Ophthalmology – Gyrate Atrophy

Basics

Description

Gyrate atrophy of the choroid and retina is a rare, progressive autosomal recessive chorioretinal dystrophy caused by deficiency of the enzyme ornithine aminotransferase (OAT).

The disease typically begins during the first decade of life with:

• Nyctalopia
• Progressive loss of peripheral vision
• High myopia
• Progressive visual-field constriction

Characteristic sharply demarcated areas of peripheral chorioretinal atrophy gradually enlarge and coalesce. With advancing disease, the atrophy progresses toward the posterior pole, eventually resulting in loss of central vision.

Epidemiology

Gyrate atrophy is rare worldwide.

The highest reported prevalence is in Finland, where its frequency has been estimated at approximately 1 in 50,000.

Clinical manifestations usually begin during the first decade of life.

Risk Factors

The principal risk factor is inheritance of pathogenic mutations affecting ornithine aminotransferase.

Although the disorder occurs worldwide, a particularly large number of affected patients have historically been reported in Finland.

Genetics

Gyrate atrophy has an autosomal recessive inheritance pattern.

The responsible OAT gene is located on chromosome 10q26.

Numerous pathogenic variants have been identified.

Genetic counseling is appropriate for affected patients and their families.

Pathophysiology

The fundamental abnormality is deficiency of ornithine aminotransferase (OAT), a mitochondrial enzyme involved in ornithine metabolism.

OAT deficiency produces a dramatic elevation in circulating ornithine.

Plasma ornithine concentrations are typically approximately 10–20 times normal.

The markedly elevated ornithine concentration is believed to exert a toxic effect on the retinal pigment epithelium (RPE) and associated chorioretinal structures.

Progressive degeneration consequently involves:

• Retinal pigment epithelium
• Choriocapillaris
• Photoreceptors
• Other retinal structures as disease advances

The result is progressive chorioretinal atrophy and deterioration of retinal function.

Etiology

The disease results from OAT enzyme deficiency caused by pathogenic variants in the OAT gene.

The resulting hyperornithinemia is central to the development of retinal degeneration.

Commonly Associated Conditions

Although the ophthalmic manifestations dominate the clinical picture, systemic abnormalities have occasionally been reported.

These include:

• EEG abnormalities
• Hair abnormalities
• Skeletal muscle abnormalities demonstrated by CT or MRI
• Cerebral white-matter abnormalities
• Cerebral atrophy on MRI

Diagnosis

History

First Decade

Patients usually initially develop:

• Night blindness
• Decreased peripheral vision
• Myopia
• Astigmatism

Nyctalopia is frequently among the earliest manifestations.

Second Decade

During adolescence, patients commonly develop posterior subcapsular cataracts.

Later Disease

Progressive retinal degeneration causes increasingly severe constriction of the visual field.

Central visual acuity is initially relatively preserved but gradually deteriorates as the chorioretinal atrophy advances toward the posterior pole.

Significant central visual loss commonly develops by middle age.

Physical Examination

Refractive Error

Virtually all affected patients are myopic.

The degree of myopia may be substantial, historically reported in the approximate range of:

−4.00 to −20.00 D

Astigmatism is also common.

Lens Findings

Posterior subcapsular cataracts commonly become apparent by adolescence or early adulthood.

They may contribute substantially to visual deterioration but do not account for the progressive peripheral visual-field loss.

Fundus Findings

The funduscopic appearance is highly characteristic.

Early disease demonstrates multiple, sharply demarcated, round areas of chorioretinal atrophy involving the peripheral and midperipheral retina.

The abnormalities are typically:

• Bilateral
• Relatively symmetric
• Well circumscribed
• Initially separated by areas of relatively preserved retina

With time, individual areas of atrophy enlarge and coalesce.

The boundary between normal and atrophic retina characteristically develops a scalloped or gyrate appearance, giving the disease its name.

As the disorder progresses, chorioretinal atrophy extends centripetally toward the posterior pole.

In advanced disease, most or essentially all of the fundus may become involved.

Diagnostic Tests and Interpretation

Plasma Ornithine

Measurement of plasma ornithine concentration is a key diagnostic investigation.

Levels are generally approximately 10–20 times above normal.

Marked hyperornithinemia in a patient with the characteristic fundus appearance strongly supports the diagnosis.

Molecular genetic testing of the OAT gene can provide definitive genetic confirmation.

Fluorescein Angiography

Fluorescein angiography typically demonstrates hyperfluorescence corresponding to areas of chorioretinal atrophy.

