Gyrate atrophy of the choroid and retina
Gyrate atrophy of the choroid and retina (GA) is an inherited ocular condition characterized by the degeneration of retinal and choroidal tissues due to mutations in the ornithine aminotransferase (OAT) enzyme. This autosomal recessive disorder leads to a buildup of ornithine in the bloodstream, resulting in hyperornithemia, which is toxic to the eye and can lead to significant vision loss. Initial symptoms typically emerge in childhood and include myopia (nearsightedness) and night blindness, progressing to tunnel vision and potential blindness by middle age. Affected individuals may also develop cataracts and display characteristic yellow lesions in the peripheral retina. Diagnosis involves identifying these retinal lesions and measuring elevated ornithine levels in urine or plasma, along with genetic testing for OAT mutations. While there is no cure for GA, treatments such as dietary restrictions of arginine and vitamin B6 supplementation can help slow disease progression for some patients. Life expectancy is generally unaffected, and most individuals with GA maintain normal intelligence, although some may experience developmental challenges.
Gyrate atrophy of the choroid and retina
ALSO KNOWN AS: Gyrate atrophy with ornithine-delta-amino transferase deficiency; ornithine ketoacid aminotransferase deficiency; gyrate atrophy of the choroid and retina with hyperornithemia; gyrate atrophy of the choroid and retina and iminoglycinuria; gyrate atrophy; HOGA
DEFINITION Gyrate atrophy (GA) results from a buildup of the amino acid ornithine due to mutations in the ornithine aminotransferase (OAT) enzyme. This autosomal recessive inherited disorder derives from the inactivation of OAT, which is responsible for metabolizing ornithine to glutamic acid and proline via an intermediate.
Risk Factors
Autosomal recessive inheritance or spontaneous mutations of the OAT gene represent the only risk factors for GA. Consanguinity, or interrelatedness, between parents increases the chances of inheriting a mutated allele. The presence of two mutated genes is necessary for presentation of the disease. Children of parents who are both carriers have a 25 percent chance of presenting with GA.
Etiology and Genetics
Inherited or other spontaneous mutations in both paternal and maternal OATalleles results in the clinical disorder gyrate atrophy. The protein produced by mutated OAT genes can be truncated or contain an change, leading to an OAT protein with little or no function. Individuals who are heterozygotic, possessing only one mutated gene, are unaffected. Dozens of OAT mutations have been described. A combination of any two will result in GA, though different mutations can lead to variants of GA that respond differently to therapy and progress at different rates. Finns are disproportionately affected.
The functional OAT gene has been mapped to the long arm of chromosome 10 (10q26) in Homo sapiens. The OAT gene is approximately 21 kilobases (kb) long and contains eleven exons, which are segments of a gene that code for a portion of the protein. The active OAT protein consists of six identical protein subunits, forming a monomer. Each of the processed monomers has a mass of 45 kilodaltons (kDa), giving the OAT homohexamer a molecular weight of approximately 270 kDa. Mutations that interfere with the association of OAT monomers may lead to GA.
Nonfunctional OAT pseudogenes, designated OAT-like (OATL), have been mapped to the short arm of the X chromosome. Pseudogenes contain much of the same genetic sequence as the genes to which they are similar but often lack segments required to produce the functional protein or have mutations that inactivate them.
The OAT protein is located in the mitochondrial matrix, which is the innermost portion of the mitochondrion, and converts ornithine and alpha-ketoglutarate to glutamate semialdehyde and glutamate. The inability to metabolize ornithine leads to a condition called hyperornithemia, or an excess of ornithine in the bloodstream. This excess ornithine is toxic to the choroid and retina and also affects type II muscle fibers, though the progression of muscle changes is much slower than those seen in the eye. Ornithine levels in plasma and urine are five to twenty times normal.
Typical initial symptoms are myopia and night blindness in childhood, followed by progressive tunnel vision. Patients often develop cataracts between the ages of ten and twenty and are effectively blind by the age of forty to fifty. Most are of normal intelligence, though some experience developmental or intellectual disabilities. The peripheral retina presents with clearly bounded yellow lesions. These lesions also affect the choroid, the vascularized layer of the eye that extends under the retina. Some newborns present with excess ammonia in their bloodstream, a condition called hyperammonemia, but this does not persist beyond infancy.
Symptoms
Myopia, or nearsightedness, and nyctalopia, or night blindness, in early childhood often are the first symptoms. A doctor should be consulted if a child has difficulty seeing distant objects or cannot see at night. Untreated, GA progresses slowly through a course of diminishing peripheral vision, leading to eventual blindness.
Screening and Diagnosis
Diagnosis of gyrate atrophy can be made by observation of the characteristic lesions in the retina combined with elevation of urine or plasma levels of ornithine. A polymerase chain reaction (PCR) test can be used to test for specific mutations in the OAT gene. Prenatally, cells can be cultured and tested for OAT levels. The OAT may also be isolated and tested for abnormal activity. Muscular histological examination can show atrophy of Type II muscle fibers and tubular aggregates in the sarcoplasma.
Treatment and Therapy
Individuals with particular mutations in the OAT gene, including the V332M and A226V alleles, have shown a positive response to pyridoxine (vitamin B6) therapy. Restriction of dietary arginine also slows progression of the disease, due to the role of arginine as a metabolic precursor of ornithine in the urea cycle. Previous studies have demonstrated that this severely restricted diet can be difficult to maintain.
Prevention and Outcomes
In some patients, pyridoxine or proline supplementation can also improve prognosis. No cure exists for GA, and treatment will not completely halt disease progression. Life expectancy is not affected.
Bibliography
Doimo, Mara, et al. "Functional Analysis of Missense Mutations of OAT, Causing Gyrate Atrophy of Choroid and Retina." Human Mutation 34.1 (2013): 229–36. Print.
Elnahry, Ayman G. and Koushik Tripathy. Gyrate Atrophy of the Choroid and Retina. StatPearls, National Library of Medicine, 2023, www.ncbi.nlm.nih.gov/books/NBK557759/. Accessed 9 Sept. 2024.
Katagiri, Satoshi, et al. "OAT Mutations and Clinical Features in Two Japanese Brothers with Gyrate Atrophy of the Choroid and Retina." Documenta Ophthalmologica 128.2 (2014): 137–48. Print.
Kim, Sang Jin, et al. "Gyrate Atrophy of the Choroid and Retina Diagnosed by Ornithine-δ-aminotransferase Gene Analysis: A Case Report." Korean Journal of Ophthalmology 27.5 (2013): 388–91. Print.
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Wright, Kenneth W., Peter H. Spiegel, and Lisa S. Thompson, eds. Handbook of Pediatric Retinal Disease. New York: Springer, 2006. Print.