Inherited retinal diseases natural history: Understanding different genetic pathways of photoreceptor degeneration and their phenotypic biomarkers

Abstract

Purpose:

Inherited retinal disease (IRD) refers to a genetically heterogenous group of blinding conditions caused by pathogenic variants in the genes responsible for classical photoreceptor and/or retinal pigment epithelial function. This thesis aims to find the correlation between genotype and phenotype in IRD and to search for the best biomarkers for monitoring disease progression and evaluating responses to therapy.

Methods:

A retrospective review of IRD patients, assessing the best corrected visual acuity (BCVA), fundus photography, spectral domain-optical coherence tomography (SD-OCT), electroretinography (ERG), and perimetry.

Results:

The specific pathophysiology of MERTK- and IMPDH1-associated retinopathy explains the concurrent rod and cone disturbance leading to rod-cone dystrophy with early cone involvement. On the other hand, the pathophysiology of KCNV2-and CLN3-associated retinopathy explains the cone-prone degeneration leading to cone-rod dystrophy or cone dystrophy. We identified some potential gene-specific biomarkers: ellipsoid zone (EZ) length in MERTK-associated retinopathy; EZ and fundus autofluorescence (FAF) in CLN3-disease; ffERG with focus on b-wave amplitude jump, a-wave and b-wave peak time delay, and the b:a ratio in KCNV2-associated retinopathy are the proposed potential biomarkers to monitor the diseases. No specific biomarkers were found in IMPDH1-associated retinopathy. However, we found that the exon 10 in the IMPDH1 gene is the locus of pathogenic variants and should be the target of future therapeutical trials. ERG abnormalities preceded the visual or retinal structural changes in the assessed IRD conditions and composed at least half of the proposed biomarkers.

Conclusion:

Different genes lead to different pathogenic pathways of IRD. Specific biomarkers are needed for monitoring disease progression and evaluating future therapy. Electrophysiology remains crucial in assisting the diagnosis of IRD.