Gyrate atrophy

Key Points at a Glance

1. What is Gyrate Atrophy?

Gyrate Atrophy of the Choroid and Retina (GACR) is a metabolic retinal dystrophy caused by deficiency of ornithine aminotransferase (OAT). OAT uses vitamin B6 (pyridoxal phosphate; PLP) as a coenzyme to convert ornithine to glutamate semialdehyde. This deficiency leads to a 10–20 fold increase in plasma ornithine, resulting in progressive atrophy of the choroid and retina.

Epidemiology and Genetics

Epidemiology

Worldwide incidence: approximately 1:1,500,000 to 1:2,770,000^{4, 5)}

Finland: higher frequency of 1:50,000 due to founder effect⁵⁾

Causative Gene

OAT gene: located on chromosome 10q26.13, encoding 439 amino acids⁵⁾

Known variants: ClinVar lists 44 likely pathogenic and 82 pathogenic variants⁵⁾

Inheritance Pattern

Autosomal recessive inheritance: requires mutant alleles from both parents

Carriers: heterozygous carriers may sometimes show mild phenotypes⁴⁾

Many pathogenic variants in the OAT gene have been reported, but genotype-phenotype correlation is not established⁵⁾. The proportion of patients showing vitamin B6 responsiveness is reported to range from an estimated 5% to 30% in systematic reviews⁵⁾.

Q Is gyrate atrophy inherited?

Because it is autosomal recessive, if both parents are carriers, the probability of the child developing the disease is 25%. Heterozygous carriers have about 46% of normal OAT mRNA levels and may show mild phenotypes⁴⁾. If you are concerned about inheritance, genetic counseling is recommended.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

The course of symptoms is shown by age group.

Age	Main Symptoms
Late childhood	Night blindness, high myopia
10s–20s	Visual field constriction, cataract
After age 40	Macular disorder/blindness

Night blindness: The first subjective symptom, often appearing in late childhood (around age 10).
High myopia: The mean spherical equivalent refraction is reported as -8.96 D, presenting significantly higher myopia compared to other hereditary retinal diseases ⁵⁾.
Visual field constriction: As peripheral atrophy progresses, ring scotoma and visual field constriction appear.
Visual acuity loss: Caused by macular involvement or cataract. Posterior subcapsular cataract appears in almost all patients by their 20s.

Clinical Findings

Fundus Findings

In the early stage, well-defined round to oval chorioretinal atrophic patches appear scattered from the mid-periphery to the far periphery of the retina. This gives the appearance of a “gyrate” fundus. The disease stage is classified from Stage I to IV according to the Takki classification ⁷⁾.

From around the 20s, individual atrophic patches enlarge and coalesce, progressing toward the posterior pole with a scalloped border. Both the retinal pigment epithelium (RPE) and the choriocapillaris are affected.

Foveoschisis

Foveoschisis is an important complication of this disease ^{1, 6, 7)}. It differs from CME in that it shows no leakage on fluorescein angiography.

Guan et al. reported a case of a 6-year-old girl whose foveal thickness improved from 645 μm to 554 μm after starting vitamin B6 therapy ⁶⁾. This case suggests improvement of foveoschisis with vitamin B6.

Jena et al. followed three siblings with ultra-widefield imaging (UWFI) over 5 years, documenting foveal thickness changes and stage-wise progression of atrophy ⁷⁾.

Systemic Findings and Complications

Cognitive dysfunction: Mild cognitive dysfunction and brain atrophy on MRI have been reported.
Creatine deficiency: Secondary creatine deficiency in the brain and muscles may occur⁵⁾. Neurological symptoms are limited to less than 10% of all patients⁵⁾.
Zonular weakness: The zonules supporting the lens become fragile, which may cause pseudophacodonesis¹⁾.

Risk of Misdiagnosis

Cases of misdiagnosis as retinitis pigmentosa (RP) have been reported¹⁾, and plasma ornithine measurement is essential for a definitive diagnosis (see Diagnosis and Testing Methods).

