Gyrate Atrophy

Actionability Pediatric Summary Report

Secondary Findings in Pediatric Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Gene: OAT (HGNC:8091)
• Literature Search: 06/29/2020
• Curation Status: Released (1.0.3)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
OAT	ornithine aminotransferase deficiency (0009796)	258870	Moderate Actionability

Actionability Assertion Rationale

• There was some variability in the final assertion between moderate and strong. The consensus decision was to assert moderate because the penetrance is based on a selected population; and due to the rarity of the disease, the evidence for effectiveness was limited to a single small observational study. Two scorers supported an assertion of strong because this is a very rare disease, and there is a biochemical test, and an available, effective treatment.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Visual impairment / Dietary management including arginine restriction and vitamin/amino acid supplementation	2	3C	2C	3	10CC

Severity of Outcome

Prevalence of the Genetic Condition

Gyrate atrophy (GA) is a very rare condition, with just over 200 biochemically confirmed cases reported in the international literature. The incidence is highest in Finland, with an estimated frequency of 1:50,000 individuals and an estimated frequency for heterozygotes of 1:110 individuals but cases have been reported worldwide.

Clinical Features (Signs / symptoms)

GA due to deficiency of the enzyme ornithine aminotransferase (OAT) is characterized by a triad of progressive chorioretinal degeneration, early cataract formation, and type II muscle fiber atrophy. GA first presents as night blindness and constriction of the visual field caused by sharply demarcated circular areas of chorioretinal atrophy in the periphery. Atrophic areas progressively increase, coalesce, and spread towards the macula leading to central visual loss and blindness (vision less than 20/200). The exact mechanism leading to chorioretinal atrophy is unknown. Other ocular manifestations include myopia with astigmatism, macular changes (e.g., cystoid macular edema, intraretinal cystic spaces), and vitreoretinal complications. Some patients may also have intellectual disability, speech defects aggressive behavior, or epilepsy. Occasional central and peripheral nervous system abnormalities and muscular weakness have also been reported.

Natural History (Important subgroups & survival / recovery)

Age at diagnosis ranges from 1 month to 44 years. The condition is characterized by the development of chorioretinal atrophic patches that start in the mid-peripheral retina in the first decade of life. Myopia, night blindness, changes in the macula (including cystic changes), and visual field affection usually start in the first or second decade. Most patients with GA have posterior subcapsular cataracts by the end of the second decade. Irreversible loss of vision and blindness generally occurs between 40 and 55 years of age but is highly variable. Some studies have shown that females may retain larger visual fields when compared to males. One study comparing the natural history of Japanese patients to Finnish patients found worse visual function in Japanese patients, suggesting that the natural history of the condition may vary between populations.

Likelihood of Outcome

Mode of Inheritance

Autosomal recessive

Prevalence of Genetic Variants

The population prevalence of OAT pathogenic variants was unavailable.

Based on historical case series, all defects causing gyrate atrophy appear to be in the OAT gene.

Tier 3

Penetrance (Includes any high-risk racial or ethnic subgroups)

Small historical cross-sectional studies of patients (n=7-40 patients, age ranges from 7-47 years, follow-up between 1.6-13.4 years) with GA reported the following clinical observations:

Ocular Findings

• Varying degrees of posterior sutural cataracts: 14/14 patients, 27/28 lenses (96-100%)

• Pigment epithelial defects: range from 3/10 (30%) to 17/21 patients (81%)

• Optic disc drusen (proteinaceous calcified nodules): 3/21 patients (14%)

• Macular involvement: 9/21 patients (43%)

• Peripapillary atrophy (bilateral, varying sizes): 12/21 patients (57%, all adults)

• Disturbed function of the neural retina: 10/10 patients (100%)

Peripheral Neuropathy

• Symptomatic neuropathy not considered disabling (paresthesias, abnormal sensations in hands and /or feet): 4/40 (10%)

• Type II muscle fiber atrophy: 7/7 (100%), based on biopsy of thigh muscle

• Affected muscles in the lower extremities and gross fatty changes: 7/7 (100%)

Central Nervous System Abnormalities

• Focal epileptiform activity: 6/33 (18%) of patients, including 5 of the 8 youngest patients (4-15 years of age).

Tier 3

Relative Risk (Includes any high-risk racial or ethnic subgroups)

No information on relative risk was identified.

Expressivity

Age at diagnosis is highly variable. High phenotypic variability is noted among patients even within the same family, as well as variable disease progression.

Tier 4

A cross-sectional study of 35 Finnish subjects with GA carrying the Finnish founder pathogenic variant L402P (homozygous or compound heterozygous) found that severity of the ophthalmologic symptoms and signs and the clinical course of disease varied markedly between subjects, even in the same age group.

Tier 5

Intervention Effectiveness

Patient Management

Proper management of GA requires a multidisciplinary team of pediatricians, ophthalmologists, neurologists, geneticists, dieticians, and other health professionals.

Tier 4

The following evaluations are recommended upon diagnosis of GA, with follow-up every 1-2 years:

• A thorough ocular and medical history including current ocular needs and medications, and history of retinotoxic medication use

• Family history of eye disease

• Clinical eye examination including visual acuity tests, biomicroscopy, measurement of intraocular pressure, and dilated indirect ophthalmoscopy

• Imaging, including:

- Colored or wide-field fundus photography (wide-field imaging is preferred for patients based on symptoms)

- Spectral domain optical coherence tomography

- Fundus and infrared (when available) autofluorescence

• Visual field testing including kinetic, static and microperimetry (when available)

• Full-field electroretinography (ERG) when appropriate.

