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

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

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.

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.

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.

Intravitreal ranibizumab for choroidal neovascularization secondary to gyrate atrophy in a young patient: a multimodal imaging analysis.

PURPOSE: To present a case of choroidal neovascularization (CNV) due to gyrate atrophy (GA) treated with intravitreal ranibizumab. METHODS: A 35-year-old man presented with sudden loss of vision and central scotoma in the right eye, as well as progressive night vision deterioration over the past several years in both eyes. His best-corrected visual acuity (BCVA) was 6/60 in the right eye and 6/5 in the left eye. Funduscopy revealed bilateral confluent areas of chorioretinal atrophy and optical coherence tomography showed subretinal fluid consistent with CNV development in the right eye, which was confirmed by fundus fluorescein angiography (FFA) and indocyanine green angiography (ICGA). The left eye was normal. The patient had a family history of GA. Elevated levels of plasma ornithine were detected, establishing the diagnosis. RESULTS: The patient received a regimen of 3 monthly off-label intravitreal ranibizumab injections in the right eye. At the 6-month follow-up, no subretinal fluid was noticed and BCVA was 6/48. No other injections were performed, but the patient was advised to start an arginine-restricted diet and take vitamin B6 (pyridoxine) 300 mg daily. The BCVA was preserved and chorioretinal atrophy had not progressed on funduscopy, FFA, or ICGA 1 year later. CONCLUSIONS: Intravitreal ranibizumab can offer promising anatomical and functional results, maintaining visual acuity in patients with CNV secondary to GA, especially if used in combination with arginine-restricted diet and vitamin B6 supplementation.

OAT mutations and clinical features in two Japanese brothers with gyrate atrophy of the choroid and retina.

BACKGROUND: Gyrate atrophy (GA) of the choroid and retina is an extremely rare inherited chorioretinal dystrophy. Ornithine aminotransferase (OAT) gene mutations are identified in patients with GA. The purpose of this study was to report a novel deletion mutation of the OAT gene and describe clinical features of two brothers with GA in a Japanese family. METHODS: We performed ophthalmic examinations, including best-corrected visual acuity, slit-lamp biomicroscopy, dilated funduscopy, fundus autofluorescence imaging, optical coherence tomography, visual field testing, and full-field electroretinography (ERG). Serum ornithine concentrations and OAT activities were analyzed. Mutation screening of the OAT gene was performed using Sanger sequencing. RESULTS: Both brothers had compound heterozygous mutations (p.K169DfsX10 and p.R426X), one of which was novel. Their unaffected parents carried one of the mutations heterozygously. An arginine-restricted diet was started in the younger brother at the age of 2 years, while the diet was not initiated in the older brother until the age of 6 years. After more than 15 years of follow-up, the dietary treatment seemed to slow the progression of the chorioretinal lesions in the younger brother. However, when compared at the same age, the younger brother had more reduced ERG amplitudes and constricted visual fields than his older brother. CONCLUSIONS: We identified a novel frameshift mutation (p.K169DfsX10) in the OAT gene. While an early arginine-restricted dietary treatment suppressed the fundus changes of GA to some degree in the younger brother, the efficacy of suppressing the progression of visual function loss could not be clearly determined.

Gyrate atrophy: clinical and genetic findings in a female without arginine-restricted diet during her first 39 years of life and report of a new OAT gene mutation.