Q How fast does the disease progress?

The amplitude of the electroretinogram is said to decrease with a half-life of about 16 years. Jena et al. recorded progression of atrophy over 5 years of UWFI follow-up⁷⁾, and although there are individual differences, it generally progresses slowly. Early intervention with dietary therapy may slow progression.

3. Causes and Risk Factors

Genetic Background

The disease is caused by pathogenic variants in both alleles of the OAT gene (10q26.13). OAT is a PLP (pyridoxal phosphate, the active form of vitamin B6)-dependent enzyme, so in some variants, OAT activity can be restored by vitamin B6 administration.

The main reported variant examples are shown below.

c.425-1G>A (splice site variant): Identified in a case showing vitamin B6 responsiveness³⁾
c.1186C>T / c.748C>T: Cases of heterozygous carriers presenting with a mild phenotype⁴⁾
c.251C>T / c.648+2T>G: A pediatric case complicated by foveoschisis⁶⁾
c.991C>T: A case presenting as hyperammonemia in the neonatal period⁸⁾

In heterozygous carriers, OAT mRNA decreases to about 46% of normal, which may result in a mild phenotype ⁴⁾. It has been suggested that nonsense-mediated mRNA decay (NMD) may contribute to the pathogenesis of GACR ⁴⁾.

Plasma Ornithine Levels as a Guide

Plasma ornithine levels serve as an indicator for diagnosis and monitoring of treatment efficacy.

Condition	Ornithine Level
Normal	25–115 μM
Typical GA	400–1500 μM
Neonatal period	Low → High

Measured values in GA patients have been reported as 1463.2 μM ³⁾, 1180 μM ⁶⁾, and 1063 nmol/mL ¹⁾.

It is important to note that the physiological function of OAT varies with age.

Neonatal period: In the intestine, OAT works in the direction of ornithine synthesis. Deficiency leads to hypoornithinemia and hyperammonemia ⁸⁾.
After infancy: OAT functions in the direction of ornithine degradation. Deficiency leads to ornithine accumulation, resulting in the hyperornithinemia characteristic of GA.

4. Diagnosis and testing methods

Diagnostic process

The core of GA diagnosis is the confirmation of markedly elevated plasma ornithine (10–20 times normal). Amino acid analysis should be performed in patients with night blindness, high myopia, and characteristic peripheral atrophic patches.

Various tests

Plasma amino acid analysis: Marked elevation of plasma ornithine is the basis of diagnosis. Characteristically, levels are 10–20 times normal (400–1500 μM or higher).
Fundus examination: Confirm well-demarcated atrophic patches that progress from the periphery to the posterior pole.
Ultra-widefield fundus imaging (UWFI): Useful for visualizing the full extent of peripheral lesions and monitoring progression ⁷⁾.
Optical coherence tomography (OCT): Used to detect foveoschisis and monitor foveal thickness ⁶⁾.
Electroretinography (ERG): Full-field ERG quantitatively assesses rod and cone function decline.
Genetic analysis (WES/WGS): Identifies pathogenic variants in the OAT gene, leading to a definitive diagnosis ^{3, 4)}.

Differential diagnosis

Disease	Distinguishing features
Choroideremia	No RPE pigment, X-linked
Retinitis pigmentosa	Bone-spicule pigmentation
Paving stone degeneration	Does not involve posterior pole

Measurement of plasma ornithine is the most important test to differentiate GA from these diseases. Misdiagnosis as RP has been reported ¹⁾, so ornithine levels should always be checked in patients with peripheral atrophic patches.

Q How is it differentiated from retinitis pigmentosa?

Plasma ornithine measurement is decisive. GA shows marked hyperornithinemia (10–20 times normal), while ornithine levels are normal in RP ¹⁾. Fundus findings: bone-spicule pigmentation is characteristic of RP, while GA predominantly shows well-demarcated atrophic patches.

5. Standard treatment

Treatment for GA aims to slow the progression of retinal degeneration by lowering plasma ornithine.

