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.

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.

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 with hyperornithinemia, cystinuria and lysinuria responsive to vitamin B6.

In this report, an 8-year-old girl is presented with the complaint of progressive night blindness. The authors have performed eye funduscopy, which showed chorioretinal atrophy in gyrate shape. A high level of plasma ornithine was determined. Urinary excretion of ornithine as well as lysine and cystine were increased. Patient was treated with high dose pyridoxine supplement (500 mg/dl). The night blindness condition of the patient improved. After 1 month of pyridoxine therapy ornithine level of her plasma was successfully reduced and blindness improved.

Osteoporosis associated with gyrate atrophy: a case report.

Gyrate atrophy (GA) is a rare degenerative, hereditary disease characterized by markedly high serum ornithine levels resulting from the deficiency of ornithine-delta-amino transferase (OAT), a mitochondrial matrix enzyme. Hyperornithinaemia is accompanied by lysinuria and reduced lysine plasma levels in GA. Type I collagen is known to play a role in osteoporosis pathogenesis. Lysine has a role in cross ligament formation of type I collagen, a bone matrix element, and thus, in bone strength. Although the most common complaint in GA is visual problems, the disease may include muscle involvement, as well. Reduced physical activity resulting from muscle involvement and hypolysinemia in GA may lead to osteoporosis. However, there is no data in the literature concerning the relation between GA and osteoporosis. In this report a GA case with early osteoporosis, besides visual deterioration and muscular signs, is reported, and the relation between GA and osteoporosis is emphasized for the first time.

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.

Peripheral nervous system in gyrate atrophy of the choroid and retina with hyperornithinemia.

OBJECTIVE: To evaluate peripheral nervous system involvement in gyrate atrophy of the choroid and retina with hyperornithinemia (GA). BACKGROUND: GA is an inborn error of amino acid metabolism caused by mutations in the enzyme ornithine aminotransferase. Patients with GA have hyperornithinemia, progressive centripetal loss of vision, minor CNS abnormalities, and type II muscle fiber atrophy with accumulation of tubular aggregates. The authors previously showed that muscle and brain creatine stores are depleted in the patients with GA. METHODS: The authors searched evidence of peripheral nervous involvement in 40 patients with GA (mean age 31.6 +/- 16.3 years; range 5 to 74 years) by using neurography, quantitative sensory threshold testing, and evoked potential testing. RESULTS: Neurography revealed abnormalities in 21 (53%) of the patients. The abnormalities associated with the severity of the ophthalmologic changes and the age of the patients. With quantitative sensory threshold testing, abnormal large-fiber function was found in seven (18%) and abnormal small-fiber function was found in four (10%) patients. Somatosensory evoked potential and brainstem auditory evoked potential responses were abolished in five patients. CONCLUSIONS: These findings of peripheral nervous system involvement in GA suggest that GA is a systemic disease affecting not only CNS but also the peripheral nervous system.

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.

[Gyrate atrophy and craniopharyngioma: a case report]. / Atrophie gyrée et craniopharyngiome: à propos d'un cas.

We report the case of a 13-year-old girl who developed a craniopharyngioma and a gyrate atrophy. No genetic link between these two diseases has ever been reported. This case recalls the characteristic features of gyrate atrophy.

Ophthalmologic heterogeneity in subjects with gyrate atrophy of choroid and retina harboring the L402P mutation of ornithine aminotransferase.

OBJECTIVE/PURPOSE: To investigate clinical variation in a genetically homogenous group of subjects with gyrate atrophy of choroid and retina with hyperornithinemia (GA). The group was made up of homozygotes and compound heterozygotes for mutation L402P in the ornithine aminotransferase (OAT) gene. DESIGN: Cross-sectional study. PARTICIPANTS: Thirty-five Finnish subjects (18 men) with GA with a mean age of 33 years (range, 5-74 years) carrying the Finnish founder mutation L402P. METHODS: All subjects were examined between 1993 and 1995. The analysis was composed of, in addition to careful clinical evaluation, studies of visual fields with Goldmann perimeter, photographing of the eye fundi, and corneal electroretinography (ERG) recordings. MAIN OUTCOME MEASURES: The changes in eye fundi, visual acuity, cataract changes in the lens, visual field constriction, and ERG responses were determined. RESULTS: Myopia, early cataracts, and highly abnormal ERG were typical for the GA subjects. The changes progressed rather uniformly with age. However, visual acuity, funduscopic findings, and visual fields showed great phenotypic variation. Despite the great interindividual variation, both eyes of each subject were always similarly affected. CONCLUSIONS: This study of 35 subjects with GA carrying a single mutation shows that the ophthalmologic symptoms and findings vary widely. The data also reveal that GA subjects are already affected by severe visual impairment in young adulthood. However, the diagnosis is often made very late.

Genotype-phenotype correlation of a pyridoxine-responsive form of gyrate atrophy.

