Vitamin B6-Responsive Gyrate atrophy with Cystoid Macular Edema in a Consanguineous Young Male: A Treatable Metabolic Retinopathy.
Gyrate atrophy is a rare autosomal recessive chorioretinal dystrophy caused by ornithine aminotransferase deficiency, resulting in toxic accumulation of plasma ornithine and progressive retinal degeneration. We describe a 20-year-old male, born to consanguineous parents, who presented with progressive diminution of vision, nyctalopia, and peripheral visual field loss. Fundus examination revealed sharply demarcated, scalloped areas of midperipheral chorioretinal atrophy with relative macular sparing. Optical coherence tomography demonstrated cystoid macular edema, whereas plasma ornithine levels were markedly elevated. The patient was treated with dietary protein restriction and pyridoxine supplementation, with biochemical improvement and stabilization of visual function. Early recognition, metabolic monitoring, and evaluation of pyridoxine responsiveness may delay visual deterioration and improve visual prognosis in gyrate atrophy.
2026-07-26 | Rapid improvement of cystoid macular edema in a patient with gyrate atrophy.
Gyrate atrophy (GA) is a rare autosomal recessive disease caused by a defect in the enzyme ornithine aminotransferase (OAT). We report a case of a 4-year-old boy with GA of the choroid and retina. Following initiation of an arginine-restricted diet and targeted supplementation, there was rapid improvement in his cystoid macular edema (CME) and foveoschisis. We also report clinical and imaging findings from his 2-year-old sister, who carries the same genetic variant. This report highlights the potential for early metabolic intervention to produce rapid anatomical improvement in GA-associated CME. Further studies are needed to determine which mutations respond better to specific treatments.
2026-03-23 | Gyrate Atrophy of the Choroid and Retina: A Case Report
Gyrate atrophy (GA) of the choroid and retina is a rare, autosomal recessive metabolic disorder caused by a deficiency of the mitochondrial enzyme ornithine aminotransferase. This report describes the clinical characteristics, multimodal imaging findings, and therapeutic outcomes in a 28-year-old Moroccan male from a first-degree consanguineous union who presented with a lifelong history of progressive nyctalopia and high myopia. Best-corrected visual acuity was 20/60 in the right eye and 20/100 in the left. Funduscopy revealed pathognomonic "circumferential garland" chorioretinal atrophic lacunae with scalloped margins and peripapillary atrophy. Multimodal imaging via fundus autofluorescence confirmed profound hypo-autofluorescence in atrophic zones, while infrared retinography highlighted well-demarcated, hyper-reflective scalloped patches. Spectral-domain optical coherence tomography identified significant cystoid macular edema (CME) predominantly within the outer retina. Laboratory analysis confirmed a pathognomonic hyperornithinemia of 950 µmol/L. Following management with a low-arginine diet, vitamin B6, and oral acetazolamide, the six-month follow-up showed a reduction in plasma ornithine levels to 252 µmol/L, correlating with a one-line improvement in visual acuity and stabilization of the macular status. This case underscores the utility of multimodal imaging in diagnosing GA and identifying treatable macular complications like CME, which remain significant obstacles to visual rehabilitation.
2026-02-17 | Gyrate atrophy of the choroid and retina: a tertiary center experience.
Gyrate atrophy of the choroid and retina (GACR) is a rare amino acid metabolism disorder. Night blindness, cataracts, vision loss, and impaired cognitive functions can be seen. An arginine-restricted diet, combined with pyridoxine, lysine, proline, or creatine supplementation, can be used in conjunction with treatments for ophthalmological findings. Patients followed by the Gazi University Faculty of Medicine, Department of Pediatric Metabolism and Nutrition, and Department of Ophthalmology who were genetically or biochemically diagnosed with GACR were included in the study. The patients' medical records were retrospectively reviewed between 2000 and 2023. Seven patients with a mean age of 18.08 ± 8.6 years and a mean age at diagnosis of 10.4 ± 5.6 years were included. The earliest diagnosed patient was 15 months old. All patients had high plasma ornithine levels at the time of diagnosis, and they were all started on an arginine-restricted diet. Ophthalmological treatments were decided on a patient-specific basis. GACR is easily recognizable, but there is still no consensus on treatment modalities. The patients primarily present with progressive ophthalmological findings. An arginine-restricted diet is combined with supplementation with pyridoxine, lysine, proline, or creatine to improve metabolic control. Ophthalmological treatments are mainly applied to reduce cystoid macular edema. Early diagnosis and early initiation of therapy should be aimed at patients, and a multidisciplinary approach should be demonstrated both in diagnosis and follow-up.
2025-11-27 | Impact of high-dose vitamins on a patient with hyperornithinemia-hyperammonemia-homocitrullinuria syndrome
Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive metabolic disorder caused by a mutation of SLC25A15 encoding for the mitochondrial ornithine carrier. Recent study suggested that impaired mitochondrial function may play a major role in central nervous system impairment in HHH syndrome. We hypothesized that if the mitochondrial dysfunction was associated with neurological impairment in HHH syndrome, antioxidants might be effective to avoid aggravation of the brain injury. We presented the clinical outcome in a patient with HHH syndrome undergoing a high-dose vitamin treatment and discussed the effect of this treatment. The male patient was definitively diagnosed by compound heterogeneous pathogenic variants in the SLC25A15 gene. He was started vitamin B1, C and E therapy at age of 3 years. The blood lactate (Lac) levels gradually decreased and serum β-hydroxybutyrate/acetoacetate (β-OHB/AcAc) ratio also decreased at age of 7 years. A verbal development score in Kyoto Scale of Psychological Development was 65 at age of 3 years. However, quotient of Verbal Comprehension Index in Wechsler Intelligence Scale for Children - Fourth Edition increased to 109 at age of 7 years during this vitamin therapy. The outcome in our patient suggested that high-dose vitamin therapy might contribute to preventing cognitive disability. Moreover, the decreased blood Lac level and serum β-OHB/AcAc ratio also suggested that the effect of this therapy might be due to improving the mitochondrial function such as citric acid cycle . This case report suggest that the high-dose vitamin therapy may enhance mitochondrial function in HHH syndrome.
gene therapies
2024-11-04 | Combined intraocular and intravenous gene delivery for therapy of gyrate atrophy of the choroid and retina.
