Review

Authors: Alain Gaudric, Isabelle Audo, Catherine Vignal...

Besides cystoid macular edema due to a blood-retinal barrier breakdown, another type of macular cystoid spaces referred to as non-vasogenic cystoid maculopathies (NVCM) may be detected on optical coherence tomography but not on fluorescein angiography. Various causes may disrupt retinal cell cohesion or impair retinal pigment epithelium (RPE) and Müller cell functions in the maintenance of retinal dehydration, resulting in cystoid spaces formation. Tractional causes include vitreomacular traction, epiretinal membranes and myopic foveoschisis. Surgical treatment does not always allow cystoid space resorption. In inherited retinal dystrophies, cystoid spaces may be part of the disease as in X-linked retinoschisis or enhanced S-cone syndrome, or occur occasionally as in bestrophinopathies, retinitis pigmentosa and allied diseases, congenital microphthalmia, choroideremia, gyrate atrophy and Bietti crystalline dystrophy. In macular telangiectasia type 2, cystoid spaces and cavitations do not depend on the fluid leakage from telangiectasia. Various causes affecting RPE function may result in NVCM such as chronic central serous chorioretinopathy and paraneoplastic syndromes. Non-exudative age macular degeneration may also be complicated by intraretinal cystoid spaces in the absence of fluorescein leakage. In these diseases, cystoid spaces occur in a context of retinal cell loss. Various causes of optic atrophy, including open-angle glaucoma, result in microcystoid spaces in the inner nuclear layer due to a retrograde transsynaptic degeneration. Lastly, drug toxicity may also induce cystoid maculopathy. Identifying NVCM on multimodal imaging, including fluorescein angiography if needed, allows guiding the diagnosis of the causative disease and choosing adequate treatment when available.

Topics: Humans; Glaucoma, Open-Angle; Macular Edema; Fluorescein Angiography; Macular Degeneration; Tomography, Optical Coherence; Retinal Telangiectasis

PubMed: 35927124
DOI: 10.1016/j.preteyeres.2022.101092

Review

Authors: Berith M Balfoort, Mark J N Buijs, Anneloor L M A Ten Asbroek...

UNLABELLED

Gyrate atrophy of the choroid and retina (GACR) is a rare inborn error of amino acid metabolism caused by bi-allelic variations in OAT. GACR is characterised by vision decline in early life eventually leading to complete blindness, and high plasma ornithine levels. There is no curative treatment for GACR, although several therapeutic modalities aim to slow progression of the disease by targeting different steps within the ornithine pathway. No international treatment protocol is available. We systematically collected all international literature on therapeutic interventions in GACR to provide an overview of published treatment effects.

METHODS

Following the PRISMA guidelines, we conducted a systematic review of the English literature until December 22nd 2020. PubMed and Embase databases were searched for studies related to therapeutic interventions in patients with GACR.

RESULTS

A total of 33 studies (n = 107 patients) met the inclusion criteria. Most studies were designed as case reports (n = 27) or case series (n = 4). No randomised controlled trials or large cohort studies were found. Treatments applied were protein-restricted diets, pyridoxine supplementation, creatine or creatine precursor supplementation, l-lysine supplementation, and proline supplementation. Protein-restricted diets lowered ornithine levels ranging from 16.0-91.2%. Pyridoxine responsiveness was reported in 30% of included mutations. Lysine supplementation decreased ornithine levels with 21-34%. Quality assessment showed low to moderate quality of the articles.

CONCLUSIONS

Based primarily on case reports ornithine levels can be reduced by using a protein restricted diet, pyridoxine supplementation (variation-dependent) and/or lysine supplementation. The lack of pre-defined clinical outcome measures and structural follow-up in all included studies impeded conclusions on clinical effectiveness. Future research should be aimed at 1) Unravelling the OAT biochemical pathway to identify other possible pathologic metabolites besides ornithine, 2) Pre-defining GACR specific clinical outcome measures, and 3) Establishing an international historical cohort.

Topics: Choroid; Gyrate Atrophy; Humans; Metabolism, Inborn Errors; Mutation; Retina

PubMed: 34340878
DOI: 10.1016/j.ymgme.2021.07.010

Authors: Berith M Balfoort, Filip Van Den Broeck, Marion M Brands...

PURPOSE

Gyrate atrophy of the choroid and retina (GACR) is an autosomal recessive inherited metabolic disorder (IMD) characterised by progressive retinal degeneration, leading to severe visual impairment. The rapid developments in ophthalmic genetic therapies warrant knowledge on clinical phenotype of eligible diseases such as GACR to define future therapeutic parameters in clinical trials.