We report the clinical and genetic data obtained at a 17-year follow-up examination of a patient with gyrate atrophy, without an arginine-restricted diet. Patient examinations included visual acuity (VA), perimetry, biomicroscopy, funduscopy, fundus photography, fundus autofluorescence (FAF), spectral-domain optical coherence tomography (OCT), and standard full-field electroretinography (ERG). Blood samples were taken for measurement of serum ornithine level and molecular genetic analysis of the OAT gene. The female was 22 years of age when gyrate atrophy was diagnosed based on peripheral chorioretinal atrophy and an increased ornithine level. Reexamination after 17 years revealed a reduced VA (0.25 OU), dense cataract, extensive peripheral chorioretinal atrophy, a further increased ornithine level, but only slow progression of visual field constriction, and still detectable ERG amplitudes. FAF was absent in the atrophic periphery and almost homogeneous at the posterior pole except parafoveally. OCT showed interruption of the foveal inner/outer segment junction and parafoveal microcystoid spaces. After cataract surgery, VA increased to the same values as those found at the age of 22 years (0.5 OD, 0.6 OS). Molecular analysis revealed a new deletion c.532_536delTGGGG (p.Trp178X) and a known mutation c.897C>G (p.Tyr299X) in the OAT gene. Although the patient had refused to diet during her first 39 years of life, the gyrate atrophy showed a very slow progression. FAF allows evaluating the integrity of the retinal pigment epithelium and may help to delimit gyrate atrophy from choroideremia. Interruption of foveal inner/outer segment junction and cystoid macula edema appears in gyrate atrophy.

[Gyrate atrophy of the choroid and retina in children]. / Zanik girlandowaty naczyniówki i siatkwki u dzieci.

THE AIM: the history and clinical findings of 3.5 and 5.5-years old siblings with gyrate atrophy (GA) of the choroid and retina are presented. PATIENTS AND METHOD: Siblings: a girl at the age 3.5 years and her brother 5.5 years were examined. Clinical and biochemical findings were performed. RESULTS: The best corrected visual acuity of both girl and boy was below normal values. Myopia of middle degree and myopic astigmatism was presented in both eyes of siblings. On fundus examination sharply defined bizarre shaped atrophic areas of peripheral choroid and retina were seen in both eyes of children. Fluorescein angiography of gyrate atrophy. The boy's plasma ornithine level was increased to 974.950 umol/L and the girl's to 1007.188 umol/L. The concentration of ornithine, lysine and arginine in the urea of these patients was high. CONCLUSION: Early clinical and biochemical diagnosis of gyrate atrophy of the choroid and retina in children is very important, because low protein diet with elimination of arginine can reduce the progression of this severe disease.

Use of an arginine-restricted diet to slow progression of visual loss in patients with gyrate atrophy.

OBJECTIVE: To quantify the effect of long-term reduction of plasma ornithine levels through adherence to an arginine-restricted diet on visual function in patients of all ages with gyrate atrophy of the retina and choroid. METHODS: A long-term observational study was conducted on 27 patients with gyrate atrophy, 17 of whom elected to comply with the arginine-restricted diet and 10 who were unable to comply. The mean rates of change in the electroretinogram combined response, electroretinogram flicker response, and kinetic and static perimetry were determined. RESULTS: After mean follow-up of 13.9 years for the patients on the diet and 14.1 years for those not on the diet, the mean rates of change for the diet group compared with those of the no-diet group were statistically significantly slower for all outcome measures (age-adjusted P<.05) except for static perimetry (P =.06). CONCLUSIONS: Adhering to an arginine-restricted diet so as to lower the plasma ornithine level below an average of 5.29 to 6.61 mg/dL (400-500 micromol/L) will slow the loss of function as measured by sequential electroretinography and visual field examinations.

Low-protein diet and progression of retinal degeneration in gyrate atrophy of the choroid and retina: a twenty-six-year follow-up.

Gyrate atrophy of the choroid and retina is an autosomal recessive chorioretinal dystrophy which leads to a slowly progressive loss of vision. The primary defect is due to a deficiency of the enzyme ornithine delta-aminotransferase, which is responsible for markedly elevated levels of ornithine in plasma and other body fluids. Although several therapeutic regimens have been proposed, the reduction in ornithine accumulation obtained by reducing the intake of its precursor arginine (semisynthetic low-arginine diet) is the one most practised. In this clinical and molecular study we report a patient with hyperornithinaemia and gyrate atrophy of the choroid and retina who had been diagnosed when she was 3 years 9 months old. She also presented mild mental retardation, delayed language development and speech defects. The patient has recently been found to be homozygous for the new Gly91Arg amino acid substitution of the enzyme ornithine delta-aminotransferase. This mutation lies in a region of the mature protein that is considered crucial for the mitochondrial targeting activity. In this patient, a 28-year treatment with a completely natural low-protein diet (0.8 g/kg per day of natural protein) has been able to significantly reduce ornithine plasma levels, and to greatly delay the natural progression of the chorioretinal changes. This study suggests that, in the long-term treatment of gyrate atrophy, the efficacy in slowing the progression of chorioretinal changes and the palatability of a completely natural low-protein diet make this treatment a potentially viable alternative in patients refusing the semisynthetic diet.

