Novel Insights Into Gyrate Atrophy of the Choroid and Retina (GACR): A Cohort Study

Abstract

Gyrate atrophy of the choroid and retina (GACR, OMIM #258870) is a rare inherited metabolic disorder characterized by progressive chorioretinal degeneration and hyperornithinemia. Current therapeutic modalities potentially slow disease progression but are not successful in preventing blindness. To allow for trial development, increased knowledge of the clinical phenotype and current therapeutic outcomes is required. In this study, we analyzed 27 patients with GACR. The median age at inclusion was 24 years (range 8-58), with a median age at diagnosis of 14 years (range 0-42). Symptoms began at a mean age of 9 years (range 0-21). Mixed-models analysis showed a significant association between dietary natural protein intake and plasma ornithine levels. Ornithine increased significantly with age, independent of dietary natural protein intake. We found no statistically significant association between ornithine levels and best-corrected visual acuity over time. Patients who started a natural protein-restricted diet below 10 years of age had better VF outcomes compared to patients that started at a later age. MR spectroscopy was used to asses cerebral creatine deficiency, which was present in 15/20 patients, of whom 10 were supplemented with creatine at the time. Finally, using the Michigan Retinal Degeneration Questionnaire, we provided a first insight into the vision-related disability reported by patients with GACR and showed that higher foveal sensitivity was associated with less perceived disability. To conclude, this study provides insights into the phenotype, genotype, biochemistry, and treatment effects of GACR, which can be used for care pathways and clinical trial design.

FIGURE 1

Retinal color photography of the right eye (OD) of four individuals with GACR. (A) A 25‐year‐old patient with variable compliance that was diagnosed in childhood but did not adhere to therapy in the first decade of life. The retinal photograph shows patches of chorioretinal atrophy in the periphery of the retina. (B) An 11‐year‐old patient, the full sibling of patient A, that was diagnosed after birth and adhered to a natural protein‐restricted diet ever since. This patient had a completely normal retina upon retinal photography. (C) A 31‐year‐old patient diagnosed at 16 with variable compliance since. The retinal photography shows coalesced atrophic lesions both in the periphery as well as centrally. (D) A 40‐year‐old patient diagnosed at age 25. The retinal photography shows peripheral atrophic lesions with a small lesion surrounding the optic nerve and some residual central retinal tissue.

FIGURE 2

Plasma ornithine over time in patients with GACR with and without therapy. Different colors indicate different patients. Linear regression was used to draw regression lines for each individual patient. The dashed lines delineate the reference range for plasma ornithine in our reference laboratory (27 and 98 μmol/L). A scatterplot with individually plotted ornithine values can be found in the supplemental (Figure S1).

FIGURE 3

Plasma ornithine in patients on dietary protein restriction, with and without reported compliance struggles, compared to untreated patients. The dashed lines delineate the reference range for plasma ornithine in our reference laboratory (27 and 98 μmol/L). Plasma ornithine is significantly lower in all patients on dietary protein restriction, independent of compliance. Significance was tested using a one‐way ANOVA with Tukey's multiple comparison test. No correction for reported dietary protein intake was made. Values from P13 taken in the neonatal phase during hyperammonemia and reversed OAT flux were excluded from this analysis. **** = p‐value < 0.0001.