Vision on gyrate atrophy: why treat the eye?

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

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

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

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

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

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

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

Liver-directed gene therapy for ornithine aminotransferase deficiency.

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

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

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

Variable phenotypes of gyrate atrophy in siblings with a nonsense mutation in OAT gene.

Background: Gyrate Atrophy (GA) is a rare autosomal recessive disorder characterized by progressive chorioretinal degeneration. It is caused due to mutations in OAT gene that encodes a defective ornithine-δ-aminotransferase enzyme. We aim to identify the molecular cause of the disease and correlate it with the phenotype.Materials and Methods: Clinical, biochemical and genetic analyses were performed in siblings with GA.Case Description: A 10-year-old girl presented with impaired vision was clinically diagnosed to have peripheral chorioretinal degeneration in both eyes due to GA with vitreous hemorrhage in the right eye. Similar chorioretinal degeneration was observed in the patient's sibling, while parents were normal. Biochemical analysis of plasma by LC-MS/MS showed an elevated ornithine level of 892.8 µmol/L in the patient and 572.3 µmol/L in the sibling. Familial genetic screening by Sanger sequencing revealed a nonsense mutation in exon 11 of the OAT gene (c.1192C>T; p.Arg398Ter) in all the family members with a homozygous mutation in the patient and sibling, and heterozygous mutation in the parents. The patient was under follow-up with an arginine-restricted diet. At the last follow-up, the vitreous hemorrhage of right eye had resolved with an improvement in visual acuity and left eye remained stable with 6/12.Conclusion: Our patient is a rare case of gyrate atrophy presented with vitreous hemorrhage and nonsense OAT gene mutation, inherited in the autosomal recessive pattern. This report highlights the phenotypic variability among the siblings with the same mutation in OAT gene for the first time.

First report of c.425-1G>A mutation in ornithine aminotransferase gene causing gyrate atrophy of the choroid and retina with hyperornithinemia.

BACKGROUND: Gyrate atrophy is a rare autosomal recessive inherited genetic disease. Progressive deterioration of peripheral night vision and blindness are the foremost clinical manifestations of the disease caused by mutations of ornithine aminotransferase gene. CASE: The presented case was an 18-year-old male referred for a progressive reduction of visual acuity, which started when the subject was 7 years old, blurred vision, and hypotonic muscles. OBSERVATIONS: The findings by liquid chromatography with tandem mass spectrometry and high-performance liquid chromatography methods exhibited a high level of ornithine: 248 µmol/L (reference range: 44-206 µmol/L) and 818 µmol/L (reference: 25-123 µmol/L), respectively. After genetic counseling and conducting further investigation, a novel mutation (c.425-1G>A) in ornithine aminotransferase gene was recognized through whole exome sequencing and the mutation was verified using Sanger sequencing method, which is associated with gyrate atrophy phenotype. CONCLUSION: The exact mechanism of chorioretinal atrophy in hyperornithinemia is not known but the increased ornithine level is the clinical manifestation of gyrate atrophy of choroid and retina, muscle weakness, moderate mental retardation, and low cerebral creatine. Pathogenic variant in the ornithine aminotransferase gene associated with gyrate atrophy, may be beneficial as a biomarker to initial diagnosis and treatment of gyrate atrophy disease.

A novel c.980C>G variant in OAT results in identifiable gyrate atrophy phenotype associated with retinal detachment in a young female.

Background: Gyrate atrophy of the choroid and retina (GA) is a rare autosomal recessive disorder characterized by nyctalopia, myopia, sharply demarcated expanding peripheral chorioretinal atrophic lesions, early cataract, progressive visual loss and hyperornithinemia. Only three cases of GA associated with rhegmatogenous retinal detachments (RRD) have been reported. The genotype-phenotype correlation of RRD in GA is limited by lack of genetic information in the previously reported cases. Here we report two young sisters with a characteristic GA phenotype associated with a novel variant in the ornithine aminotransferase gene (OAT), in whom one developed unilateral RRD at the age of 9 years.Materials and Methods: Retrospective report of two cases including genetic analysis and multimodal retinal imaging.Results: A 9-year-old Saudi girl presented with a funnel-shaped RRD, extensive proliferative vitreoretinopathy, peripheral choroidal detachment and neovascular glaucoma in her right eye. Fundus examination of her left eye showed an attached retina with sharply-demarcated peripheral chorioretinal atrophic patches suggestive of GA. Whole exome sequencing confirmed GA by revealing a homozygous c.980 C > G (p. Pro327Arg) variant in exon 8 of OAT. The RRD was inoperable. The chorioretinal lesions in the left eye enlarged slowly over 3 years of follow up. Examination of the proband's older sister revealed a similar but more advanced GA phenotype in both eyes.Conclusions: A characteristic GA phenotype associated with a novel variant in OAT is reported. This variant might be associated with childhood-onset RRD in the proband.

