RPE Abnormality Is a Potential Primary Cause for Retinal Degeneration in Mucopolysaccharidosis Type VI Patients and a Rat Model.

Purpose: Mucopolysaccharidosis type VI (MPS VI) is a rare autosomal recessive lysosomal storage disorder caused by pathogenic variants in ARSB, leading to deficiency of N-acetylgalactosamine 4-sulfatase and accumulation of glycosaminoglycans. Although enzyme replacement therapy (ERT) alleviates systemic symptoms, its efficacy for ocular complications is limited. Because ocular manifestations may require distinct therapeutic approaches, a precise understanding of the underlying retinal pathology is essential. This study aimed to characterize ocular and retinal involvement in MPS VI through clinical and experimental analyses. Methods: Comprehensive ophthalmic examinations were performed in siblings with MPS VI, and histological and electrophysiological assessments were conducted in an MPS VI rat model. Retinal morphology, retinal pigment epithelium (RPE) integrity, and electroretinographic responses were evaluated. Results: In patients, no apparent photoreceptor degeneration was detected, although subtle functional impairment could not be excluded. Consistently, MPS VI rats exhibited preserved photoreceptor structures but reduced electroretinogram amplitudes. Although RPE abnormalities were not evident in patients, rats showed pronounced RPE alterations, suggesting RPE involvement as a potential origin of retinal dysfunction. Conclusions: Our findings suggest that retinal dysfunction in MPS VI may primarily arise from RPE pathology rather than photoreceptor loss. Detailed retinal evaluations in aging patients are warranted, and therapeutic approaches targeting the RPE, such as localized ERT or RPE cell transplantation may provide future benefits.