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Gyrate Atrophy: for professionals

Overview

PrevalenceRare, 200 cases reported in literature
InheritanceAutosomal recessive
Genes Involved (OMIM No.)OAT (#258870)
SymptomsNyctalopia
Progressive loss of visual acuity
Concentric visual field loss
Muscle weakness
Ocular FeaturesProgressive myopia
Cataracts
Macular oedema
Sharply demarcated areas of chorioretinal atrophy
Retinal thinning
Retinal tubulations
Systemic featuresThin hair
Central nervous system manifestations (e.g., diffuse brain atrophy) Hyperammonaemia in newborns (rare)
Key InvestigationsOphthalmic:
Fundoscopy Fundus autofluorescence (FAF)
Optical coherence tomography (OCT)
Electroretinogram (ERG)
Systemic:
Plasma ornithine levels
Molecular DiagnosisWhole genome sequencing with retinal gene panel
ManagementOcular:
Regular ophthalmic monitoring
Management of refractive errors
Monitoring and treatment of macular oedema
Low vision services and assistive technology
Systemic:
Low-protein diet with arginine restriction
Pyridoxine (vitamin B6) supplementation (if responsive)
Lysine supplementation
Creatine supplementation
Multidisciplinary approach with paediatric and adult metabolic specialists and dieticians
Therapies under ResearchOngoing studies on the impact of dietary modifications and novel therapeutic approaches.

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Clinical phenotype

Gyrate atrophy of the choroid and retina is a rare autosomal recessive retinal dystrophy caused by a deficiency in ornithine aminotransferase (OAT), leading to elevated plasma ornithine levels. Patients present in the first decade with night blindness (nyctalopia). Fundus examination shows circular patches of chorioretinal atrophy in the peripheral retina. As the disease progresses, these lesions merge and spread towards the posterior pole, resulting in peripheral vision loss. Macular involvement occurs later.1,2

Presenting features

Ocular

  • Nyctalopia: Typically, the first symptom, presenting in childhood.
  • Progressive myopia: Early onset and progressively worsening.
  • Concentric visual field loss: Noted during the second decade of life, progressing over time.
  • Loss of visual acuity: Secondary to cystoid macular oedema and photoreceptor loss.3
  • Cataracts typically occur by the second decade of life.4

Systemic

  • Thin hair
  • Muscle weakness: Secondary to creatine deficiency in a minority of patients.
  • Central nervous system manifestations: Including diffuse brain atrophy and learning difficulties in some cases.5
  • Hyperammonaemia in newborns: Rare cases presenting with poor feeding, vomiting, and diarrhoea.6

Fundal appearance

  • Early fundus examination:
    • Bilateral patchy, sharply demarcated circular areas of chorioretinal atrophy with hyperpigmented margins in the mid to far periphery.1,7
  • Progression:
    • During the second decade, peripheral atrophic lesions coalesce and spread towards the posterior pole.
    • Form a confluent lesion with a scalloped border between healthy and diseased retinal pigment epithelium (RPE).
    • Remaining healthy RPE in uninvolved areas is hyperpigmented, distinguishing gyrate atrophy from choroideremia.
  • Macular involvement:
    • Macula and central vision are spared until late in the disease, often preserved into the fourth or fifth decade.
    • In a study of 21 patients, 38% had macular involvement with atrophy7

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Genetics

Gyrate dystrophy is caused by mutations in the OAT gene, leading to deficiency or dysfunction of the OAT enzyme.8,9

  • Gene: OAT (Ornithine Aminotransferase).
  • OMIM No.: #258870
  • Inheritance pattern: Autosomal Recessive
  • Function and effect of pathogenic variant: OAT catalyzes the conversion of ornithine to glutamate in the urea cycle. Deficiency of OAT results in the accumulation of ornithine, leading to retinal degeneration and other systemic manifestations.

Further information about each gene can be found on OMIM and Medline Plus.

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Key investigations

Ocular

  1. Fundoscopy: Reveals characteristic chorioretinal atrophy.7
  2. Fundus Autofluorescence (FAF): Shows focal or confluent areas of absent signal corresponding to atrophic regions.10
  3. Fluorescein angiography: early hyperfluorescence due to areas of chorioretinal atrophy, late staining from dye pooling in the choroid, window defects from retinal pigment epithelium loss, cystoid macular oedema with petaloid hyperfluorescence, macular schisis, and peripheral vascular leakage in advanced stages.11-13
  4. Optical Coherence Tomography (OCT): Identifies retinal thinning, loss of IS/OS junction in the periphery, cystoid macular oedema (frequent and also seen on SD-OCT), retinal gliosis, outer retinal tubulation and choroidal neovascularisation.13,14
  5. Electroretinogram (ERG): Detects early rod-cone dysfunction progressing to extinguished responses.15
  6. Genetic testing: WGS with retinal panel

Systemic

  1. Plasma Ornithine Levels: Elevated 10-20 times above normal.

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Diagnosis

A definitive diagnosis of gyrate dystrophy involves integrating clinical features, biochemical testing results, and genetic testing outcomes.

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Differential Diagnoses

Differential diagnoses include choroideraemia, didanosine toxicity, myopic degeneration, and retinitis pigmentosa.

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Management

The management of gyrate dystrophy aims to address ocular and systemic manifestations of the disease and mitigate complications.