There may also be leakage near the transition between preserved and atrophic retinal tissue.

Optical Coherence Tomography

OCT is useful for evaluating the macula and documenting structural complications.

Potential findings include:

• Progressive retinal thinning and atrophy
• Cystoid macular edema
• Epiretinal membrane
• Outer retinal and RPE abnormalities

Electroretinography

ERG abnormalities develop early.

Initially, both:

• Scotopic responses
• Photopic responses

are reduced.

This indicates dysfunction involving both rod and cone systems.

As retinal degeneration progresses, ERG amplitudes continue to decline.

In advanced adulthood, ERG responses may become nondetectable.

Differential Diagnosis

The major differential diagnosis is choroideremia.

Choroideremia

Choroideremia also produces progressive degeneration of the choroid, RPE, and retina with nyctalopia and peripheral visual-field loss.

However, it is typically X-linked, primarily affecting males, whereas gyrate atrophy is autosomal recessive.

The characteristic scalloped lesions and markedly elevated plasma ornithine strongly support gyrate atrophy.

Other inherited retinal/choroidal dystrophies may also enter the differential diagnosis depending on the phenotype.

Treatment

There is currently no treatment that reliably reverses established chorioretinal atrophy.

The primary therapeutic strategy is to reduce plasma ornithine concentrations in an attempt to slow retinal degeneration.

Dietary Treatment

Low-Arginine Diet

A low-protein, arginine-restricted diet is the principal long-term treatment.

Arginine restriction reduces the amount of substrate available for production of ornithine and consequently lowers plasma ornithine concentrations.

Long-term dietary treatment may slow progression of chorioretinal degeneration, particularly when initiated early.

Evidence from affected siblings suggests that patients beginning dietary restriction at a younger age may experience slower progression than siblings beginning treatment later.

However, retinal degeneration may continue despite excellent dietary compliance.

Because substantial protein restriction can have nutritional consequences, dietary therapy should be supervised by clinicians and dietitians experienced in metabolic disease.

Pyridoxine Therapy

Some patients demonstrate biochemical responsiveness to vitamin B6 (pyridoxine).

Pyridoxine acts as a cofactor for ornithine aminotransferase and may increase residual enzyme activity in responsive mutations.

However, most patients are not pyridoxine responsive.

A therapeutic trial may therefore be considered with monitoring of plasma ornithine levels to determine whether a meaningful biochemical response occurs.

Cataract Treatment

Visually significant posterior subcapsular cataracts may be treated with cataract extraction.

Patients should be counseled that cataract removal addresses only the lenticular component of their visual impairment.

Postoperative visual potential may remain substantially limited by the underlying retinal and choroidal degeneration.

Ongoing Care

Follow-Up Recommendations

Gyrate atrophy is a lifelong progressive disease.

Regular ophthalmic follow-up should assess:

• Visual acuity
• Refraction
• Visual fields
• Cataract progression
• Macular status
• Extent of chorioretinal atrophy
• Development of cystoid macular edema or epiretinal membrane

Serial retinal imaging and functional testing can help document progression.

Patient Monitoring

Plasma ornithine levels should be monitored when dietary or pyridoxine therapy is being used.

Patients undergoing significant dietary protein and arginine restriction require appropriate nutritional supervision to ensure adequate growth and general health, particularly during childhood.

Patient Education

Patients and families should understand that gyrate atrophy is a hereditary and progressive retinal disease.

Early recognition is important because dietary reduction of ornithine may slow progression, particularly when treatment begins during childhood.

Genetic counseling should be offered to affected individuals and their families.

Low-vision rehabilitation should be considered as visual impairment progresses.

Prognosis

The long-term visual prognosis is generally poor.

The typical progression is:

Nyctalopia in childhood → peripheral chorioretinal atrophy → progressive visual-field constriction → posterior pole involvement → central visual loss

Despite treatment, retinal function usually continues to decline, although early and sustained reduction of plasma ornithine may slow the rate of progression.

Key Ophthalmology Points

Gyrate atrophy = OAT deficiency + hyperornithinemia + progressive scalloped chorioretinal atrophy.

The classic diagnostic combination is childhood nyctalopia, high myopia, sharply demarcated scalloped areas of peripheral chorioretinal atrophy, and plasma ornithine levels approximately 10–20 times normal.

Treatment centers on early arginine restriction, with a trial of pyridoxine in potentially responsive patients.