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Learn about research to date, connect to other researchers and apply for funding. We support research on gyrate atrophy and we support efforts to connect gyrate atrophy researchers to each other to enable collaboration. While there is much to learn from related diseases, we do not support research on other diseases. See below for guidelines and instructions to apply.
Overview of gyrate atrophy
(summarized and lightly edited from https://eyewiki.aao.org/Gyrate_atrophy#Pathophysiology, accessed October 5, 2019)
Gyrate Atrophy is a rare autosomal recessive retinal dystrophy characterized by progressive chorioretinal degeneration, early cataract formation and myopia. It is caused by a deficiency in the enzyme ornithine aminotransferase (OAT), which results in a 10- to 20-fold increase in plasma ornithine concentrations. Patients classically present in the first decade of life with nyctalopia, accompanied by characteristic circular areas of chorioretinal atrophy distributed in the peripheral fundus. With time, the atrophic lesions coalesce and progress centripetally toward the posterior pole, correlating with progressive loss of peripheral vision. Macular involvement occurs late in the disease.
Gyrate Atrophy is due to various mutations in the OAT gene, which is found on chromosome 10q26. Inheritance is autosomal recessive. These mutations lead to truncation of the enzyme ornithine aminotransferase (OAT), causing protein instability and rapid degradation. A subset of patients carry a genetic variant that is favorably responsive to the co-factor pyridoxine administration and has been shown to partially restore the structure and function of OAT.
Patients initially present with myopia and nyctalopia that begins in late childhood. As the disease progresses in the second decade of life, patients report progressive loss of peripheral vision. Early posterior subcapsular cataracts develop in virtually all patients, frequently in the second decade of life. Vision loss secondary to cystoid macular edema is common. Levels of ornithine have been reported to be as high as 10 to 20 times higher than normal in plasma, urine, spinal fluid, and aqueous humor. Gene sequencing analysis is helpful in confirming and identifying the allelic variant.
There is no curative regimen for gyrate atrophy. Lowering the elevated systemic ornithine is presumed to slow the progression of disease. However, the utility of such measures is difficult to prove given the disease's rarity and slow progression. Whereas small case series and anecdotal evidence on human subjects suggest that correction of hyperornithinemia can be helpful, animal models have been able to provide more concrete evidence:
Low-protein, Arginine-Restricted diet: Arginine is an amino acid derived from dietary protein that serves as the precursor to ornithine. As a result, adhering to a low protein diet that restricts arginine also lowers systemic levels of ornithine. Animal models with OAT-deficient mice have shown that reducing arginine and thereby ornithine can slow progression of ERG and histologic abnormalities when compared to controls. In prospective cohort studies in human subjects, similarly dietary restriction of arginine has been suggested to slow the rate of irreversible vision loss as measured by sequential ERG and visual field examinations, more so if started at younger age. However, compliance is challenging in light of the highly restrictive nature of the diet and the need for close monitoring by a pediatrician with experience in metabolic disease.
Vitamin B6 Supplementation: Pyridoxine (vitamin B6) is an essential co-factor to the OAT enzyme. Only a minority of patients have significant reduction in plasma ornithine in response to pharmacologic doses of vitamin B6. In a study of 7 patients with gyrate atrophy treated with vitamin B6, three had reduction in ornithine by at least 50%. Only patients with a drop in ornithine levels after vitamin B6 supplementation should be maintained on this regimen.
For more information, see http://omim.org/entry/258870 or https://eyewiki.aao.org/Gyrate_atrophy#Pathophysiology.
Research Papers on Gyrate Atrophy
Abdelmassih Y, El-Khoury S, Cherfan CG. Dexamethasone implant for the treatment of gyrate atrophy associated macular edema. J Fr Ophtalmol. 2019 Jan;42(1):e1-e4.
Alparslan Ş, Fatih MT, Muhammed Ş, Adnan Y. Cystoid macular edema secondary to gyrate atrophy in a child treated with sub-tenon injection of triamcinolone acetonide. Rom J Ophthalmol. 2018 Jul-Sep;62(3):246-249.
Brody, L. C., Mitchell, G. A., Obie, C., Michaud, J., Steel, G., Fontaine, G., Robert, M.-F., Sipila, I., Kaiser-Kupfer, M., Valle, D. Ornithine delta-aminotransferase mutations in gyrate atrophy: allelic heterogeneity and functional consequences. J. Biol. Chem. 267: 3302-3307, 1992.
Caruso, R. C., Nussenblatt, R. B., Csaky, K. G., Valle, D., Kaiser-Kupfer, M. I. Assessment of visual function in patients with gyrate atrophy who are considered candidates for gene replacement. Arch. Ophthal. 119: 667-669, 2001.
Casalino, Giuseppe, Luisa Pierro, Maria Pia Manitto, Michel Michaelides, and Francesco Bandello. Resolution of Cystoid Macular Edema following Arginine-restricted Diet and Vitamin B6 Supplementation in a Case of Gyrate Atrophy. Journal of AAPOS. 22.4: 321-23.