Gyrate atrophy of the choroid and retina (GACR) is due to ornithine aminotransferase (OAT) deficiency, which causes hyperornithinemia, leading to retinal pigment epithelium, followed by choroidal and retinal degeneration. Adeno-associated virus serotype 8 (AAV8) vector-mediated OAT (AAV8-OAT) liver gene transfer reduces ornithinemia in the Oat-/- mouse model of GACR and improves retinal function and structure. Since OAT is expressed in various tissues including the retina, we investigated the efficacy of restoration of OAT expression in either retina or liver or both tissues on the retinal phenotype of Oat-/- mice. Intravenous and subretinal administration of AAV8-OAT resulted in intraocular and liver OAT expression with reduced ornithinemia after intravenous AAV8-OAT administration, while intraocular ornithine levels were significantly reduced only following combined gene delivery. Accordingly, only Oat-/- animals treated with combined intravenous and subretinal AAV8-OAT administrations showed significant improvements in both retinal morphology and function. This work shows the benefits of combined liver and retinal OAT supplementation for the treatment of GACR.
2024-01-18 | Vision on gyrate atrophy: why treat the liver?
Gyrate Atrophy of the Choroid and Retina (GACR) currently lacks any effective treatment and a highly restricted, yet cumbersome, low-arginine diet is the only available therapeutic option. In our work, we found that replacement of ornithine-aminotransferase (OAT) activity in the liver lowers ornithine concentrations in the blood and the eye, thus improving retinal structure and function (Boffa et al, 2023). In this Correspondence, N. Brunetti-Pierri and I. Boffa argue that liver-directed gene therapy is the preferred option for treatment of gyrate atrophy of the choroid and retina. [Image: see text]
2023-12-14 | 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.
2023-04-12 | 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.
2023-04-12 | Targeting the liver to treat the eye.
Over the last two decades, gene therapy has given hope of potential cure for many rare diseases. In the simplest form, gene therapy is the transfer or editing of a genetic material to cure a disease via nonviral or viral vehicles. Gene therapy can be performed either in vivo by injecting a vector carrying the gene or tools for gene editing directly into a tissue or into the systemic circulation, or ex vivo when patient cells are genetically modified outside of the body and then introduced back into the patient (Yilmaz et al, 2022). Adeno-associated viral vectors (AAV) have been the vectors of choice for in vivo gene therapy. There has been a lot of promising research on the development of novel tissue and cell-specific serotypes in order to improve efficacy and safety for clinical applications (Kuzmin et al, 2021). In this issue of EMBO Molecular Medicine, Boffa and colleagues present a novel AAV-based liver-directed gene therapy for ornithine aminotransferase deficiency.
cell therapies
2025-10-23 | Liver transplantation can prevent the progression of neurological damage in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome and maintain long-term metabolic stability - The largest single-center experience.
Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome is a rare urea cycle disorder caused by mutations in the SLC25A15 gene, leading to metabolic and neurological impairments. Liver transplantation (LT) may restore urea cycle function and prevent disease progression. This retrospective study analyzed six patients with HHH syndrome who underwent LT between 2016 and 2022. Pre- and post-transplant evaluations included biochemical tests, genetic analysis, neurological assessments, and quality-of-life measures. LT successfully normalized metabolic parameters (ammonia and amino acid levels) and allowed patients to resume normal diets. Early transplantation resulted in neurological improvement in 5 of 6 patients (83.3%), including reduced lower limb spasticity and improved walking ability. Two patients (33.3%) achieved nearly normal gait, and one patient (16.7%) recovered to normal motor function within three months after LT. Quality-of-life scores improved in 2 patients (33.3%). The overall survival rate was 83.3%, with one patient dying from unrelated causes 5 years post-transplant. No significant long-term complications were observed in the surviving patients. Liver transplantation is an effective treatment for HHH syndrome, halting neurological decline and improving quality of life. Early LT before irreversible damage provides the best outcomes, making it a viable option for patients with progressive symptoms unresponsive to conventional therapies. Not applicable.
2021-04-14 | Successful living donor liver transplantation plus domino-auxiliary partial orthotopic liver transplantation for pediatric patients with metabolic disorders.
To investigate the efficacy of living donor liver transplantation (LDLT) plus domino-auxiliary partial orthotopic liver transplantation (D-APOLT) in pediatric patients with metabolic disorders. From May 2017 to October 2018, two patients with ornithine aminotransferase deficiency (OTCD) and one patient with type I Crigler-Najjar syndrome (CNS1) received LDLT, their livers were prepared as donors for D-APOLT. Two patients with CNS1 received domino liver grafts from OTCD patients; one OTCD patient received a domino liver graft from a CNS1 patient. The mean follow-up was 26.6 months. The liver function and ammonia remained in the normal range at the end of the follow-up in all recipients. One D-APOLT patient experienced portal vein thrombosis 2 days after transplantation and required reoperation, this patient presented an imbalance of portal blood perfusion between the native and the domino liver at 8 months after liver transplant. The imbalance was improved by interventional radiology treatment. Two LDLT patients experienced early mild acute rejection. The non-cirrhotic livers from pediatric patients with metabolic liver disease can be used as domino donor grafts for selected pediatric patients with different metabolic liver disease. D-APOLT achieves ideal recipient outcomes and provides a strategy to expand donor source for children.
