Article

A Case of Advanced Gyrate Atrophy of the Retina and Choroid

A genetic retinal disease associated with hyperornithinemia.

Gyrate atrophy (GA) of the retina and choroid has been described as a rare autosomal recessive genetic disease due to a mutation in the OAT gene on chromosome 10, which encodes for ornithine-δ-aminotransferase.1,2 A deficiency of this enzyme leads to drastically elevated levels of the amino acid ornithine in serum, cerebrospinal fluid, and aqueous humor.3 While the most common manifestations of GA occur in the eyes, systemic findings could occur as well. These include fine sparse hair, muscular atrophy, and EEG abnormalities that signal degenerative brain changes.4,5

GA-associated ophthalmic findings can initially present as myopia and nyctalopia in childhood with progressive visual field constriction and early cataract formation due to enlarging regions of degeneration in the peripheral retina.4,6 On fundoscopy, GA manifests as chorioretinal degeneration that appears as discrete scalloped patches of atrophy that begin in the periphery of the retina and progressively coalesce and spread to the central region of the macula, resulting in eventual total visual field deterioration.1,6

Over time, these circular lesions with scalloped margins seen in gyrate atrophy increase in size, leaving patients with profound central vision loss and blindness within the fourth to seventh decades of life.7 Complications of GA include development of macular holes, cystoid macular edema, and choroidal neovascularization, which can all further exacerbate central vision loss.8

Here we discuss a rare case of a patient in her third decade of life presenting with ocular symptoms of advanced gyrate atrophy with striking photos captured by Optos ultrawidefield fundus photography.

CASE PRESENTATION

A 32-year-old pseudophakic female presented to clinic for an ophthalmic examination with chronic progressive vision loss and night blindness. Past ocular history included cataract surgery OU in her early 20s, and prior to that she had high myopia in the -13 D range. Her visual acuity was 20/100 bilaterally, and Humphrey visual field testing showed bilateral dense visual field restriction with partial loss of central vision (Figure 1). Optos ultrawidefield fundus photography (Figure 2) and fluorescein angiography (Figure 3) demonstrated profound peripheral chorioretinal atrophy with scalloped margins within and involving the macula along with diffuse peripheral window defects with mild late disc and macular leakage bilaterally.

FIGURE 1: HVF 10-2 shows visual field loss involving both central fields.
IMAGE COURTESY WEI CHEN LAI, BS

FIGURE 2: Optos ultrawidefield images of the right eye (A) and left eye (B) show symmetric advanced peripheral chorioretinal atrophy with scalloped margins involving the macula.
IMAGE COURTESY WEI CHEN LAI, BS

FIGURE 3: Optos ultrawidefield fluorescein angiograph images of the right eye (A) and left eye (B) showing symmetric bilateral significant peripheral window defects of choroidal vasculature corresponding to the peripheral chorioretinal atrophy. There is also bilateral mild disc and macular leakage.
IMAGE COURTESY WEI CHEN LAI, BS

Advanced gyrate atrophy of the retina and choroid accompanied by chronic cystoid macular edema (CME) in both eyes was diagnosed. Serum ornithine was elevated, and she was found to have a mutated ornithine-δ-aminotransferase (OAT) gene. She was married without children, and she was advised to have her extended family evaluated for GA or carrier mutations.

The patient was referred for genetic and dietary counseling as well as for low-vision services. She was counseled on the need for an arginine-restricted diet with vitamin B6 supplementation, and was started on topical prednisone, bromfenac, and dorzolamide to treat the CME in both eyes. Her vision and imaging remain stable 1 year from presentation.

DISCUSSION

Gyrate atrophy is one of the few metabolic retinal disorders where the pathophysiology of the biochemical defect is well described. OAT has been shown to be expressed at high levels in the retinal pigment epithelium (RPE), and thus the RPE is considered the first site of damage due to GA.9 When RPE cells are damaged, photoreceptors in the retina are unable to receive nutrition due to choriocapillaris degeneration, resulting in progressive visual field impairment.9,10

Systemic clinical manifestations of GA include alopecia, muscular weakness, EEG changes, atrophy of the brain, developmental delay, and epilepsy.5 This is speculated to be due to hyperornithinemia inhibiting creatine synthesis. A secondary deficiency of phosphocreatine has been associated with sparse hair on the scalp as well as type 2 muscle fiber atrophy in muscle biopsy of patients with GA.11 Our patient did exhibit thin hair. Diagnosis is made through a combination of associated clinical features, elevated ornithine levels greater than 10 to 20 times in serum than normal, and OAT gene mutation detection.

To diagnose and monitor GA, ultrawidefield imaging of the retinal periphery can demonstrate the extent of atrophy in relation to the macula. Fluorescein angiography (FA) and optical coherence tomography (OCT) can both aid in confirmation of macular involvement as a complication of GA,12 indicating a loss of reflectivity in the RPE-choriocapillaris complex and nerve fiber layer thinning.13 Visual field and ERG testing can also be a useful follow-up tool to track progressive visual field constriction as well as response to treatment. Of note, family members should also be evaluated with eye exams and genetic testing.

Treatment of gyrate atrophy involves dietary restriction of foods containing the amino acid arginine, which serves as a precursor to ornithine.3 Genetic and dietary counseling are of paramount importance. Arginine-rich foods that should be reduced include dairy products, nuts, seeds, cereal, meat, chocolate, and more.14 Restriction of arginine has been reported to effectively lower ornithine levels in serum, delaying central vision loss.15 Additionally, vitamin B6 serves as a cofactor, increasing the activity of the OAT enzyme, and should be considered as an essential micronutrient necessary for patients with GA.16,17 Creatine supplementation has also been shown to improve muscle weakness and developmental delay by replacing phosphocreatine levels essential for neuromuscular functions.18,20 Dietary modification thus remains first-line treatment to slow disease progression of chorioretinal degeneration in patients with GA.

