Gyrate Atrophy

Gyrate atrophy of the choroid and retina is a rare, inherited eye disease that causes progressive vision loss. It is caused by a genetic mutation that leads to a deficiency of an enzyme called ornithine aminotransferase. This deficiency causes a buildup of an amino acid called ornithine in the blood and body fluids, which is toxic to the cells in the retina (the light-sensitive tissue at the back of the eye). The first symptom of gyrate atrophy is usually night blindness, which typically begins in childhood. As the disease progresses, patients experience a gradual loss of peripheral (side) vision, leading to "tunnel vision." Many patients also develop cataracts (clouding of the eye's lens) at a young age. Central vision is usually preserved until later in life, but most patients eventually become legally blind between the ages of 40 and 55. While there is currently no cure for gyrate atrophy, treatments are aimed at lowering the levels of ornithine in the blood to slow the progression of vision loss. This may involve a strict, low-protein diet that restricts the intake of an amino acid called arginine, which the body converts into ornithine. Some patients may also benefit from taking high doses of vitamin B6. Regular eye exams are important to monitor the disease and manage complications like cataracts or swelling in the macula.

Condition category: Retinal Dystrophy

Prevalence: Less than 1 in 100,000

Inheritance patterns: Autosomal Recessive

Age of onset: Late childhood (first decade of life)

Clinical overview: Gyrate atrophy of the choroid and retina (GACR) is a rare, autosomal recessive inherited retinal dystrophy characterized by progressive vision loss. It is caused by a deficiency of the mitochondrial enzyme ornithine aminotransferase (OAT), which leads to a significant elevation of plasma ornithine levels (hyperornithinemia). The condition is clinically defined by a triad of progressive chorioretinal degeneration, early cataract formation, and type II muscle fiber atrophy. The hallmark ophthalmic feature of gyrate atrophy is the development of sharply demarcated, circular patches of chorioretinal atrophy in the peripheral fundus. These lesions progressively coalesce and advance toward the macula, leading to night blindness, progressive visual field constriction, and eventually, loss of central vision. Patients typically become legally blind by the fourth to sixth decade of life. In addition to the ocular manifestations, gyrate atrophy can be associated with systemic features, including mild cognitive impairment, delayed language development, and skeletal muscle atrophy. The condition is genetically heterogeneous, with over 60 mutations identified in the OAT gene. The OMIM number for the phenotype is 258870, and the OMIM number for the OAT gene is 613349. The Orphanet number is ORPHA:414.

Patient and family guide: Gyrate atrophy of the choroid and retina is a rare, inherited eye disease that causes progressive vision loss. It is caused by a genetic mutation that leads to a deficiency of an enzyme called ornithine aminotransferase. This deficiency causes a buildup of an amino acid called ornithine in the blood and body fluids, which is toxic to the cells in the retina (the light-sensitive tissue at the back of the eye). The first symptom of gyrate atrophy is usually night blindness, which typically begins in childhood. As the disease progresses, patients experience a gradual loss of peripheral (side) vision, leading to "tunnel vision." Many patients also develop cataracts (clouding of the eye's lens) at a young age. Central vision is usually preserved until later in life, but most patients eventually become legally blind between the ages of 40 and 55. While there is currently no cure for gyrate atrophy, treatments are aimed at lowering the levels of ornithine in the blood to slow the progression of vision loss. This may involve a strict, low-protein diet that restricts the intake of an amino acid called arginine, which the body converts into ornithine. Some patients may also benefit from taking high doses of vitamin B6. Regular eye exams are important to monitor the disease and manage complications like cataracts or swelling in the macula.

Symptoms and clinical features: The clinical presentation of gyrate atrophy of the choroid and retina typically begins in the first decade of life. The earliest and most common initial symptom is night blindness (nyctalopia), which occurs due to the early involvement of the peripheral retina. Patients also frequently present with myopia (nearsightedness) during childhood. As the disease progresses into the intermediate stages (typically the second and third decades of life), patients experience a progressive constriction of their visual fields. This corresponds to the expansion and coalescence of the characteristic circular patches of chorioretinal atrophy in the mid-periphery of the fundus. Visually significant posterior subcapsular cataracts also commonly develop during this stage, further contributing to visual impairment. In the advanced stages of the disease (typically the fourth to sixth decades), the chorioretinal atrophy spreads centripetally to involve the macula, leading to a significant decline in central visual acuity. Complications such as cystoid macular edema, foveoschisis, and epiretinal membranes can also occur and exacerbate central vision loss. Most patients become legally blind between 40 and 55 years of age. Systemic features, such as mild cognitive impairment, delayed language development, and skeletal muscle atrophy (specifically type II muscle fibers), may also be present but are often asymptomatic or mild.