2011-07-26 | Optic Vesicle-like Structures Derived from Human Pluripotent Stem Cells Facilitate a Customized Approach to Retinal Disease Treatment
Abstract Differentiation methods for human induced pluripotent stem cells (hiPSCs) typically yield progeny from multiple tissue lineages, limiting their use for drug testing and autologous cell transplantation. In particular, early retina and forebrain derivatives often intermingle in pluripotent stem cell cultures, owing to their shared ancestry and tightly coupled development. Here, we demonstrate that three-dimensional populations of retinal progenitor cells (RPCs) can be isolated from early forebrain populations in both human embryonic stem cell and hiPSC cultures, providing a valuable tool for developmental, functional, and translational studies. Using our established protocol, we identified a transient population of optic vesicle (OV)-like structures that arose during a time period appropriate for normal human retinogenesis. These structures were independently cultured and analyzed to confirm their multipotent RPC status and capacity to produce physiologically responsive retinal cell types, including photoreceptors and retinal pigment epithelium (RPE). We then applied this method to hiPSCs derived from a patient with gyrate atrophy, a retinal degenerative disease affecting the RPE. RPE generated from these hiPSCs exhibited a disease-specific functional defect that could be corrected either by pharmacological means or following targeted gene repair. The production of OV-like populations from human pluripotent stem cells should facilitate the study of human retinal development and disease and advance the use of hiPSCs in personalized medicine.
2011-04-04 | Genetic correction and analysis of induced pluripotent stem cells from a patient with gyrate atrophy
Gene-corrected patient-specific induced pluripotent stem (iPS) cells offer a unique approach to gene therapy. Here, we begin to assess whether the mutational load acquired during gene correction of iPS cells is compatible with use in the treatment of genetic causes of retinal degenerative disease. We isolated iPS cells free of transgene sequences from a patient with gyrate atrophy caused by a point mutation in the gene encoding ornithine-δ-aminotransferase ( OAT ) and used homologous recombination to correct the genetic defect. Cytogenetic analysis, array comparative genomic hybridization (aCGH), and exome sequencing were performed to assess the genomic integrity of an iPS cell line after three sequential clonal events: initial reprogramming, gene targeting, and subsequent removal of a selection cassette. No abnormalities were detected after standard G-band metaphase analysis. However, aCGH and exome sequencing identified two deletions, one amplification, and nine mutations in protein coding regions in the initial iPS cell clone. Except for the targeted correction of the single nucleotide in the OAT locus and a single synonymous base-pair change, no additional mutations or copy number variation were identified in iPS cells after the two subsequent clonal events. These findings confirm that iPS cells themselves may carry a significant mutational load at initial isolation, but that the clonal events and prolonged cultured required for correction of a genetic defect can be accomplished without a substantial increase in mutational burden.
2009-04-01 | Over-expression of a tomato N-acetyl-L-glutamate synthase gene (SlNAGS1) in Arabidopsis thaliana results in high ornithine levels and increased tolerance in salt and drought stresses
A single copy of the N-acetyl-L-glutamate synthase gene (SlNAGS1) has been isolated from tomato. The deduced amino acid sequence consists of 604 amino acids and shows a high level of similarity to the predicted Arabidopsis NAGS1 and NAGS2 proteins. Furthermore, the N-terminus ArgB domain and the C-terminus ArgA domain found in SlNAGS1 are similar to the structural arrangements that have been reported for other predicted NAGS proteins. SlNAGS1 was expressed at high levels in all aerial organs, and at basic levels in seeds, whereas it was not detected at all in roots. SlNAGS1 transcript accumulation was noticed transiently in tomato fruit at the red-fruit stage. In addition, an increase of SlNAGS1 transcripts was detected in mature green tomato fruit within the first hour of exposure to low oxygen concentrations. Transgenic Arabidopsis plants have been generated expressing the SlNAGS1 gene under the control of the cauliflower mosaic virus (CaMV) 35S promoter. Three homozygous transgenic lines expressing the transgene (lines 1-7, 3-8, and 6-5) were evaluated further. All three transgenic lines showed a significant accumulation of ornithine in the leaves with line 3-8 exhibiting the highest concentration. The same lines demonstrated higher germination ability compared to wild-type (WT) plants when subjected to 250 mM NaCl. Similarly, mature plants of all three transgenic lines displayed a higher tolerance to salt and drought stress compared to WT plants. Under most experimental conditions, transgenic line 3-8 performed best, while the responses obtained from lines 1-7 and 6-5 depended on the applied stimulus. To our knowledge, this is the first plant NAGS gene to be isolated, characterized, and genetically modified.
antibodies
2026-06-01 | Macular neovascularization in patients with Gyrate atrophy.
Two cases of macular neovascularization (MNV) in female patients with genetically confirmed Gyrate Atrophy of the choroid and retina (GACR) are presented. Both patients experienced sudden central vision loss, with subfoveal MNV confirmed on multimodal imaging including optical coherence tomography angiography. The first patient showed improvement in best-corrected visual acuity (BCVA) from 20/60 to 20/30 following three monthly intravitreal anti-VEGF injections, followed by a treat-and-extend regimen. The second patient experienced five MNV recurrences over a five-year period, each managed with anti-VEGF therapy, achieving long-term visual stability at 20/40. Persistent subretinal fibrosis developed in both cases. These cases represent the first reported instance of recurrent MNV in GACR. A review of clinical findings and existing literature suggests that the pathogenesis may involve both GACR-associated retinal pigment epithelial dysfunction and high myopia. Anti-VEGF therapy proved effective in preserving vision, but the recurrent nature of MNV highlights the necessity of long-term follow-up. This report provides novel insight into a rare but vision-threatening complication of GACR and underscores the importance of early detection, treatment, and continued monitoring in affected patients.
2021-08-10 | Treatment of Intraretinal Cystic Spaces Associated With Gyrate Atrophy of the Choroid and Retina With Intravitreal Bevacizumab.