Dietary therapy

Low-protein, arginine-restricted diet: Limits intake of arginine, a precursor of ornithine, to reduce plasma ornithine.

Compliance: Long-term continuation is often difficult ^{6, 7)}. Continuous support by a registered dietitian is necessary.

Vitamin B6

Dosage: In B6-responsive cases, high-dose vitamin B6 (e.g., 500 mg/day) has been reported to lower ornithine and improve foveoschisis ⁶⁾.

Response rate: Ranges from 5 to 30% ⁵⁾. It is determined by the type of mutation.

Creatine Supplementation

Purpose: OAT deficiency inhibits AGAT, leading to secondary creatine deficiency in the brain and muscles ⁵⁾.

Effect: Creatine supplementation aims to correct systemic complications.

Details of Dietary Therapy

Arginine-restricted diet (low-protein diet): Restricts arginine, a precursor of ornithine. Long-term continuation is expected to lower plasma ornithine and delay progression of retinal degeneration. Maintaining compliance is the biggest challenge ^{6, 7)}.
L-lysine 10–15 g/day: Administration of L-lysine, which competes with arginine for transporters, has been reported to lower ornithine by 21–31% ⁵⁾.

Vitamin B6 Therapy

Vitamin B6 (pyridoxine) is a precursor of PLP, the coenzyme of OAT. In patients with B6-responsive mutations, vitamin B6 administration restores OAT activity.

In a patient with the splice site mutation c.425-1G>A, administration of a low-protein diet and vitamin B6 for 3 months reduced plasma ornithine by 44% ³⁾.

A 6-year-old girl with c.251C>T/c.648+2T>G mutations underwent dietary therapy and vitamin B6 administration for 9 months, and her ornithine level decreased from 257.92 μM to 132.71 μM. Furthermore, OCT showed improvement in foveal thickness from 645 μm to 554 μm ⁶⁾.

Not all patients are responsive to vitamin B6. The response rate ranges from 5 to 30% ⁵⁾. Responsiveness is determined by administering high-dose vitamin B6 for several weeks and monitoring changes in plasma ornithine levels.

Treatment of Cataract and Macular Complications

Cataract surgery: Surgery is indicated when posterior subcapsular cataract progresses. It is often performed in the late 20s. Care must be taken regarding the fragility of the zonules during surgery ^{1, 5)}.
Carbonic anhydrase inhibitors: Acetazolamide 250 mg three times daily may be used in cases with cystoid macular edema ¹⁾.

Q Does vitamin B6 work for everyone?

The response rate is estimated at 5–30%, so it is not effective for all patients ⁵⁾. B6 responsiveness depends on the type of OAT mutation; for example, the splice site mutation c.425-1G>A has shown responsiveness ³⁾. After diagnosis, a trial of several weeks of administration is performed, and responsiveness is determined by a decrease in plasma ornithine.

6. Pathophysiology and Detailed Mechanism

Role of OAT and Effects of Deficiency

OAT is a PLP-dependent enzyme that converts ornithine to glutamate semialdehyde. OAT deficiency leads to marked accumulation of plasma ornithine, but several hypotheses have been proposed as to why the retina and choroid are specifically affected ⁵⁾.

Five Hypotheses for Retina-Specific Damage

The following hypotheses have been proposed to explain why the retina is specifically damaged ⁵⁾.

Direct ornithine toxicity: High concentrations of ornithine are directly toxic to RPE cells. RPE cells take up ornithine via the cationic amino acid transporter CAT-1.
Proline deficiency: OAT deficiency impairs the conversion of ornithine to proline. The proline metabolic cycle between the RPE and photoreceptors is disrupted.
Polyamine abnormality: Accumulation of ornithine alters polyamine synthesis, affecting cell proliferation and survival.
Oxidative stress due to glutathione deficiency: OAT deficiency affects the glutathione synthesis pathway, increasing oxidative stress.
Creatine deficiency: Ornithine accumulation inhibits AGAT (arginine:glycine amidinotransferase), reducing creatine synthesis ⁵⁾.