Ocular

  1. Regular monitoring: Measure visual function and fundus changes, with prompt intervention for complications such as macular involvement and choroidal neovascularisation.
  2. Cystoid macula oedema: referral to medical retina for consideration of either sub-tenon injection of triamcinolone acetonide, dexamethasone implantation, intravitreal bevacizumab, and topical NSAIDs.16,17
  3. Cataracts: surgical intervention with IOL insertion
  4. Low vision services: Utilisation of low vision aids and adaptive techniques to maximise visual function and enhance quality of life.

Systemic

  1. Multidisciplinary Support:
    • Involvement of paediatric and adult metabolic specialists and dieticians.
  2. Dietary Management: referral to dieticians/metabolic specialists to reduce ornithine levels and slow disease progression.
    • Dietary restriction of arginine18
    • Vitamin B6 supplementation19
    • Lysine supplementation20
    • Creatinine supplementation21

Family management and counselling

Pierson syndrome is inherited in an autosomal recessive manner. Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic diagnosis.

Emotional and social support

Genetic counsellors and Eye Clinic Liaison Officers (ECLOs) act as an initial point of contact for newly diagnosed patients and their parents in clinic. They provide emotional and practical support to help patients and parents deal with the diagnosis and maintain independence. They work closely with the local council’s sensory support team and are able to advise on the broad range of services provided, such as visual rehabilitation, home assessment, work and access to qualified teachers for children with visual impairment (QTVI) among other services.

Related links

Referral to a specialist centre

In the UK, patients should be referred to their local genomic ophthalmology (if available) or clinical genetics services to receive a more comprehensive genetic management of their conditions (genetic testing and genetic counselling) and having the opportunity to participate in clinical research.

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Further information and support

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References

  1. Takki K, Milton R. The Natural History of Gyrate Atrophy of the Choroid and Retina. Ophthalmology. 1981 Apr;88(4):292-301.
  2. Simell O, Takki K. Raised plasma ornithine and gyrate atrophy of the choroid and retina. Lancet. 1973;301(7809):1031-1033.
  3. Sergouniotis PI, Davison AE, Lenassi E, et al. Retinal structure, function, and molecular pathologic features in gyrate atrophy. Ophthalmology. 2012 Mar;119(3):596-605.
  4. Kaiser-Kupfer M, Kuwabara T, Uga S, Takki K, Valle D. Cataracts in gyrate atrophy: clinical and morphologic studies. Invest Ophthalmol Vis Sci. 1983 Apr;24(4):432-436.
  5. Valtonen M, Nanto-Salonen K, Jaaskelainen S, et al. Central nervous system involvement in gyrate atrophy of the choroid and retina with hyperornithinaemia. J Inherit Metab Dis. 1999 Dec;22(8):855-866.
  6. 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):146-153.
  7. Zhioua Braham I, Ammous I, Maalej R, et al. Multimodal imaging of foveoschisis and macular pseudohole associated with gyrate atrophy: a family report. BMC Ophthalmol. 2018 Apr 12;18(1):89.
  8. Brody LC, Mitchell GA, Obie C, et al. Ornithine delta-aminotransferase mutations in gyrate atrophy: allelic heterogeneity and functional consequences. J Biol Chem. 1992 Feb 5;267(5):3302-3307.
  9. Valle D, Simell O. Ornithine Delta-Aminotransferase Deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The Metabolic and Molecular Bases of Inherited Disease. 7th ed. New York: McGraw-Hill; 1995. p. 1147-1185.
  10. Sergouniotis PI, Davidson AE, Lenassi E, et al. Retinal structure, function, and molecular pathologic features in gyrate atrophy. Ophthalmology. 2012 Mar;119(3):596-605.
  11. Vannas-Sulonen K. Progression of gyrate atrophy of the choroid and retina. A long-term follow-up by fluorescein angiography. Acta Ophthalmol (Copenh). 1987 Feb;65(1):101-109.
  12. Tripathy K, Chawla R, Sharma YR, Gogia V. Ultrawide field fluorescein angiogram in a family with gyrate atrophy and foveoschisis. Oman J Ophthalmol. 2016 May-Aug;9(2):104-106.
  13. Oliveira TL, Andrade RE, Muccioli C, et al. Cystoid macular edema in gyrate atrophy of the choroid and retina: a fluorescein angiography and optical coherence tomography evaluation. Am J Ophthalmol. 2005 Jul;140(1):147-149.
  14. Valtonen M, Nanto-Salonen K, Heinanen K, et al. 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. 1996 Sep;19(6):729-734.
  15. Raitta C, Carlson S, Vannas-Sulonen K. Gyrate atrophy of the choroid and retina: ERG of the neural retina and the pigment epithelium. Br J Ophthalmol. 1990 Jun;74(6):363-367.
  16. 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.
  17. 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.
  18. 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 U S A. 2000 Feb 1;97(3):1224-1229.
  19. Kaiser-Kupfer MI, Caruso RC, Valle D, Reed GF. Use of an arginine-restricted diet to slow progression of visual loss in patients with gyrate atrophy. Arch Ophthalmol. 2004 Jul;122(7):982-984.
  20. 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 Mar;56(3):616-622.
  21. Alparslan S, 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.

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Updated on June 3, 2024
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