To evaluate the use of intravitreal bevacizumab injections for the treatment of intraretinal cystic spaces associated with gyrate atrophy of the choroid and retina. Retrospective chart review of 5 eyes of 3 patients with intraretinal cystic spaces associated with gyrate atrophy and treated with intravitreal bevacizumab injections was performed. Information obtained included history, examination findings, optical coherence tomography (OCT), OCT angiography, fluorescein angiography, and microperimetric findings before and after the injections. The mean age of patients was 11 ± 4.6 years. All patients received three monthly bevacizumab injections. The mean corrected distance visual acuity was 0.27 ± 0.10 at baseline and improved to 0.36 ± 0.12 after the injections (P = .015). The mean central macular thickness was 569 ± 127 µm at baseline and improved to 422 ± 123 µm after the injections (P = .067). Microperimetry and OCT angiography performed in 1 patient before and after the three injections showed improved macular sensitivity and vascular density measurements following the injections. Intravitreal bevacizumab is safe and effective in the treatment of intraretinal cystic spaces associated with gyrate atrophy. [J Pediatr Ophthalmol Strabismus. 2020;57(6):400-406.].
2018-10-18 | Bevacizumab for the treatment of intraretinal cystic spaces in a patient with gyrate atrophy of the choroid and retina
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.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.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.
2018-07-09 | Bilateral choroidal neovascularization associated with gyrate atrophy managed with intravitreal bevacizumab.
To report a case with gyrate atrophy (GA) complicated by bilateral choroidal neovascularization (CNV) treated with intravitreal bevacizumab. A 20-year-old man presented with a complaint of sudden visual decrease in his both eyes. Best-corrected visual acuity (BCVA) was 20/400 and 20/500, with a spherical refractive error of -2.00 and -1.75 D, in the right and left eyes, respectively. Dilated fundus examination revealed multiple bilateral, sharply defined chorioretinal atrophy areas in the midperipheral and peripheral zone with the suspicion of CNV in both eyes. Spectral-domain optical coherence tomography revealed bilateral cystoid macular edema consistent with CNV development which was confirmed by fundus fluorescein angiography. Single dose of intravitreal bevacizumab injections were performed to both eyes of the patient. At the first month after the injection, the BCVA improved and OCT revealed scar formation without any intraretinal/subretinal fluid in both eyes. At the first-year follow-up, the maculas remained dry on the OCT and the BCVA was preserved. No additional injections were needed. Intravitreal bevacizumab might be a treatment alternative, which provides satisfactory anatomical and functional results and leads to a better central vision in cases with GA complicated by CNV.
other
2024-07-27 | 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.
2012-01-20 | Substrate Specificity of the Two Mitochondrial Ornithine Carriers Can Be Swapped by Single Mutation in Substrate Binding Site
Mitochondrial carriers are a large family of proteins that transport specific metabolites across the inner mitochondrial membrane. Sequence and structure analysis has indicated that these transporters have substrate binding sites in a similar location of the central cavity consisting of three major contact points. Here we have characterized mutations of the proposed substrate binding site in the human ornithine carriers ORC1 and ORC2 by carrying out transport assays with a set of different substrates. The different substrate specificities of the two isoforms, which share 87% identical amino acids, were essentially swapped by exchanging a single residue located at position 179 that is arginine in ORC1 and glutamine in ORC2. Altogether the substrate specificity changes demonstrate that Arg-179 and Glu-180 of contact point II bind the Cα carboxylate and amino group of the substrates, respectively. Residue Glu-77 of contact point I most likely interacts with the terminal amino group of the substrate side chain. Furthermore, it is likely that all three contact points are involved in the substrate-induced conformational changes required for substrate translocation because Arg-179 is probably connected with Arg-275 of contact point III through Trp-224 by cation-π interactions. Mutations at position 179 also affected the turnover number of the ornithine carrier severely, implying that substrate binding to residue 179 is a rate-limiting step of the catalytic transport cycle. Given that Arg-179 is located in the vicinity of the matrix gate, it is concluded that it is a key residue in the opening of the carrier to the matrix side. Mitochondrial carriers are a large family of proteins that transport specific metabolites across the inner mitochondrial membrane. Sequence and structure analysis has indicated that these transporters have substrate binding sites in a similar location of the central cavity consisting of three major contact points. Here we have characterized mutations of the proposed substrate binding site in the human ornithine carriers ORC1 and ORC2 by carrying out transport assays with a set of different substrates. The different substrate specificities of the two isoforms, which share 87% identical amino acids, were essentially swapped by exchanging a single residue located at position 179 that is arginine in ORC1 and glutamine in ORC2. Altogether the substrate specificity changes demonstrate that Arg-179 and Glu-180 of contact point II bind the Cα carboxylate and amino group of the substrates, respectively. Residue Glu-77 of contact point I most likely interacts with the terminal amino group of the substrate side chain. Furthermore, it is likely that all three contact points are involved in the substrate-induced conformational changes required for substrate translocation because Arg-179 is probably connected with Arg-275 of contact point III through Trp-224 by cation-π interactions. Mutations at position 179 also affected the turnover number of the ornithine carrier severely, implying that substrate binding to residue 179 is a rate-limiting step of the catalytic transport cycle. Given that Arg-179 is located in the vicinity of the matrix gate, it is concluded that it is a key residue in the opening of the carrier to the matrix side.
2001-02-01 | Hereditary retinal dystrophies and choroidal neovascularization.
Choroidal neovascularization infrequently occurs in patients affected by hereditary retinal dystrophies. We studied eight patients suffering from different hereditary retinal dystrophies (Best's disease, reticular dystrophy, butterfly-shaped dystrophy, gyrate atrophy, and retinitis pigmentosa) who developed choroidal neovascularization. All patients underwent complete ophthalmic evaluation, electrophysiology, colour vision testing, and fluorescein angiography. In some patients, ICG video-angiography was also performed. Laser treatment was carried out in only one patient. The mean duration of follow-up was 41.7 months (range 6-148 months). At CNV diagnosis, the mean VA was 0.23 (range 0.02-0.6). At the last follow-up, mean VA was 0.34 (range HM to 0.9). At the last follow-up, fluorescein angiography showed a focal, atrophic scar in seven eyes, a fibrotic membrane in two eyes and a still active membrane in two cases. We emphasize the relatively favourable visual prognosis in patients suffering from inherited retinal dystrophies complicated with choroidal neovascularization. Therapeutic approaches other than laser treatment could be attempted in these patients.
small molecules
2026-08-13 | Case report on Vitamin B6-Responsive Gyrate atrophy with Cystoid Macular Edema in a Consanguineous Young Male: A Treatable Metabolic Retinopathy.