Although dietary restriction and supplementation can slow down progressive night blindness and visual field constriction in patients with GA, continued decrease in central vision can occur from refractive changes (myopia, cataracts) and macular changes (CME, choroidal neovascularization, epiretinal membrane).18,19 Treatment of these associated macular changes, such as CME in our patient, can result in visual acuity improvements. UV-protected sunglasses are also recommended for further protection. However, by ages 40 to 55, visual loss and blindness may become irreversible once the chorioretinal atrophy spreads to the central macular area. GA patients should follow with low vision services from the time of diagnosis.

Unlike many inherited retinal conditions that currently do not have therapeutic treatment options, GA is unique. Early diagnosis can significantly delay disease progression by employing the various available treatment strategies quickly. Furthermore, prompt recognition in affected patients may also lead to earlier diagnosis in family members who are potentially at risk. Proper diagnosis and management of GA requires a multidisciplinary team approach that includes early diagnosis with close monitoring, treatment of associated ocular complications, genetic testing and counseling, protein-restricted dietary modification and supplementation, and low vision services. NRP

REFERENCES

  1. Takki K, Simell O. Genetic aspects in gyrate atrophy of the choroid and retina with hyperornithinaemia. Br J Ophthalmol. 1974;58(11):907-916. doi:10.1136/bjo.58.11.907
  2. Simell O, Takki K. Raised plasma-ornithine and gyrate atrophy of the choroid and retina. Lancet. 1973;1(7811):1031-1033. doi:10.1016/s0140-6736(73)90667-3
  3. 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;97(3):1224-1229. doi:10.1073/pnas.97.3.1224
  4. Elnahry AG, Elnahry GA. Gyrate atrophy of the choroid and retina: a review. Eur J Ophthalmol. 2021. doi:10.1177/11206721211067333
  5. Fleury M, Barbier R, Ziegler F, et al. Myopathy with tubular aggregates and gyrate atrophy of the choroid and retina due to hyperornithinaemia. J Neurol Neurosurg Psychiatry. 2007;78(6):656-657. doi:10.1136/jnnp.2006.101386
  6. Takki KK, Milton RC. The natural history of gyrate atrophy of the choroid and retina. Ophthalmology. 1981;88(4):292-301. doi:10.1016/s0161-6420(81)35031-3
  7. 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;120(2):146-153. doi:10.1001/archopht.120.2.146
  8. 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;62(3):246-249.
  9. Wang T, Lawler AM, Steel G, Sipila I, Milam AH, Valle D. Mice lacking ornithine-delta-aminotransferase have paradoxical neonatal hypoornithinaemia and retinal degeneration. Nat Genet. 1995;11(2):185-190. doi:10.1038/ng1095-185
  10. Wang T, Milam AH, Steel G, Valle D. A mouse model of gyrate atrophy of the choroid and retina. Early retinal pigment epithelium damage and progressive retinal degeneration. J Clin Invest. 1996;97(12):2753-2762. doi:10.1172/JCI118730
  11. Kaiser-Kupfer MI, Kuwabara T, Askanas V, et al. Systemic manifestations of gyrate atrophy of the choroid and retina. Ophthalmology. 1981;88(4):302-306. doi:10.1016/s0161-6420(81)35030-1
  12. Oliveira TL, Andrade RE, Muccioli C, Sallum J, Belfort R Jr. Cystoid macular edema in gyrate atrophy of the choroid and retina: a fluorescein angiography and optical coherence tomography evaluation. Am J Ophthalmol. 2005;140(1):147-149. doi:10.1016/j.ajo.2004.12.083
  13. Meyer CH, Hoerauf H, Schmidt-Erfurth U, et al. Correlation of morphologic changes between optical coherence tomography and topographic angiography in a case of gyrate atrophy. Ophthalmologe. 2000;97(1):41-46. doi:10.1007/s003470050009
  14. Valle D, Walser M, Brusilow SW, Kaiser-Kupfer M. Gyrate atrophy of the choroid and retina: amino acid metabolism and correction of hyperornithinemia with an arginine-deficient diet. J Clin Invest. 1980;65(2):371-378. doi:10.1172/JCI109680
  15. Santinelli R, Costagliola C, Tolone C, et al. Low-protein diet and progression of retinal degeneration in gyrate atrophy of the choroid and retina: a twenty-six-year follow-up. J Inherit Metab Dis. 2004;27(2):187-196. doi:10.1023/B:BOLI.0000028779.29966.05
  16. Kennaway NG, Stankova L, Wirtz MK, Weleber RG. Gyrate atrophy of the choroid and retina: characterization of mutant ornithine aminotransferase and mechanism of response to vitamin B6. Am J Hum Genet. 1989;44(3):344-352.
  17. Weleber RG, Kennaway NG, Buist NR. Vitamin B6 in management of gyrate atrophy of choroid and retina. Lancet. 1978;2(8101):1213. doi:10.1016/s0140-6736(78)92211-0
  18. Weleber RG, Kennaway NG, Buist NR. Gyrate atrophy of the choroid and retina: approaches to therapy. Int Ophthalmol. 1981;4(1-2):23-32. doi:10.1007/BF00139577
  19. Tada K, Saito T, Omura K, Hayasaka S, Mizuno K. Hyperornithinaemia associated with gyrate atrophy of the choroid and retina: in vivo and in vitro response to vitamin B6. J Inherit Metab Dis. 1981;4(2):61-62. doi:10.1007/BF02263591
  20. 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(15):867-870. doi:10.1056/NEJM198104093041503