Deficit of human ornithine aminotransferase in gyrate atrophy: Molecular, cellular, and clinical aspects.

Gyrate Atrophy (GA) of the choroid and retina (MIM# 258870) is an autosomal recessive disorder due to mutations of the OAT gene encoding ornithine-delta-aminotransferase (OAT), associated with progressive retinal deterioration and blindness. The disease has a theoretical global incidence of approximately 1:1,500,000. OAT is mainly involved in ornithine catabolism in adults, thus explaining the hyperornithinemia as hallmark of the disease. Patients are treated with an arginine-restricted diet, to limit ornithine load, or the administration of Vitamin B6, a precursor of the OAT coenzyme pyridoxal phosphate. Although the clinical and genetic aspects of GA are known for many years, the enzymatic phenotype of pathogenic variants and their response to Vitamin B6, as well as the molecular mechanisms explaining retinal damage, are poorly clarified. Herein, we provide an overview of the current knowledge on the biochemical properties of human OAT and on the molecular, cellular, and clinical aspects of GA.

Regression of macular edema with topical brinzolamide and nepafenac alone and identification of a novel gyrate atrophy mutation / Regressão de edema macular com o uso tópico de brinzolamida e nepafenac e identificação de uma nova mutação na atrofia girata

ABSTRACT Gyrate atrophy is a rare metabolic autosomal recessive disorder caused by ornithine aminotransferase enzyme deficiency that leads to characteristic progressive, degenerative chorioretinal findings. Patients complain mostly of low vision, night blindness, and peripheral vision loss. Posterior subcapsular cataract, myopia, choroid neovascularization, and intraretinal cysts may be accompanying factors related to vision loss. We encountered a patient with vision loss secondary to posterior subcapsular cataract and intraretinal cysts. After treatment with topical brinzolamide and nepafenac (and without any diet mo dification and/or supplementation), we observed 143- and 117-mm macular thickness resolutions with 2 and 1 Snellen lines of visual gain in his right and left eyes, respectively. Also, we detected a novel homozygous mutation in the ornithine aminotransferase gene: c.1253T>C (p.Leu418Pro). Carbonic anhydrase inhibitors and/or non-steroid anti-inflammatory drugs can control macular edema in patients with gyrate atrophy-associated intraretinal cysts. The genetic variants may also be a determinant in the responsiveness to the therapy type.

RESUMO A atrofia girata é um distúrbio autossômico recessivo metabólico raro causado pela deficiência da enzima ornitina ami notransferase, que leva a achados degenerativos coriorretinianos progressivos característicos. Os pacientes queixam-se principalmente de baixa visão, cegueira noturna e perda de vi são periférica. A catarata subcapsular posterior, a miopia, a neovascularização da coróide e os cistos intrarretinianos podem ser fatores associados à perda da visão. Encontramos um paciente com perda de visão secundária à catarata subcapsular posterior e cistos intrarretinianos. Após o tratamento com brinzolamida tópica e nepafenaco (e sem modificação e/ou suplementação da dieta), observamos resoluções de espessura macular de 143 e 117 mm e com 2 e 1 linhas de Snellen de ganho visual nos olhos direito e esquerdo, respectivamente. Além disso, detectamos uma nova mutação homozigótica no gene da ornitina aminotransfera se: c.1253T>C (p.Leu418Pro). Inibidores da anidrase carbônica e/ou drogas anti-inflamatórias não esteróides podem controlar o edema macular em pacientes com cistos intrarretinianos associados à atrofia girata. As variantes genéticas também podem ser determinantes na responsividade ao tipo de terapia.

Regression of macular edema with topical brinzolamide and nepafenac alone and identification of a novel gyrate atrophy mutation.