METHODS

Retrospective chart analysis was performed in nineteen patients. Data were analysed using IBM SPSS Statistics version 28.0.1.1.

RESULTS

Nineteen patients were included with a mean age of 32.6 years (range 8-58). Mean age at onset of ophthalmic symptoms was 7.9 years (range 3-16). Median logMAR of visual acuity at inclusion was 0.26 (range -0.18-3.00). Mean age at cataract surgery was 28.8 years (n = 11 patients). Mean spherical equivalent of the refractive error was -8.96 (range -20.87 to -2.25). Cystoid maculopathy was present in 68% of patients, with a loss of integrity of the foveal ellipsoid zone (EZ) in 24/38 eyes. Of the 14 patients treated with dietary protein restriction, the four patients who started the diet before age 10 showed most benefit.

CONCLUSION

This study demonstrates the severe ophthalmic disease course associated with GACR, as well as possible benefit of early dietary treatment. In addition to visual loss, patients experience severe myopia, early-onset cataract, and CME. There is a loss of foveal EZ integrity at a young age, emphasising the need for early diagnosis enabling current and future therapeutic interventions.

Topics: Humans; Retrospective Studies; Male; Female; Adult; Visual Acuity; Middle Aged; Child; Gyrate Atrophy; Young Adult; Adolescent; Choroid; Tomography, Optical Coherence; Retina; Fluorescein Angiography; Follow-Up Studies; Fundus Oculi

PubMed: 38847892
DOI: 10.1007/s00417-024-06540-8

Authors: Eleanor Palmer, Karolina M Stepien, Christopher Campbell...

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.

Topics: Humans; Female; Male; Infant; Child; Gyrate Atrophy; Macular Edema; Retrospective Studies; Retina; Cataract

PubMed: 37667371
DOI: 10.1186/s13023-023-02840-0

Authors: Maamouri Rym, Ferchichi Molka, Ben Chehida Amel...

PubMed: 38111946
DOI: 10.18240/ijo.2023.12.28

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.

Authors: Fulvio Floriani, Carla Borri Voltattorni, Barbara Cellini...

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.

Topics: Humans; Atrophy; Choroid; Gyrate Atrophy; Mutation; Ornithine; Ornithine-Oxo-Acid Transaminase; Pyridoxal Phosphate; Retina

PubMed: 36834788
DOI: 10.3390/ijms24043369

Review

Authors: Artjola Puja, Jinyu Lu, Jianhai Du...

Deficiency of the mitochondrial enzyme ornithine aminotransferase (OAT) causes gyrate atrophy of the choroid and retina (GACR), a rare autosomal inherited disorder characterized by a substantial elevation in plasma ornithine and progressive chorioretinal degeneration. While OAT is expressed in many tissues, the deficiency mainly affects the retinal pigment epithelium (RPE)/choroid and retina, progressing from the periphery to the macula. RPE has been identified as the initial site of damage in GACR. Amino acid metabolism is crucial for the RPE function and its support for retinal metabolism. In GACR, in addition to ornithine, the metabolism of multiple amino acids is disrupted. This review explores the tissue-specific differences in amino acid metabolism between macular and peripheral ocular regions that may contribute to the pathophysiology of the disease.

Topics: Humans; Gyrate Atrophy; Amino Acids; Retinal Pigment Epithelium; Ornithine-Oxo-Acid Transaminase; Animals; Organ Specificity; Choroid

PubMed: 39930209
DOI: 10.1007/978-3-031-76550-6_46

Authors: Alireza Javadzadeh, Davood Gharabaghi

BACKGROUND

Gyrate atrophy of the retina and choroid is a rare autosomal recessive inherited disease, characterized by progressive chorioretinal atrophy that results in progressive deterioration of peripheral and night vision and leading to blindness.

CASE PRESENTATION

This report presents a case of a 28-year-old man consulting for a progressive fall of visual acuity with hemeralopia. Eye fundoscopy showed regions of confluent rounded chorioretinal atrophy. The visual field and retinal angiography were altered. A high level of plasma ornithine (629 nmol/mL) was detected and a diagnosis of gyrate atrophy of the retina and choroid was made. The patient was treated with high dose Pyridoxine supplement (300 mg/d for 6 months) and the ornithine level of his serum was successfully reduced.

CONCLUSION

The exact mechanism of chorioretinal atrophy in hyper-ornithinemia is not known and a small percentage of the affected people respond to Vitamin B6 supplementation.

PubMed: 17565677
DOI: 10.1186/1752-1947-1-27

Authors: Tugce Horozoglu Ceran, Berrak Sekeryapan Gediz, Kenan Sonmez...

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

PubMed: 38089080
DOI: 10.14744/bej.2023.72473