Gyrate atrophy is a rare autosomal recessive chorioretinal dystrophy caused by ornithine aminotransferase deficiency, resulting in toxic accumulation of plasma ornithine and progressive retinal degeneration. We describe a 20-year-old male, born to consanguineous parents, who presented with progressive diminution of vision, nyctalopia, and peripheral visual field loss. Fundus examination revealed sharply demarcated, scalloped areas of midperipheral chorioretinal atrophy with relative macular sparing. Optical coherence tomography demonstrated cystoid macular edema, whereas plasma ornithine levels were markedly elevated. The patient was treated with dietary protein restriction and pyridoxine supplementation, with biochemical improvement and stabilization of visual function. Early recognition, metabolic monitoring, and evaluation of pyridoxine responsiveness may delay visual deterioration and improve visual prognosis in gyrate atrophy.
2026-07-26 | Rapid improvement of cystoid macular edema in a patient with gyrate atrophy.
Gyrate atrophy (GA) is a rare autosomal recessive disease caused by a defect in the enzyme ornithine aminotransferase (OAT). We report a case of a 4-year-old boy with GA of the choroid and retina. Following initiation of an arginine-restricted diet and targeted supplementation, there was rapid improvement in his cystoid macular edema (CME) and foveoschisis. We also report clinical and imaging findings from his 2-year-old sister, who carries the same genetic variant. This report highlights the potential for early metabolic intervention to produce rapid anatomical improvement in GA-associated CME. Further studies are needed to determine which mutations respond better to specific treatments.
2026-03-23 | Gyrate Atrophy of the Choroid and Retina: A Case Report
Gyrate atrophy (GA) of the choroid and retina is a rare, autosomal recessive metabolic disorder caused by a deficiency of the mitochondrial enzyme ornithine aminotransferase. This report describes the clinical characteristics, multimodal imaging findings, and therapeutic outcomes in a 28-year-old Moroccan male from a first-degree consanguineous union who presented with a lifelong history of progressive nyctalopia and high myopia. Best-corrected visual acuity was 20/60 in the right eye and 20/100 in the left. Funduscopy revealed pathognomonic "circumferential garland" chorioretinal atrophic lacunae with scalloped margins and peripapillary atrophy. Multimodal imaging via fundus autofluorescence confirmed profound hypo-autofluorescence in atrophic zones, while infrared retinography highlighted well-demarcated, hyper-reflective scalloped patches. Spectral-domain optical coherence tomography identified significant cystoid macular edema (CME) predominantly within the outer retina. Laboratory analysis confirmed a pathognomonic hyperornithinemia of 950 µmol/L. Following management with a low-arginine diet, vitamin B6, and oral acetazolamide, the six-month follow-up showed a reduction in plasma ornithine levels to 252 µmol/L, correlating with a one-line improvement in visual acuity and stabilization of the macular status. This case underscores the utility of multimodal imaging in diagnosing GA and identifying treatable macular complications like CME, which remain significant obstacles to visual rehabilitation.
2026-02-17 | Gyrate atrophy of the choroid and retina: a tertiary center experience.
Gyrate atrophy of the choroid and retina (GACR) is a rare amino acid metabolism disorder. Night blindness, cataracts, vision loss, and impaired cognitive functions can be seen. An arginine-restricted diet, combined with pyridoxine, lysine, proline, or creatine supplementation, can be used in conjunction with treatments for ophthalmological findings. Patients followed by the Gazi University Faculty of Medicine, Department of Pediatric Metabolism and Nutrition, and Department of Ophthalmology who were genetically or biochemically diagnosed with GACR were included in the study. The patients' medical records were retrospectively reviewed between 2000 and 2023. Seven patients with a mean age of 18.08 ± 8.6 years and a mean age at diagnosis of 10.4 ± 5.6 years were included. The earliest diagnosed patient was 15 months old. All patients had high plasma ornithine levels at the time of diagnosis, and they were all started on an arginine-restricted diet. Ophthalmological treatments were decided on a patient-specific basis. GACR is easily recognizable, but there is still no consensus on treatment modalities. The patients primarily present with progressive ophthalmological findings. An arginine-restricted diet is combined with supplementation with pyridoxine, lysine, proline, or creatine to improve metabolic control. Ophthalmological treatments are mainly applied to reduce cystoid macular edema. Early diagnosis and early initiation of therapy should be aimed at patients, and a multidisciplinary approach should be demonstrated both in diagnosis and follow-up.
2025-11-27 | Impact of high-dose vitamins on a patient with hyperornithinemia-hyperammonemia-homocitrullinuria syndrome
Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive metabolic disorder caused by a mutation of SLC25A15 encoding for the mitochondrial ornithine carrier. Recent study suggested that impaired mitochondrial function may play a major role in central nervous system impairment in HHH syndrome. We hypothesized that if the mitochondrial dysfunction was associated with neurological impairment in HHH syndrome, antioxidants might be effective to avoid aggravation of the brain injury. We presented the clinical outcome in a patient with HHH syndrome undergoing a high-dose vitamin treatment and discussed the effect of this treatment. The male patient was definitively diagnosed by compound heterogeneous pathogenic variants in the SLC25A15 gene. He was started vitamin B1, C and E therapy at age of 3 years. The blood lactate (Lac) levels gradually decreased and serum β-hydroxybutyrate/acetoacetate (β-OHB/AcAc) ratio also decreased at age of 7 years. A verbal development score in Kyoto Scale of Psychological Development was 65 at age of 3 years. However, quotient of Verbal Comprehension Index in Wechsler Intelligence Scale for Children - Fourth Edition increased to 109 at age of 7 years during this vitamin therapy. The outcome in our patient suggested that high-dose vitamin therapy might contribute to preventing cognitive disability. Moreover, the decreased blood Lac level and serum β-OHB/AcAc ratio also suggested that the effect of this therapy might be due to improving the mitochondrial function such as citric acid cycle . This case report suggest that the high-dose vitamin therapy may enhance mitochondrial function in HHH syndrome.
gene therapies
2024-11-04 | Combined intraocular and intravenous gene delivery for therapy of gyrate atrophy of the choroid and retina.
