Molecular and cellular mechanisms underlying gyrate atrophy: Why is the retina primarily affected?

Abstract

Gyrate atrophy of the choroid and retina (GACR; OMIM #258870) is a rare early-onset autosomal recessive disorder, caused by bi-allelic pathogenic variants in the gene coding for ornithine aminotransferase (OAT) resulting in hyperornithinaemia. Clinically, GACR is characterized by the concentric loss of visual fields due to progressive chorioretinal atrophy. Because OAT is systemically expressed, it is not clear why primarily the retina is damaged in GACR patients. In this review, we first provide an extensive overview of the clinical features and current treatment modalities for GACR. Next, we discuss the different pathways involved in ornithine metabolism, including the urea cycle, polyamine synthesis, creatine synthesis, proline synthesis and degradation and provide our vision on how OAT deficiency is thought to affect these pathways in the retinal pigment epithelium (RPE). We provide several hypotheses to explain the retinal pathology observed in GACR and discuss perspectives on future research.