Chao J, Rao P, Hart J. Zonular weakness in patients with gyrate atrophy of the choroid and retina. JCRS Online Case Reports. October 2017. 5(4): 69-72
Chatziralli I, Theodossiadis G, Emfietzoglou I, Theodossiadis P. Intravitreal ranibizumab for choroidal neovascularization secondary to gyrate atrophy in a young patient: a multimodal imaging analysis. Eur J Ophthalmol. 2015 Oct 21;25(6):e119-22.
Cui X, Jauregui R, Park KS, Tsang SH. Multimodal characterization of a novel mutation causing vitamin B6-responsive gyrate atrophy. Ophthalmic Genet. 2018 Aug;39(4):512-516.
Elnahry AG, Hassan FK, Abdel-Kader AA. Bevacizumab for the treatment of intraretinal cystic spaces in a patient with gyrate atrophy of the choroid and retina. Ophthalmic Genet. 2018 Dec;39(6):759-762.
S. Hayasaka, T. Saito, H. Nakajima, O. Takahashi, K. Mizuno, and K. Tada. Clinical trials of vitamin B6 and proline supplementation for gyrate atrophy of the choroid and retina. Br J Ophthalmol. 1985 Apr; 69(4): 283–290.
Heinänen K, Näntö-Salonen K, Komu M, Erkintalo M, Heinonen OJ, Pulkki K, Valtonen M, Nikoskelainen E, Alanen A, Simell O. Muscle creatine phosphate in gyrate atrophy of the choroid and retina with hyperornithinaemia--clues to pathogenesis. Eur J Clin Invest. 1999 May;29(5):426-31.
Inanc M, Tekin K, Teke MY. Bilateral choroidal neovascularization associated with gyrate atrophy managed with intravitreal bevacizumab. Int Ophthalmol. 2018 Jun;38(3):1351-1355.
Kaarina Vannas‐Sulonen, Progression of gyrate atrophy of the choroid and retina. A long‐term follow‐up by fluorescein angiography. Acta Ophthalmologica. Volume 65, issue 1. Feb 1987: 101-109
Kaiser-Kupfer M, Kuwabara , Uga S, Takki K, Valle D. Cataracts in gyrate atrophy: clinical and morphologic studies. Invest. Ophthal. Vis. Sci. 24: 432-436, 1983
Kaiser-Kupfer MI, Caruso RC, Valle D, Reed GF (2004). Use of an arginine-restricted diet to slow progression of visual loss in patients with gyrate atrophy. Arch Ophthalmol122:982–984
Kaiser-Kupfer MI, Caruso RC, Valle D. Gyrate atrophy of the choroid and retina: further experience with long-term reduction of ornithine levels in children. Arch Ophthalmol. 2002 Feb;120(2):146-53.
Kuwabara T, Ishikawa Y, Kaiser-Kupfer MI (1981) Experimental model of gyrate atrophy in animals. Ophthalmology 88:331–335
Lahbil D, Hamdani M, D’khissy M et al (2000) Gyrate atrophy of the choroid and retina: a case report. J Fr Ophthalmol 23:788–793
Mashima YG, Weleber RG, Kennaway NG, Inana G. Genotype-phenotype correlation of a pyridoxine-responsive form of gyrate atrophy. Ophthalmic Genet. 1999 Dec;20(4):219-24.
Michaud J, Thompson GN, Brody LC et al. Pyridoxine-responsive gyrate atrophy of the choroid and retina: clinical and biochemical correlates of the mutation A226V. Am J Hum Genet. 1995; 56(3): 616-22.
Montioli R1, Desbats MA2, Grottelli S3, Doimo M2, Bellezza I3, Borri Voltattorni C1, Salviati L4, Cellini B5. Molecular and cellular basis of ornithine δ-aminotransferase deficiency caused by the V332M mutation associated with gyrate atrophy of the choroid and retina. Ophthalmic Genet. 2018 Aug;39(4):512-516.
Nänto-Salonen K, Komu M, Lundbom N, Heinänen K, Alanen A, Sipilä I, Simell O. Reduced brain creatine in gyrate atrophy of the choroid and retina with hyperornithinemia. Neurology. 1999 Jul 22;53(2):303-7.
ODonnell JJ, Sandman RP, Martin SR (1978) Gyrate atrophy of the retina: inborn error of L-ornithine: 2-oxoacid aminotransferase. Science 200:200–201
Piozzi E, Alessi S, Santambrogio S, Cillino G, Mazza M, Iggui A, Cillino S. Carbonic Anhydrase Inhibitor with Topical NSAID Therapy to Manage Cystoid Macular Edema in a Case of Gyrate Atrophy. Eur J Ophthalmol. 2017 Nov 8;27(6):e179-e183.