Two clinical subtypes of gyrate atrophy (GA) have been defined based on in vivo or in vitro evidence of response to vitamin B6 (pyridoxine), which is the cofactor of the enzyme ornithine aminotransferase (OAT) shown to be defective in GA. We identified the E318K mutation in the OAT gene, heterozygously in three patients and homozygously in one patient, all of whom were vitamin B6-responsive by previous in vivo and in vitro studies. Dose-dependent effects of the E318K mutation were observed in the homo- and heterozygotes in the OAT activity, increase of OAT activity in the presence of pyridoxal phosphate, and apparent Km for pyridoxal phosphate. The highest residual level of OAT activity and mildness of clinical disease correlated directly with the dose of the mutant E318K allele present in the patient.

Gyrate atrophy of the choroid and retina: lymphocyte ornithine-delta-aminotransferase activity in different mutations and carriers.

Deficiency of omithine-delta-aminotransferase (OAT) causes gyrate atrophy of the choroid and retina with hyperornithinemia (GA; McKusick 258870), a progressive autosomal recessive chorioretinal degeneration leading to early blindness. As residual enzyme activity may vary in different mutations of the OAT gene and explain individual variations in disease progression, a sensitive HPLC modification of the OAT assay in lymphocytes was developed, based on measurement of the dihydroquinozolinium reaction product. The OAT activities (ranges) of 43 Finnish GA patients with mutations L402P/L402P, R180T/L402P, N89K/ L402P, and L402P/x (x = previously unknown allele), were <1-10, <1-13, <1-17, and <1 pmol x min(-1) mg protein(-1), respectively. The OAT activities (mean+/-SD) of nine L402P/ wild heterozygotes were 70+/-50 (range 33-193), and those of 15 healthy control subjects 184+/-60 (range 85-291) pmol x min(-1) mg protein(-1). This lymphocyte assay is an easy, rapid, and sensitive method for reliable recognition of GA homozygotes. OAT mutations of the Finnish patients show similar residual enzyme activity in the lymphocytes. OAT activities in the L402P heterozygotes and healthy control subjects overlap, suggesting that, for reliable carrier detection, the OAT alleles have to be studied. However, as all OAT mutations are not known, direct measurement of enzyme activity has a role in heterozygote identification and possibly also in prenatal diagnosis of GA.

Gyrate atrophy-like phenotype with normal plasma ornithine.

PURPOSE: To describe the clinical characteristics of a chorioretinal disease with a gyrate atrophy-like phenotype and normal plasma ornithine. METHODS: One family with three men who had progressive chorioretinal disease and three additional patients with simplex cases were examined clinically and with standard electroretinography, electrooculography, and dark adaptometry. RESULTS: In the family, a 70-year-old man and his two sons (39 and 41 years of age) were affected. On ophthalmoscopy, sharply demarcated peripheral patches of retinal pigment epithelium and choroidal atrophy were seen to progress to the posterior pole in the father's eye. In three unrelated men (62, 70, and 80 years of age), chorioretinal atrophy was present in the mid- and far periphery. Visual acuity was normal in the two youngest of all six patients; however, electroretinogram and electrooculogram waves were reduced. Advanced visual field defects and visual acuity loss occurred in the four older patients. Electroretinogram and electrooculogram were reduced, and the dark adaptation thresholds were elevated. In all patients, serum ornithine levels were normal. Ornithine-delta-aminotransferase activity in cultured skin fibroblasts and the apparent Michaelis constant (Km) for ornithine and alpha-ketoglutarate were within the normal range in all patients. CONCLUSIONS: A gyrate atrophy-like phenotype can result from causes other than deficient ornithine-delta-aminotransferase. Its occurrence in three male members in two generations in one family suggests an autosomal dominant inheritance in at least some such patients.

Association of thyroid disease with retinitis pigmentosa and gyrate atrophy.

PURPOSE: To compare the prevalence of thyroid disease in patients with retinitis pigmentosa, in patients with gyrate atrophy of the choroid and retina, and in patients with no history of ocular disease. METHOD: Forty-four patients with retinitis pigmentosa, 34 patients with gyrate atrophy, and 30 normal control patients with no ocular disease were evaluated in a case-control study for the presence of thyroid disease. RESULTS: Thyroid disease was diagnosed in six of 44 patients with retinitis pigmentosa and seven of 34 patients with gyrate atrophy but in only one of 30 control patients. Compared with control patients, the odds ratio for the occurrence of thyroid disease was 6.2 for patients with retinitis pigmentosa and 12.7 for patients with gyrate atrophy. CONCLUSION: These data suggest an increased occurrence of thyroid disease in patients with retinitis pigmentosa and gyrate atrophy.

Anterior subcapsular plaque cataract in hyperornithinaemia gyrate atrophy--a case report.

Hyperornithinaemia gyrate atrophy (HOGA) is a rare autosomal recessive disorder in which chorioretinal degeneration occurs with cataracts, myopia, and hyperornithinaemia. We report the case of an 18-year-old female who presented with the typical features of HOGA, including posterior subcapsular cataracts and elevated plasma ornithine. She later developed distorted vision in both eyes owing to wrinkling of the anterior lens capsules. Histological examination following lens extraction showed the wrinkling was caused by focal distortion from capsular fibrosis (anterior subcapsular plaque cataract). This specific lens change has not been linked previously with HOGA.