Gyrate atrophy of the choroid and retina: further experience with long-term reduction of ornithine levels in children.

OBJECTIVE: To determine whether the long-term reduction of plasma ornithine levels by way of an arginine-restricted diet in patients with gyrate atrophy will slow the progression of this chorioretinal degeneration. DESIGN: Natural history study of 2 pairs of siblings with gyrate atrophy treated with an arginine-restricted diet. MAIN OUTCOME MEASURES: Fundus photography and electrophysical and psychophysical retinal function tests. RESULTS: After 16 to 17 years of receiving an arginine-restricted diet, the younger sibling in each pair, who was prescribed the diet at an earlier age than the older sibling, demonstrated a slower progression of lesions compared with the older sibling. CONCLUSIONS: If started at an early age, long-term substantial reduction of plasma ornithine levels may appreciably slow the progression of the chorioretinal lesions and, to a lesser extent, the progressive loss of retinal function in patients with gyrate atrophy.

Correction of ornithine accumulation prevents retinal degeneration in a mouse model of gyrate atrophy of the choroid and retina.

Deficiency of ornithine-delta-aminotransferase (OAT) in humans results in gyrate atrophy of the choroid and retina (GA), an autosomal recessive disorder characterized by ornithine accumulation and a progressive chorioretinal degeneration of unknown pathogenesis. To determine whether chronic, systemic reduction of ornithine can prevent this form of retinal degeneration, we used an arginine-restricted diet to maintain long term reduction of ornithine in a mouse model of OAT-deficiency (Oat(-/-)) produced by gene targeting. We evaluated the mice over a 12-month period by measurement of plasma amino acids, electroretinograms, and retinal histologic and ultrastructural studies. We found that an arginine-restricted diet substantially reduces plasma ornithine levels and completely prevents retinal degeneration in Oat(-/-). This result indicates that ornithine accumulation is a necessary factor in the pathophysiology of the retinal degeneration in GA and that restoration of OAT activity in retina is not required for effective treatment of GA.

Gyrate atrophy of the choroid and retina. Long-term reduction of ornithine slows retinal degeneration.

Gyrate atrophy of the choroid and retina is an autosomal recessive, chorioretinal dystrophy that begins in childhood and leads to blindness in the fourth to seventh decade of life. The primary defect is deficiency of ornithine-delta-amino-transferase, which results in accumulation of ornithine. We examined six pairs of affected siblings to determine if intrafamilial variability in the phenotype was less than interfamilial, and to determine if long-term (5- to 7-year) reduction of ornithine with an arginine-restricted diet had an effect on the progression of the chorioretinal degeneration. All but one set of siblings underwent periodic ophthalmologic examinations. The clinical diagnosis was confirmed with the demonstration of hyperornithinemia and deficiency of ornithine-delta-aminotransferase. The molecular defects in their ornithine-delta-amino-transferase genes also were determined. The two younger pairs of siblings were given an arginine-restricted diet and followed up for 5 to 7 years. We found strikingly similar phenotypes in affected members of the same pair of siblings. In the young patients receiving the diet, there was substantial reduction of ornithine levels. These children had only modest progression of their ocular disease during this period. Furthermore, a comparison of the outcome of the younger with their older siblings at an equivalent age showed that the younger siblings, who started receiving the diet at an earlier age, had much less ocular disease. We conclude that intrafamilial phenotypic variation in gyrate atrophy is less than interfamilial and, therefore, that genetic heterogeneity plays a role in the phenotypic variability of gyrate atrophy. Furthermore, we conclude that chronic reduction of ornithine with an arginine-restricted diet dramatically slows the progression of the chorioretinal dystrophy.