Gyrate atrophy is a rare metabolic autosomal recessive disorder caused by ornithine aminotransferase enzyme deficiency that leads to characteristic progressive, degenerative chorioretinal findings. Patients complain mostly of low vision, night blindness, and peripheral vision loss. Posterior subcapsular cataract, myopia, choroid neovascularization, and intraretinal cysts may be accompanying factors related to vision loss. We encountered a patient with vision loss secondary to posterior subcapsular cataract and intraretinal cysts. After treatment with topical brinzolamide and nepafenac (and without any diet mo dification and/or supplementation), we observed 143- and 117-mm macular thickness resolutions with 2 and 1 Snellen lines of visual gain in his right and left eyes, respectively. Also, we detected a novel homozygous mutation in the ornithine aminotransferase gene: c.1253T>C (p.Leu418Pro). Carbonic anhydrase inhibitors and/or non-steroid anti-inflammatory drugs can control macular edema in patients with gyrate atrophy-associated intraretinal cysts. The genetic variants may also be a determinant in the responsiveness to the therapy type.

R180T variant of δ-ornithine aminotransferase associated with gyrate atrophy: biochemical, computational, X-ray and NMR studies provide insight into its catalytic features.

Among the over 50 gyrate atrophy-causing mutations of ornithine δ-aminotransferase (OAT), the R180T involves an active site residue located at the dimer interface, which in the crystal structure of OAT complexed with 5-fluoromethylornithine engages a salt bridge with the α-carboxylate of the substrate analogue. Starting from the previous finding that no transaminase activity was detected in CHO-K1 cells expressing the R180T variant, here we try to shed light at the protein level on the structural and/or functional defects of the R180T variant. To this aim, the variant has been cloned, expressed, purified and characterized by a combination of biochemical and structural studies. Although the R180T variant shares a similar overall conformation with the wild-type, its crystal structure solved at 1.8 Çº reveals slight structural alterations at the active site and at the dimeric interface. These changes are consistent with the spectroscopic and kinetic results, indicating that the variant, as compared with the wild-type OAT, shows (a) an increased Km value for l-ornithine (l-Orn), (b) an altered pyridoxal 5'-phosphate binding mode and affinity and (c) an increased thermostability. In addition, the R180T mutant exhibits a remarkable loss of catalytic activity and is endowed with the ability to catalyse not only the δ-transamination but also, albeit to a lesser extent, the α-transamination of l-Orn. Overall, these data indicate that the slight structural changes caused by the R180T mutation, preventing a proper collocation of l-Orn at the active site of OAT, are responsible for the notable reduction of the catalytic efficiency. ENZYMES: Ornithine aminotransferase EC 2.6.1.13. DATABASES: 6HX7.pdb.

Diagnostic value of a combination of next-generation sequencing, chorioretinal imaging and metabolic analysis: lessons from a consanguineous Chinese family with gyrate atrophy of the choroid and retina stemming from a novel OAT variant.

BACKGROUND/AIM: Gyrate atrophy of the choroid and retina (GACR) is an extremely rare autosomal recessive inherited disorder characterised by progressive vision loss. To identify the disease-causing gene in a consanguineous Chinese pedigree with GACR, we aimed to accurately diagnose patients with GACR through a combination of next-generation sequencing (NGS) genetic diagnosis, clinical imaging and amino acid metabolic analysis. METHODS: A consanguineous Chinese pedigree with GACR, including two patients, was recruited and a comprehensive ophthalmological evaluation was performed. DNA was extracted from a proband and her family members, and the sample from the proband was analysed using targeted NGS. Variants detected by NGS were confirmed by Sanger sequencing and subjected to segregation analysis. Tandem mass spectrometry (MS/MS) was subsequently performed for metabolic assessment. RESULTS: We identified a novel, deleterious, homologous ornithine aminotransferase (OAT) variant, c.G248A: p.S83N, which contributes to the progression of GACR in patients. Our results showed that the p.S83N autosomal recessive variant of OAT is most likely pathogenic, with changes in protein stability drastically decreasing functionality. MS/MS verified that ornithine levels in patients were significantly elevated. CONCLUSIONS: Recruitment of a third-degree first cousin consanguineous marriage family with GACR allowed us to identify a novel pathogenic OAT variant in the Chinese population, broadening the mutation spectrum. Our findings reported the diagnostic value of a combination of NGS, retinal imaging and metabolic analysis of consanguineous marriage pedigrees in low-income/middle-income and low-incidence countries, including China, and may help to guide accurate diagnosis and treatment of this disease.

