Clinical, biochemical and molecular analysis in a cohort of individuals with gyrate atrophy

**Background:** Gyrate atrophy of the choroid and retina is a rare autosomal recessive metabolic disorder caused by biallelic pathogenic variants in the OAT gene, leading to hyperornithinaemia and progressive chorioretinal degeneration. Current treatment options are limited, primarily involving a low-protein diet with amino acid supplementation, but compliance is often poor. This study aimed to describe the clinical, biochemical, and molecular findings in a cohort of individuals with gyrate atrophy.

**Methods:** Study participants were retrospectively ascertained through the North West Genomic Laboratory Hub, Manchester, UK, and diagnosed through tertiary clinics at Manchester University NHS Foundation Trust and Salford Royal NHS Foundation Trust. All cases had a biochemical and molecular diagnosis of gyrate atrophy. Retrospective phenotypic and biochemical data were collected using electronic healthcare records. Ophthalmic assessments included fundus imaging (widefield, autofluorescence, OCT, OCT-A). Blood samples were analyzed for plasma ornithine and lysine levels, and genetic testing was performed using multigene panel analysis.

**Key Results:** 18 affected individuals from 12 families (8 male, 10 female) were included. The median age at diagnosis was 8 years (range 10 months – 33 years). All had hyperornithinaemia (median 800 µmol/L; range 458–1244 µmol/L; normal 40–150 µmol/L). Common presenting features were high myopia (10/18) and nyctalopia (5/18). Ophthalmic symptoms were present in all participants above age 6 years. One third (6/18) had macular oedema, and two thirds (12/18, 66.6%) developed pre-senile cataracts; 7 underwent cataract surgery at median age 27.5 years. Median visual acuity at last assessment was 0.36 LogMAR (range 0.0–0.7). Extraocular features included developmental delay (6/18, 33%) and reduced fat-free mass (9/11 assessed). Dietary compliance was suboptimal: 6 patients did not restrict protein at all. Among those who restricted protein (n=8), median plasma ornithine decreased by 22% (from 764.5 to 597 µmol/L) over 5 years, compared to a 7% decrease in non-restrictors (n=6). Visual acuity was better in the diet-restricted group (median 0.34 LogMAR vs 0.45 LogMAR), but no significant difference in change over time was observed between groups. A statistically significant decline in visual acuity was noted in non-restrictors over 11 years (p=0.025). Genetic analysis revealed 14 different OAT variants, including 5 novel changes (c.520+1G>A, c.648G>C, c.941T>G, c.1009dupC, c.1208T>C).

**Clinical Implications:** This study highlights the high prevalence of secondary ophthalmic complications (macular oedema, cataracts) and extraocular features (developmental delay, reduced fat-free mass) in gyrate atrophy. Dietary protein restriction appears to lower plasma ornithine and may be associated with better visual outcomes, but compliance remains a major challenge. The findings support the need for multidisciplinary care, standardized imaging protocols, and early dietary intervention. The identification of novel OAT variants expands the genetic spectrum. Future research should focus on improving treatment adherence and developing novel therapies, including gene-based interventions.