Gyrate atrophy of the choroid and retina (GACR) is due to ornithine aminotransferase (OAT) deficiency, which causes hyperornithinemia, leading to retinal pigment epithelium, followed by choroidal and retinal degeneration. Adeno-associated virus serotype 8 (AAV8) vector-mediated OAT (AAV8-OAT) liver gene transfer reduces ornithinemia in the Oat-/- mouse model of GACR and improves retinal function and structure. Since OAT is expressed in various tissues including the retina, we investigated the efficacy of restoration of OAT expression in either retina or liver or both tissues on the retinal phenotype of Oat-/- mice. Intravenous and subretinal administration of AAV8-OAT resulted in intraocular and liver OAT expression with reduced ornithinemia after intravenous AAV8-OAT administration, while intraocular ornithine levels were significantly reduced only following combined gene delivery. Accordingly, only Oat-/- animals treated with combined intravenous and subretinal AAV8-OAT administrations showed significant improvements in both retinal morphology and function. This work shows the benefits of combined liver and retinal OAT supplementation for the treatment of GACR.
2024-01-18 | Vision on gyrate atrophy: why treat the liver?
Gyrate Atrophy of the Choroid and Retina (GACR) currently lacks any effective treatment and a highly restricted, yet cumbersome, low-arginine diet is the only available therapeutic option. In our work, we found that replacement of ornithine-aminotransferase (OAT) activity in the liver lowers ornithine concentrations in the blood and the eye, thus improving retinal structure and function (Boffa et al, 2023). In this Correspondence, N. Brunetti-Pierri and I. Boffa argue that liver-directed gene therapy is the preferred option for treatment of gyrate atrophy of the choroid and retina. [Image: see text]
2023-12-14 | 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.
2023-04-12 | 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.
2023-04-12 | Targeting the liver to treat the eye.
Over the last two decades, gene therapy has given hope of potential cure for many rare diseases. In the simplest form, gene therapy is the transfer or editing of a genetic material to cure a disease via nonviral or viral vehicles. Gene therapy can be performed either in vivo by injecting a vector carrying the gene or tools for gene editing directly into a tissue or into the systemic circulation, or ex vivo when patient cells are genetically modified outside of the body and then introduced back into the patient (Yilmaz et al, 2022). Adeno-associated viral vectors (AAV) have been the vectors of choice for in vivo gene therapy. There has been a lot of promising research on the development of novel tissue and cell-specific serotypes in order to improve efficacy and safety for clinical applications (Kuzmin et al, 2021). In this issue of EMBO Molecular Medicine, Boffa and colleagues present a novel AAV-based liver-directed gene therapy for ornithine aminotransferase deficiency.
cell therapies
2025-10-23 | Liver transplantation can prevent the progression of neurological damage in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome and maintain long-term metabolic stability - The largest single-center experience.
Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome is a rare urea cycle disorder caused by mutations in the SLC25A15 gene, leading to metabolic and neurological impairments. Liver transplantation (LT) may restore urea cycle function and prevent disease progression. This retrospective study analyzed six patients with HHH syndrome who underwent LT between 2016 and 2022. Pre- and post-transplant evaluations included biochemical tests, genetic analysis, neurological assessments, and quality-of-life measures. LT successfully normalized metabolic parameters (ammonia and amino acid levels) and allowed patients to resume normal diets. Early transplantation resulted in neurological improvement in 5 of 6 patients (83.3%), including reduced lower limb spasticity and improved walking ability. Two patients (33.3%) achieved nearly normal gait, and one patient (16.7%) recovered to normal motor function within three months after LT. Quality-of-life scores improved in 2 patients (33.3%). The overall survival rate was 83.3%, with one patient dying from unrelated causes 5 years post-transplant. No significant long-term complications were observed in the surviving patients. Liver transplantation is an effective treatment for HHH syndrome, halting neurological decline and improving quality of life. Early LT before irreversible damage provides the best outcomes, making it a viable option for patients with progressive symptoms unresponsive to conventional therapies. Not applicable.
2021-04-14 | Successful living donor liver transplantation plus domino-auxiliary partial orthotopic liver transplantation for pediatric patients with metabolic disorders.
To investigate the efficacy of living donor liver transplantation (LDLT) plus domino-auxiliary partial orthotopic liver transplantation (D-APOLT) in pediatric patients with metabolic disorders. From May 2017 to October 2018, two patients with ornithine aminotransferase deficiency (OTCD) and one patient with type I Crigler-Najjar syndrome (CNS1) received LDLT, their livers were prepared as donors for D-APOLT. Two patients with CNS1 received domino liver grafts from OTCD patients; one OTCD patient received a domino liver graft from a CNS1 patient. The mean follow-up was 26.6 months. The liver function and ammonia remained in the normal range at the end of the follow-up in all recipients. One D-APOLT patient experienced portal vein thrombosis 2 days after transplantation and required reoperation, this patient presented an imbalance of portal blood perfusion between the native and the domino liver at 8 months after liver transplant. The imbalance was improved by interventional radiology treatment. Two LDLT patients experienced early mild acute rejection. The non-cirrhotic livers from pediatric patients with metabolic liver disease can be used as domino donor grafts for selected pediatric patients with different metabolic liver disease. D-APOLT achieves ideal recipient outcomes and provides a strategy to expand donor source for children.