Metabolic follow-up of a Croatian patient with gyrate atrophy and a new mutation in the OAT gene: a case report.

Gyrate atrophy (GA) of the choroid and retina is a rare autosomal recessive disorder that occurs due to deficiency of the mitochondrial enzyme ornithine aminotransferase (OAT). Hyperornithinemia causes degeneration of the retina with symptoms like myopia, reduced night vision and progressive vision loss. Our patient is a 10-year-old girl with impaired vision and strabismus. As part of the metabolic work-up, plasma amino acid analysis revealed significantly increased concentration of ornithine (1039 µmol/L; reference interval 20 - 155 µmol/L). Molecular genetic analysis revealed homozygous mutation in exon 7 of the OAT gene that has not been reported previously (c.868_870delCTT p.(Leu290del)). This in frame deletion was predicted to be deleterious by in silico software analysis. Our patient was treated with pyridoxine (vitamin B6 in a dose of 2 x 100 mg/day), low-protein diet (0.6 g/kg/day) and L-lysine supplementation which resulted in a significant reduction in plasma ornithine concentrations to 53% of the initial concentration and the ophthalmologic findings showed significant improvement. We conclude that low protein diet and lysine supplementation can lead to long-term reduction in plasma ornithine concentrations and, if started at an early age, notably slow the progression of retinal function loss in patients with GA. The effect of therapy can be reliably monitored by periodical measurement of plasma ornithine concentration. To our knowledge, this is the first report of OAT deficiency in Croatia.

Molecular and cellular basis of ornithine δ-aminotransferase deficiency caused by the V332M mutation associated with gyrate atrophy of the choroid and retina.

Gyrate atrophy (GA) is a rare recessive disorder characterized by progressive blindness, chorioretinal degeneration and systemic hyperornithinemia. GA is caused by point mutations in the gene encoding ornithine δ-aminotransferase (OAT), a tetrameric pyridoxal 5'-phosphate-dependent enzyme catalysing the transamination of l-ornithine and α-ketoglutarate to glutamic-γ-semialdehyde and l-glutamate in mitochondria. More than 50 OAT variants have been identified, but their molecular and cellular properties are mostly unknown. A subset of patients is responsive to pyridoxine administration, although the mechanisms underlying responsiveness have not been clarified. Herein, we studied the effects of the V332M mutation identified in pyridoxine-responsive patients. The Val332-to-Met substitution does not significantly affect the spectroscopic and kinetic properties of OAT, but during catalysis it makes the protein prone to convert into the apo-form, which undergoes unfolding and aggregation under physiological conditions. By using the CRISPR/Cas9 technology we generated a new cellular model of GA based on HEK293 cells knock-out for the OAT gene (HEK-OAT_KO). When overexpressed in HEK-OAT_KO cells, the V332M variant is present in an inactive apodimeric form, but partly shifts to the catalytically-competent holotetrameric form in the presence of exogenous PLP, thus explaining the responsiveness of these patients to pyridoxine administration. Overall, our data represent the first integrated molecular and cellular analysis of the effects of a pathogenic mutation in OAT. In addition, we validated a novel cellular model for the disease that could prove instrumental to define the molecular defect of other GA-causing variants, as well as their responsiveness to pyridoxine and other putative drugs.

Multimodal characterization of a novel mutation causing vitamin B6-responsive gyrate atrophy.