Molecular pathology: Gyrate atrophy of the choroid and retina is caused by a deficiency of the mitochondrial matrix enzyme ornithine aminotransferase (OAT). OAT is a pyridoxal phosphate (vitamin B6)-dependent enzyme that catalyzes the conversion of the non-protein amino acid L-ornithine to pyrroline-5-carboxylic acid, which is then converted to proline and glutamic acid. This reaction is a key step in the exchange of molecules between the urea cycle and the Krebs cycle, and it plays a critical role in cellular detoxification by disposing of ornithine derived from dietary arginine. Mutations in the OAT gene lead to a deficiency or complete absence of OAT enzyme activity. This deficiency results in the accumulation of ornithine, leading to plasma ornithine levels that are 10 to 20 times higher than normal. The exact mechanism by which hyperornithinemia causes chorioretinal degeneration is not fully understood, but it is thought to involve a direct toxic effect of ornithine or its metabolites on the retinal pigment epithelium (RPE). The RPE is believed to be the initial site of damage due to its high expression of OAT and reliance on OAT activity for metabolic functions. Damage to the RPE leads to a breakdown of the outer blood-retinal barrier, exposing photoreceptor cells to toxic agents from the choroidal circulation. This ultimately results in the progressive atrophy of the RPE, choriocapillaris, and photoreceptors characteristic of gyrate atrophy. Additionally, high ornithine levels inhibit creatine biosynthesis, leading to a secondary phosphocreatine deficiency that may contribute to the systemic manifestations of the disease, such as muscle atrophy and neurological abnormalities.

Genetics: Gyrate atrophy of the choroid and retina is an autosomal recessive disorder caused by mutations in the OAT gene, located on chromosome 10q26. The OAT gene encodes the enzyme ornithine aminotransferase. More than 60 different mutations in the OAT gene have been identified in patients with gyrate atrophy, with missense mutations being the most common. These mutations lead to a decrease or complete absence of OAT enzyme activity. There is significant genetic heterogeneity, and some genotype-phenotype correlations have been observed. A subset of patients carries a genetic variant that is responsive to supplementation with the co-factor pyridoxine (vitamin B6). In these patients, pyridoxine supplementation can partially restore the function of the OAT enzyme and lower plasma ornithine levels. The responsiveness to pyridoxine is associated with specific mutations in the OAT gene. The pattern of inheritance is consistently autosomal recessive. Heterozygotes (carriers) typically have intermediate levels of OAT activity but do not develop the clinical features of gyrate atrophy. The estimated frequency of heterozygotes in the Finnish population is 1 in 110 individuals.

Diagnostic evaluation: The diagnosis of gyrate atrophy of the choroid and retina is primarily clinical, based on history and characteristic fundus findings. Fundoscopy reveals bilateral, sharply demarcated, circular areas of chorioretinal atrophy with hyperpigmented margins in the mid-periphery. As the disease progresses, these lesions coalesce and spread toward the posterior pole, forming a scalloped border. The macula is typically spared until late in the disease course. Optical Coherence Tomography (OCT) is useful for evaluating macular involvement. It often shows cystoid macular edema, foveoschisis, and epiretinal membranes. In the periphery, OCT demonstrates extensive loss of the IS/OS junction, RPE, and inner choroid reflectivity, along with significant thinning of both the inner and outer retina. Electroretinography (ERG) abnormalities are present early in the disease, showing impaired rod and cone responses that ultimately progress to a completely extinguished response. The median ERG half-life is 16.0 years for the standard combined response and 10.7 years for the flicker response. Laboratory testing confirms the diagnosis by demonstrating plasma ornithine levels that are 10 to 20 times higher than normal. Genetic testing for mutations in the OAT gene is also used to confirm the diagnosis and identify the specific allelic variant. Differential diagnosis includes choroideremia, retinitis pigmentosa, myopic degeneration, and cobblestone degeneration.

Differential diagnosis: Differential diagnosis of gyrate atrophy includes: (1) Choroideremia — X-linked, no elevated ornithine, CHM mutations. (2) Retinitis pigmentosa (advanced) — bone spicule pigmentation rather than sharply demarcated atrophy. (3) Myopic degeneration — high myopia, posterior staphyloma, peripapillary atrophy. (4) Bietti crystalline dystrophy — crystalline deposits, CYP4V2 mutations. (5) Thioridazine toxicity — medication history, nummular pigment changes. (6) Pathologic myopia with chorioretinal atrophy — axial length >26mm, lacquer cracks.

Natural history: The natural history of gyrate atrophy of the choroid and retina is characterized by a slow, progressive decline in visual function. The initial symptom is typically night blindness (nyctalopia), which begins in late childhood or the first decade of life. This is followed by progressive constriction of the visual fields due to the expansion and coalescence of peripheral chorioretinal atrophic lesions. During the second and third decades of life, the areas of atrophy enlarge and spread centripetally toward the posterior pole. Visually significant posterior subcapsular cataracts also frequently develop during the second decade. Central vision is usually spared until late in the disease course, often preserved into the fourth or fifth decade of life. Most patients become legally blind (visual acuity less than 20/200) between 40 and 55 years of age due to macular involvement by the chorioretinal atrophy or complications such as cystoid macular edema. The rate of visual decline can be variable, and some studies suggest that early initiation of an arginine-restricted diet may slow the progression of the chorioretinal lesions and the loss of retinal function.