Raitta, C., S. Carlson, and K. Vannas-Sulonen.Gyrate atrophy of the choroid and retina: ERG of the neural retina and the pigment epithelium. Br. J. Ophthalmol. 1990; 74: 363-367
Salcedo-Villanueva G, Paciuc-Beja M, Villanueva-Mendoza C, Harasawa M, Smith JM, Velez-Montoya R, Olson JL, Oliver SC, Mandava N, Quiroz-Mercado H. Progression of gyrate atrophy measured with ultra-widefield imaging. Int Ophthalmol (2016) 36: 111.
Sergouniotis PI, Davison AE, Lenassi E et al (2012) Retinal structure, function, and molecular pathologic features in gyrate atrophy. Ophthalmology 119:596–605
Shen BW,Hennig M, Hohenester E et al (1998) Crystal structure of human recombinant ornithine aminotransferase. J Mol Biol 277:81–102
Shih VE, Mandell R, Berson EL.Pyridoxine effects on ornithine ketoacid transaminase activity in fibroblasts from carriers of two forms of gyrate atrophy of the choroid and retina. Am J Hum Genet. 1988 Dec;43(6):929-33.
Simell, O., Takki, K. Raised plasma ornithine and gyrate atrophy of the choroid and retina. Lancet 301: 1031-1033, 1973.
Sipilä I, Rapola J, Simell O, Vannas A. Supplementary Creatine as a Treatment for Gyrate Atrophy of the Choroid and Retina. N Engl J Med 1981; 304:867-870
Sipila, I., Simell, O., Rapola, J., Sainio, K., Tuuteri, L. Gyrate atrophy of the choroid and retina with hyperornithinemia: tubular aggregates and type 2 fiber atrophy in muscle. Neurology 29: 996-1005, 1979.
Stoppoloni G, Prisco F, Santinelli R, Tolone C. Hyperornithinemia and gyrate atrophy of choroid and retina. Report of a case. Helv Paediatr Acta. 1978;33(4-5):429-33.
Takki K, Milton R. The Natural History of Gyrate Atrophy of the Choroid and Retina. Ophthalmology. 1981 Apr;88(4):292-301.
Valle, D., Simell, O. The hyperornithinemias. In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.): The Metabolic and Molecular Bases of Inherited Disease. Vol. II. (8th ed.) New York: McGraw-Hill (pub.) 2001. Pp. 1857-1895.
Valle D, Simell O. In: The Metabolic and Molecular Bases of Inherited Disease. Scriver C, Beaudet A, Sly W, Valle D, editors. New York: McGraw–Hill; 1995. pp. 1147–1185.
Valle D, Walser M, Brusilow SW, Kaiser-Kupfer M (1980) Gyrate atrophy of the choroid and retina: amino acid metabolism and correction of hyperornithinemia with an arginine-deﬁcient diet. J Clin Invest 65:371–378
Valtonen, M., Nanto-Salonen, K., Heinanen, K., Alanen, A., Kalimo, H., Simell, O. Skeletal muscle of patients with gyrate atrophy of the choroid and retina and hyperornithinaemia in ultralow-field magnetic resonance imaging and computed tomography. J. Inherit. Metab. Dis. 19: 729-734, 1996.
Valtonen, M., Nanto-Salonen, K., Jaaskelainen, S., Heinanen, K., Alanen, A., Heinonen, O. J., Lundbom, N., Erkintalo, M., Simell, O. Central nervous system involvement in gyrate atrophy of the choroid and retina with hyperornithinaemia. J. Inherit. Metab. Dis. 22: 855-866, 1999
Volpe P, Sawamura R, Strecker HJ (1969) Control of ornithine delta-transaminase in rat liver and kidney. J Biol Chem 244:719–726.
Wang T, Steel G, Milam AH, Valle D. Correction of ornithine accumulation prevents retinal degeneration in a mouse model of gyrate atrophy of the choroid and retina. Proc Natl Acad Sci USA. 2000 Feb 1;97(3):1224-9.
Weleber RG, Kennaway NG. Clinical trial of vitamin B6 for gyrate atrophy of the choroid and retina. Ophthalmology. 1981 Apr;88(4):316-24.
Wilson DJ, Weleber RG, Green WR (1991) Ocular clinicopathologic study of gyrate atrophy. AmJ Ophthalmol 111:24–33
Wang T, Steel G, Milam AH, Valle D (2000) Correction of ornithine accumulation prevents retinal degeneration in a mouse model of gyrate atrophy of the choroid and retina. Proc Natl Acad Sci USA 97:1224–1229
Application Guidelines and Instructions
Projects must directly advance research in treatment and/or finding a cure for Gyrate Atrophy and/or efforts to connect researchers to accelerate discovery and collaboration. We believe that patient informed research is critical. Grants generally up to $50,000 are available. To apply, please see these guidelines.