PURPOSE: Gyrate atrophy (GA) is a rare chorioretinal degeneration that results in the deterioration of night and peripheral vision, eventually leading to blindness. The disorder is caused by mutations in the gene encoding ornithine aminotransferase (OAT), causing increased levels of plasma ornithine. Treatment revolves around lowering plasma ornithine levels, with vitamin B6 supplementation being the preferred treatment. Nevertheless, most patients do not respond to this therapy. Here, we report a rare case of vitamin B6-responsive GA caused by a novel mutation in OAT and characterize the presentation with multimodal imaging. METHODS: This is a single-patient case report with a clinical diagnosis based on history, multimodal retinal imaging, laboratory findings, and DNA sequencing analysis. We include a 3D structure prediction of the novel mutant protein. RESULTS: DNA sequencing analysis demonstrated that there is a homozygous, novel variant c.473A>C: p.Y158S in OAT. Upon undergoing two weeks of vitamin B6 supplementation, the patient exhibited a 28.5% reduction in plasma ornithine levels. In a follow-up visit two years later, plasma ornithine levels were reduced by 24.1% from the levels at initial presentation and disease progression was retarded based on clinical findings. CONCLUSION: One novel homozygous missense mutation in OAT was identified and considered to be pathogenic in a patient with GA. The response for the vitamin B6 supplementation was positive, which is rare in all the GA cases reported in the literature. Our data suggests that further studies regarding the relationship between genotype and responsiveness to vitamin B6 should be conducted.

Reversal of cystoid macular edema in gyrate atrophy patients.

PURPOSE: This study reports the presentation of two families with gyrate atrophy (GA). The aim of this study was to characterize the potential effect of therapeutic regimens on macular edema. METHODS: Two unrelated patients with GA were studied for the potential effect of low protein diet (≤ 0.8 g/kg/d), and oral administration of pyridoxine (500 mg/day), on serum ornithine levels, best corrected visual acuity (BCVA), slit-lamp, OCT, and auto-fluorescence findings. Blood samples for DNA, mRNA, and exons of the OAT gene were screened for mutations and splicing effect when relevant. RESULTS: At presentation, both patients manifested typical ophthalmic features of GA including cystoid macular edema (CME). One patient also exhibited optic nerve head hamartoma. Following treatment ornithine levels have lessened, BCVA improved, and central macular thickness (CMT) markedly decreased in all four studied eyes. The molecular pathologic features included a novel splice site mutation (c.900+1G>A). CONCLUSIONS: We have identified a novel mutation and two formerly described mutations in patients with GA. Of them, one patient comprised an unusual phenotype including bilateral astrocytic hamartomas. We have recognized for the first time improvement in CME following treatment with low protein intake and pyridoxine supplement. This finding may have significance in the understanding of treatment options for macular edema regardless of underlying etiology.

Creatine biosynthesis and transport in health and disease.

Creatine is physiologically provided equally by diet and by endogenous synthesis from arginine and glycine with successive involvements of arginine glycine amidinotransferase [AGAT] and guanidinoacetate methyl transferase [GAMT]. A specific plasma membrane transporter, creatine transporter [CRTR] (SLC6A8), further enables cells to incorporate creatine and through uptake of its precursor, guanidinoacetate, also directly contributes to creatine biosynthesis. Breakthrough in the role of creatine has arisen from studies on creatine deficiency disorders. Primary creatine disorders are inherited as autosomal recessive (mutations affecting GATM [for glycine-amidinotransferase, mitochondrial]) and GAMT genes) or X-linked (SLC6A8 gene) traits. They have highlighted the role of creatine in brain functions altered in patients (global developmental delay, intellectual disability, behavioral disorders). Creatine modulates GABAergic and glutamatergic cerebral pathways, presynaptic CRTR (SLC6A8) ensuring re-uptake of synaptic creatine. Secondary creatine disorders, addressing other genes, have stressed the extraordinary imbrication of creatine metabolism with many other cellular pathways. This high dependence on multiple pathways supports creatine as a cellular sensor, to cell methylation and energy status. Creatine biosynthesis consumes 40% of methyl groups produced as S-adenosylmethionine, and creatine uptake is controlled by AMP activated protein kinase, a ubiquitous sensor of energy depletion. Today, creatine is considered as a potential sensor of cell methylation and energy status, a neurotransmitter influencing key (GABAergic and glutamatergic) CNS neurotransmission, therapeutic agent with anaplerotic properties (towards creatine kinases [creatine-creatine phosphate cycle] and creatine neurotransmission), energetic and antioxidant compound (benefits in degenerative diseases through protection against energy depletion and oxidant species) with osmolyte behavior (retention of water by muscle). This review encompasses all these aspects by providing an illustrated metabolic account for brain and body creatine in health and disease, an algorithm to diagnose metabolic and gene bases of primary and secondary creatine deficiencies, and a metabolic exploration by (1)H-MRS assessment of cerebral creatine levels and response to therapeutic measures.