Tier 2

Pediatric patients may require modified testing regimens and/or sedation for accurate assessment. Depending on their age and ability to cooperate, tests data may be unreliable or of limited information. Sedation may be considered, but functional changes such as reduction in the ERG, might be induced by sedation. The reliability of visual fields in children less than 7 years old may be insufficient.

Tier 2

Treatment of GA consists mainly of dietary modifications to help lower elevated systemic ornithine levels. Restriction of dietary arginine, a precursor of ornithine, appears to have therapeutic value. Pediatric patients undergoing arginine restriction should receive enough calories in their diet supplemented by essential amino acids, vitamins, and minerals to avoid malnutrition and excessive break down of endogenous proteins.

Tier 3

A study of two unrelated sibling pairs followed for 16-17 years found that the sibling from each pair who was prescribed an arginine-restricted diet at an earlier age demonstrated a slower progression of chorioretinal lesions.

Tier 3

A long-term observational study of 27 patients with GA, 17 who complied with the arginine-restricted diet and 10 who were noncompliant, found that at 14 years follow-up the rates of vision loss were significantly slower in the compliant group for 3 of the 4 outcome measures, when adjusted for age.

Tier 5

Additional small studies support these positive findings; however, some patients continue to develop progressive chorioretinal degeneration and electroretinographic changes despite lowered plasma ornithine levels following arginine restriction.

Tier 3

Some patients may benefit from vitamin or amino acid supplementation. Pyridoxine (vitamin B6) supplementation (120-600 mg/day) is thought to help stimulate residual OAT activity. Pyridoxine may occasionally slow progressive chorioretinal degeneration, but small historical studies (a trial of 2 patients and several case reports) reported inconsistent findings. Additional small studies found that most patients are not responsive to pyridoxine, which may be variant specific.

Tier 3

Creatine supplementation may also slow chorioretinal degeneration and improve neurological and muscular manifestations.

Tier 3

A series of 7 patients who underwent creatine supplementation reported a reduction in the number of abnormal type II skeletal muscle fibers at 1 year. At 3 months, central vision loss was halted and visual acuity stable in most patients. A separate study of creatine supplementation in 13 patients followed for 5 years (age 6-31 years) also found that abnormalities in type II skeletal fibers decreased or disappeared (reappearing in the 2 patients who discontinued the supplementation), but all patients showed progression of chorioretinal atrophy. In addition, visual acuity declined or was unchanged, visual fields were constricted or unchanged, and lens opacity developed in most patients. Creatine supplementation in another series of 4 patients (8-15 years) reported central nervous system findings similar to those of 23 untreated patients.

Tier 3

Proline and lysine supplementation may also be of benefit. One historical trial of 4 patients treated with proline supplementation reported mixed ophthalmologic findings.

Tier 3

Care should also include monitoring for co-morbidities and other system involvement, as well as providing supportive services such as low-vision training, with treatments targeting different stages of the degenerative process. Physicians should encourage low vision rehabilitation, work with school personnel, and advocate for mobility training. Patients should be informed of registries and research in the field, including clinical trials.

Tier 2

Surveillance

No recommendations regarding surveillance were identified.

Circumstances to Avoid

Food rich in arginine should be avoided or reduced, including nuts, seeds, cereal, dairy products, seafood, meat, chicken, watermelon, and chocolate.

Tier 3

Nature of Intervention

Nature of Intervention

Initial evaluations and follow-up by way of ophthalmic screening is recommended for all patients with GA. Although these evaluations are not invasive, they are extensive, must be performed at a minimum every 2 years, and are life-long.

Context: Adult Pediatric

Pediatric patients may require modified testing regimens and/or sedation for accurate assessment. Depending on the child’s age and ability to cooperate, tests may provide data that is unreliable or of limited information. The risk of sedation must be weighed against the value of the information gained at the specific age.

Context: Pediatric

Supplementation therapy for GA is administered daily and likely to be life-long. Lack of compliance with creatine supplementation may result in reappearance of symptoms upon discontinuation of therapy. Dosing has not been firmly established for any of the supplements recommended.

Context: Adult Pediatric

Chance to Escape Clinical Detection

If not detected in early stages, can be confused with other forms of chorioretinal degeneration.

Context: Adult Pediatric

Tier 3

The age at diagnosis for GA can be highly variable (1 month - 44 years) and early diagnosis and successful treatment are important prognostic factors.

Context: Adult Pediatric

Tier 4

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			OAT			258870	0009796

References List

American Academy of Ophthalmology (AAO). Recommendations on Clinical Assessment of Patients with Inherited Retinal Degenerations. AAO Clinical Statement.. (2016) Accessed: 2020-06-29. URL: https://www.aao.org/clinical-statement/recommendations-on-clinical-assessment-of-patients

Elnahry AG, Tripathy K. (2020) Gyrate Atrophy Of The Choroid and Retina. StatPearls.

GYRATE ATROPHY OF CHOROID AND RETINA; GACR. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 258870, (2016) World Wide Web URL: http://omim.org/

Gyrate atrophy of choroid and retina. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=414

Kaiser-Kupfer MI, Caruso RC, Valle D, Reed GF. (2004) Use of an arginine-restricted diet to slow progression of visual loss in patients with gyrate atrophy. Archives of ophthalmology (Chicago, Ill. : 1960). 122(0003-9950):982-4.

Peltola KE, Näntö-Salonen K, Heinonen OJ, Jääskeläinen S, Heinänen K, Simell O, Nikoskelainen E. (2001) Ophthalmologic heterogeneity in subjects with gyrate atrophy of choroid and retina harboring the L402P mutation of ornithine aminotransferase. Ophthalmology. 108(0161-6420):721-9.