The existence of HHH syndrome (hyperornithinemia, hyperammonemia, homocitrullinuria), which shows hyperornithinemia but no ocular symptoms, suggests that ornithine toxicity alone cannot explain retinal damage ²⁾.

Special Pathophysiology in the Neonatal Period

OAT knockout mice exhibit lethal hypoornithinemia and hyperammonemia in the neonatal period ⁸⁾. In humans, during the neonatal period, OAT functions in the gut to synthesize ornithine, so OAT deficiency paradoxically leads to hypoornithinemia and hyperammonemia ⁸⁾. After infancy, OAT function shifts toward degradation, leading to the typical GA phenotype with ornithine accumulation.

RPE as the Initial Site of Damage

Histologically, the RPE is the first site affected, followed by damage spreading to photoreceptors and the choriocapillaris. The progression pattern from the periphery to the posterior pole is thought to reflect the metabolic interdependence between the RPE and photoreceptors.

7. Latest Research and Future Perspectives (Investigational Reports)

Gene Therapy

Gene therapy is currently attracting attention as the most promising future treatment.

Bergen et al. discussed that gene therapy using AAV vectors targeted to the eye is promising for GACR. The clinical success of RPE65 gene therapy (Luxturna®) serves as a reference, and it is pointed out that a similar approach can be applied to GACR²⁾.

Ocular local AAV gene therapy: Local OAT gene transfer to the RPE is being investigated^{2, 5)}.
Liver-targeted AAV gene therapy: Aims to reduce systemic ornithine by restoring OAT expression in the liver. Efficacy has been confirmed in mouse models²⁾.
RPE cell replacement therapy: Replacement therapy using iPSC-derived RPE cells is being studied²⁾.
Optogenetics: The use of light-sensitive proteins to utilize residual visual function in advanced cases is being considered⁵⁾.

Clinical application is expected to take more than 10 years²⁾.

Q When will gene therapy be available?

At present, it is still at the research stage and has not yet been offered in general clinical practice. Bergen et al. discuss its potential based on results in mouse models, but clinical application in humans is expected to take more than 10 years²⁾. It is recommended to continue current standard treatments (diet therapy, vitamin B6, cataract surgery) while awaiting progress in research.

8. References

Horozoglu Ceran T, Sekeryapan Gediz B, Sonmez K. Atypical Presentation and Delayed Diagnosis of Gyrate Atrophy: Case Reports of Two Siblings. Beyoglu Eye J. 2023;8(4):301-307.
Bergen AA, Buijs MJN, ten Asbroek ALMA, et al. Vision on gyrate atrophy: why treat the eye? EMBO Mol Med. 2024;16(1):4-7.
Molaei Ramshe S, Zardadi S, Alehabib E, et al. A Novel Ornithine Aminotransferase Splice Site Mutation Causes Vitamin B6-Responsive Gyrate Atrophy. J Ophthalmic Vis Res. 2024;19(1):118-132.
Ju Y, Zong Y, Li X, et al. Mild Phenotypes of Gyrate Atrophy in a Heterozygous Carrier with One Variant Allele of OAT. Genes. 2024;15(8):1020.
Buijs MJN, Balfoort BM, Brands MM, et al. Molecular and cellular mechanisms underlying gyrate atrophy: Why is the retina primarily affected? Acta Ophthalmologica. 2025;103:e436-e455.
Guan W, Wang G, Hu F, Peng X. Partial regression of foveoschisis following vitamin B6 supplementary therapy for gyrate atrophy in a Chinese girl. BMC Ophthalmology. 2021;21:93.
Jena S, Tripathy K, Chawla R, Mansour AM. Ultrawide field imaging to document the progression of gyrate atrophy of the choroid and retina over 5 years. BMJ Case Rep. 2021;14:e244695.
Kaczmarczyk A, Baker M, Diddle J, et al. A neonate with ornithine aminotransferase deficiency; insights on the hyperammonemia-associated biochemical phenotype of gyrate atrophy. Mol Genet Metab Rep. 2022;31:100857.