Management and treatment research: ### Current management and standard of care There is currently no cure for gyrate atrophy, an inherited retinal disease caused by changes in the **OAT** gene. Reduced activity of the OAT enzyme leads to elevated blood ornithine, an amino acid associated with progressive degeneration of the choroid and retina. Management aims to lower ornithine levels, preserve remaining vision, and address eye and systemic complications. - **Arginine-restricted nutrition:** Limiting dietary arginine—an amino acid that can be converted to ornithine—may reduce blood ornithine levels. This usually involves an individualized low-protein diet developed with a metabolic specialist and dietitian to support adequate nutrition, growth, and overall health. Long-term ornithine reduction may help slow chorioretinal degeneration, particularly when started early. - **Pyridoxine (vitamin B6) response testing:** Some people with gyrate atrophy have OAT variants that respond to high-dose pyridoxine. Pyridoxine is a cofactor, meaning it helps certain enzymes function. In people who respond, treatment can substantially lower ornithine levels. A supervised trial may be used to determine whether a person is responsive. - **Creatine supplementation:** Creatine may be considered for people with low creatine or phosphocreatine levels or related muscle effects. Its ability to prevent or slow retinal degeneration has not been established. Regular follow-up with retinal and metabolic specialists is important. Eye care may include treatment of complications such as posterior subcapsular cataracts, which can be removed surgically when appropriate. Cystoid macular edema—fluid-related swelling in the central retina—may sometimes be treated with topical anti-inflammatory medicines or carbonic anhydrase inhibitors. Responses vary, and no single treatment is established for this complication. Low-vision services, orientation and mobility training, adaptive technology, and genetic counseling can help individuals and families manage changing vision and plan for support needs. ### Approved therapies There are no disease-specific FDA-approved therapies for gyrate atrophy. Dietary arginine restriction and pyridoxine treatment for people who are responsive remain the main disease-directed approaches. ### Investigational therapies There are no active disease-targeted gene therapy, drug, cell therapy, or other interventional treatment programs listed in the current pipeline for gyrate atrophy. Research continues to improve understanding of OAT deficiency, elevated ornithine, and the retinal degeneration that occurs in gyrate atrophy. Future studies may help identify additional ways to lower ornithine or protect retinal cells. ### Clinical trial participation Current listed studies are observational, screening, or registry-based rather than treatment trials. - **NCT05312736 — Gyrate Atrophy Ocular and Systemic Study:** Active, not recruiting. This study examines eye and systemic features of gyrate atrophy. - **NCT03655223 — Early Check: Expanded Screening in Newborns:** Active, not recruiting. This newborn screening study includes gyrate atrophy among the conditions evaluated. - **NCT02435940 — Inherited Retinal Degenerative Disease Registry:** Recruiting. This registry collects information from people with inherited retinal diseases and may help researchers understand disease patterns and identify potential candidates for future studies.

Outlook: The prognosis for visual function in gyrate atrophy of the choroid and retina is generally poor, as the disease is progressive and ultimately leads to severe vision loss. Most patients become legally blind (visual acuity less than 20/200) between the ages of 40 and 55 due to the progressive expansion of chorioretinal atrophy into the macula. The development of complications such as cystoid macular edema, cataracts, and choroidal neovascularization can also significantly impact visual acuity and quality of life. However, the rate of progression can be variable. Early diagnosis and intervention, particularly with a strict arginine-restricted diet or pyridoxine supplementation in responsive individuals, may slow the progression of chorioretinal lesions and preserve visual function for a longer period. Despite the severe visual impairment, patients generally have a normal lifespan, although they may experience mild systemic manifestations such as muscle weakness or cognitive impairment.

Epidemiology: Gyrate atrophy of the choroid and retina is a rare condition with approximately 200 biochemically confirmed cases reported worldwide. It is most prevalent in Finland, where the estimated frequency is about 1 in 50,000 individuals, and the carrier frequency is 1 in 110. The condition has been reported in many other countries, including the USA, Japan, Germany, UK, India, China, Australia, France, Tunisia, Egypt, Korea, Brazil, Nepal, and Turkey. There is no known predilection for gender.

Selected references: 1. Elnahry AG, et al. Gyrate Atrophy of the Choroid and Retina: A Review. Eur J Ophthalmol. 2022;32(3):1314-1323. PMID: 34894815 2. Balfoort BM, et al. A review of treatment modalities in gyrate atrophy of the choroid and retina. Mol Genet Metab. 2021. 3. Kaiser-Kupfer MI, et al. Gyrate atrophy of the choroid and retina: long-term reduction of ornithine slows retinal degeneration. Arch Ophthalmol. 1991;109(11):1539-48. PMID: 1755734 4. Wang T, et al. Correction of ornithine accumulation prevents retinal degeneration in a mouse model of gyrate atrophy of the choroid and retina. Proc Natl Acad Sci U S A. 2000;97(3):1224-9. PMID: 10655512 5. Peltola KE, et al. Gyrate atrophy of the choroid and retina: a pitfall in the diagnosis of gyrate atrophy. Ophthalmic Genet. 2002;23(3):149-53. PMID: 12211888