2011-07-26 | Optic Vesicle-like Structures Derived from Human Pluripotent Stem Cells Facilitate a Customized Approach to Retinal Disease Treatment
Abstract Differentiation methods for human induced pluripotent stem cells (hiPSCs) typically yield progeny from multiple tissue lineages, limiting their use for drug testing and autologous cell transplantation. In particular, early retina and forebrain derivatives often intermingle in pluripotent stem cell cultures, owing to their shared ancestry and tightly coupled development. Here, we demonstrate that three-dimensional populations of retinal progenitor cells (RPCs) can be isolated from early forebrain populations in both human embryonic stem cell and hiPSC cultures, providing a valuable tool for developmental, functional, and translational studies. Using our established protocol, we identified a transient population of optic vesicle (OV)-like structures that arose during a time period appropriate for normal human retinogenesis. These structures were independently cultured and analyzed to confirm their multipotent RPC status and capacity to produce physiologically responsive retinal cell types, including photoreceptors and retinal pigment epithelium (RPE). We then applied this method to hiPSCs derived from a patient with gyrate atrophy, a retinal degenerative disease affecting the RPE. RPE generated from these hiPSCs exhibited a disease-specific functional defect that could be corrected either by pharmacological means or following targeted gene repair. The production of OV-like populations from human pluripotent stem cells should facilitate the study of human retinal development and disease and advance the use of hiPSCs in personalized medicine.
2011-04-04 | Genetic correction and analysis of induced pluripotent stem cells from a patient with gyrate atrophy
Gene-corrected patient-specific induced pluripotent stem (iPS) cells offer a unique approach to gene therapy. Here, we begin to assess whether the mutational load acquired during gene correction of iPS cells is compatible with use in the treatment of genetic causes of retinal degenerative disease. We isolated iPS cells free of transgene sequences from a patient with gyrate atrophy caused by a point mutation in the gene encoding ornithine-δ-aminotransferase ( OAT ) and used homologous recombination to correct the genetic defect. Cytogenetic analysis, array comparative genomic hybridization (aCGH), and exome sequencing were performed to assess the genomic integrity of an iPS cell line after three sequential clonal events: initial reprogramming, gene targeting, and subsequent removal of a selection cassette. No abnormalities were detected after standard G-band metaphase analysis. However, aCGH and exome sequencing identified two deletions, one amplification, and nine mutations in protein coding regions in the initial iPS cell clone. Except for the targeted correction of the single nucleotide in the OAT locus and a single synonymous base-pair change, no additional mutations or copy number variation were identified in iPS cells after the two subsequent clonal events. These findings confirm that iPS cells themselves may carry a significant mutational load at initial isolation, but that the clonal events and prolonged cultured required for correction of a genetic defect can be accomplished without a substantial increase in mutational burden.
2009-04-01 | Over-expression of a tomato N-acetyl-L-glutamate synthase gene (SlNAGS1) in Arabidopsis thaliana results in high ornithine levels and increased tolerance in salt and drought stresses
A single copy of the N-acetyl-L-glutamate synthase gene (SlNAGS1) has been isolated from tomato. The deduced amino acid sequence consists of 604 amino acids and shows a high level of similarity to the predicted Arabidopsis NAGS1 and NAGS2 proteins. Furthermore, the N-terminus ArgB domain and the C-terminus ArgA domain found in SlNAGS1 are similar to the structural arrangements that have been reported for other predicted NAGS proteins. SlNAGS1 was expressed at high levels in all aerial organs, and at basic levels in seeds, whereas it was not detected at all in roots. SlNAGS1 transcript accumulation was noticed transiently in tomato fruit at the red-fruit stage. In addition, an increase of SlNAGS1 transcripts was detected in mature green tomato fruit within the first hour of exposure to low oxygen concentrations. Transgenic Arabidopsis plants have been generated expressing the SlNAGS1 gene under the control of the cauliflower mosaic virus (CaMV) 35S promoter. Three homozygous transgenic lines expressing the transgene (lines 1-7, 3-8, and 6-5) were evaluated further. All three transgenic lines showed a significant accumulation of ornithine in the leaves with line 3-8 exhibiting the highest concentration. The same lines demonstrated higher germination ability compared to wild-type (WT) plants when subjected to 250 mM NaCl. Similarly, mature plants of all three transgenic lines displayed a higher tolerance to salt and drought stress compared to WT plants. Under most experimental conditions, transgenic line 3-8 performed best, while the responses obtained from lines 1-7 and 6-5 depended on the applied stimulus. To our knowledge, this is the first plant NAGS gene to be isolated, characterized, and genetically modified.
antibodies
2026-06-01 | Macular neovascularization in patients with Gyrate atrophy.
Two cases of macular neovascularization (MNV) in female patients with genetically confirmed Gyrate Atrophy of the choroid and retina (GACR) are presented. Both patients experienced sudden central vision loss, with subfoveal MNV confirmed on multimodal imaging including optical coherence tomography angiography. The first patient showed improvement in best-corrected visual acuity (BCVA) from 20/60 to 20/30 following three monthly intravitreal anti-VEGF injections, followed by a treat-and-extend regimen. The second patient experienced five MNV recurrences over a five-year period, each managed with anti-VEGF therapy, achieving long-term visual stability at 20/40. Persistent subretinal fibrosis developed in both cases. These cases represent the first reported instance of recurrent MNV in GACR. A review of clinical findings and existing literature suggests that the pathogenesis may involve both GACR-associated retinal pigment epithelial dysfunction and high myopia. Anti-VEGF therapy proved effective in preserving vision, but the recurrent nature of MNV highlights the necessity of long-term follow-up. This report provides novel insight into a rare but vision-threatening complication of GACR and underscores the importance of early detection, treatment, and continued monitoring in affected patients.
2021-08-10 | Treatment of Intraretinal Cystic Spaces Associated With Gyrate Atrophy of the Choroid and Retina With Intravitreal Bevacizumab.
To evaluate the use of intravitreal bevacizumab injections for the treatment of intraretinal cystic spaces associated with gyrate atrophy of the choroid and retina. Retrospective chart review of 5 eyes of 3 patients with intraretinal cystic spaces associated with gyrate atrophy and treated with intravitreal bevacizumab injections was performed. Information obtained included history, examination findings, optical coherence tomography (OCT), OCT angiography, fluorescein angiography, and microperimetric findings before and after the injections. The mean age of patients was 11 ± 4.6 years. All patients received three monthly bevacizumab injections. The mean corrected distance visual acuity was 0.27 ± 0.10 at baseline and improved to 0.36 ± 0.12 after the injections (P = .015). The mean central macular thickness was 569 ± 127 µm at baseline and improved to 422 ± 123 µm after the injections (P = .067). Microperimetry and OCT angiography performed in 1 patient before and after the three injections showed improved macular sensitivity and vascular density measurements following the injections. Intravitreal bevacizumab is safe and effective in the treatment of intraretinal cystic spaces associated with gyrate atrophy. [J Pediatr Ophthalmol Strabismus. 2020;57(6):400-406.].
2018-10-18 | Bevacizumab for the treatment of intraretinal cystic spaces in a patient with gyrate atrophy of the choroid and retina
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.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.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.
2018-07-09 | Bilateral choroidal neovascularization associated with gyrate atrophy managed with intravitreal bevacizumab.
To report a case with gyrate atrophy (GA) complicated by bilateral choroidal neovascularization (CNV) treated with intravitreal bevacizumab. A 20-year-old man presented with a complaint of sudden visual decrease in his both eyes. Best-corrected visual acuity (BCVA) was 20/400 and 20/500, with a spherical refractive error of -2.00 and -1.75 D, in the right and left eyes, respectively. Dilated fundus examination revealed multiple bilateral, sharply defined chorioretinal atrophy areas in the midperipheral and peripheral zone with the suspicion of CNV in both eyes. Spectral-domain optical coherence tomography revealed bilateral cystoid macular edema consistent with CNV development which was confirmed by fundus fluorescein angiography. Single dose of intravitreal bevacizumab injections were performed to both eyes of the patient. At the first month after the injection, the BCVA improved and OCT revealed scar formation without any intraretinal/subretinal fluid in both eyes. At the first-year follow-up, the maculas remained dry on the OCT and the BCVA was preserved. No additional injections were needed. Intravitreal bevacizumab might be a treatment alternative, which provides satisfactory anatomical and functional results and leads to a better central vision in cases with GA complicated by CNV.
other
2024-07-27 | 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.
2012-01-20 | Substrate Specificity of the Two Mitochondrial Ornithine Carriers Can Be Swapped by Single Mutation in Substrate Binding Site
Mitochondrial carriers are a large family of proteins that transport specific metabolites across the inner mitochondrial membrane. Sequence and structure analysis has indicated that these transporters have substrate binding sites in a similar location of the central cavity consisting of three major contact points. Here we have characterized mutations of the proposed substrate binding site in the human ornithine carriers ORC1 and ORC2 by carrying out transport assays with a set of different substrates. The different substrate specificities of the two isoforms, which share 87% identical amino acids, were essentially swapped by exchanging a single residue located at position 179 that is arginine in ORC1 and glutamine in ORC2. Altogether the substrate specificity changes demonstrate that Arg-179 and Glu-180 of contact point II bind the Cα carboxylate and amino group of the substrates, respectively. Residue Glu-77 of contact point I most likely interacts with the terminal amino group of the substrate side chain. Furthermore, it is likely that all three contact points are involved in the substrate-induced conformational changes required for substrate translocation because Arg-179 is probably connected with Arg-275 of contact point III through Trp-224 by cation-π interactions. Mutations at position 179 also affected the turnover number of the ornithine carrier severely, implying that substrate binding to residue 179 is a rate-limiting step of the catalytic transport cycle. Given that Arg-179 is located in the vicinity of the matrix gate, it is concluded that it is a key residue in the opening of the carrier to the matrix side. Mitochondrial carriers are a large family of proteins that transport specific metabolites across the inner mitochondrial membrane. Sequence and structure analysis has indicated that these transporters have substrate binding sites in a similar location of the central cavity consisting of three major contact points. Here we have characterized mutations of the proposed substrate binding site in the human ornithine carriers ORC1 and ORC2 by carrying out transport assays with a set of different substrates. The different substrate specificities of the two isoforms, which share 87% identical amino acids, were essentially swapped by exchanging a single residue located at position 179 that is arginine in ORC1 and glutamine in ORC2. Altogether the substrate specificity changes demonstrate that Arg-179 and Glu-180 of contact point II bind the Cα carboxylate and amino group of the substrates, respectively. Residue Glu-77 of contact point I most likely interacts with the terminal amino group of the substrate side chain. Furthermore, it is likely that all three contact points are involved in the substrate-induced conformational changes required for substrate translocation because Arg-179 is probably connected with Arg-275 of contact point III through Trp-224 by cation-π interactions. Mutations at position 179 also affected the turnover number of the ornithine carrier severely, implying that substrate binding to residue 179 is a rate-limiting step of the catalytic transport cycle. Given that Arg-179 is located in the vicinity of the matrix gate, it is concluded that it is a key residue in the opening of the carrier to the matrix side.
2001-02-01 | Hereditary retinal dystrophies and choroidal neovascularization.
Choroidal neovascularization infrequently occurs in patients affected by hereditary retinal dystrophies. We studied eight patients suffering from different hereditary retinal dystrophies (Best's disease, reticular dystrophy, butterfly-shaped dystrophy, gyrate atrophy, and retinitis pigmentosa) who developed choroidal neovascularization. All patients underwent complete ophthalmic evaluation, electrophysiology, colour vision testing, and fluorescein angiography. In some patients, ICG video-angiography was also performed. Laser treatment was carried out in only one patient. The mean duration of follow-up was 41.7 months (range 6-148 months). At CNV diagnosis, the mean VA was 0.23 (range 0.02-0.6). At the last follow-up, mean VA was 0.34 (range HM to 0.9). At the last follow-up, fluorescein angiography showed a focal, atrophic scar in seven eyes, a fibrotic membrane in two eyes and a still active membrane in two cases. We emphasize the relatively favourable visual prognosis in patients suffering from inherited retinal dystrophies complicated with choroidal neovascularization. Therapeutic approaches other than laser treatment could be attempted in these patients.
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