Volume 37, Issue 1

Inherited retinal diseases are clinically and genetically highly heterogeneous conditions with many phenotypic overlaps, syndromic presentations and atypical manifestations. This article is a narrative review that offers an overview of the technical advancements improving the accuracy and efficiency of molecular genetic diagnostics for hereditary disorders in clinical practice. It focuses particularly on the integration of whole genome sequencing (WGS) into routine diagnostics, critically evaluating its potential by discussing recent data from cohort studies conducted worldwide.

Inherited retinal dystrophies and optic neuropathies (IRD) are the most frequent cause for vision loss in the working age. The huge variability of phenotypes and initial clinical presentation frequently delay the ophthalmologic diagnosis. The most frequent phenotypes are retinitis pigmentosa, macular dystrophies, cone-rod dystrophies and syndromes associated with IRDs. Causative gene variants have been identified in more than 300 genes, with a frequency variation between different ethnicities. In this series of 1 914 patients seen in Germany between 1995 and 2024, in 47.4 % of families the genetic background could be solved. Even with a common genotype, the phenotype can be variable. Genetic diagnostic testing is important for the correct diagnosis, for patient selection for current or future therapies, but also from the patient perspective.

Stargardt disease type 1 (STGD1) is caused by biallelic pathogenic variants in ABCA4 . These variants vary in their effect on the resulting protein and the disease phenotype. Not all variant combinations cause disease, which complicates the determination of the recurrence risk of STGD1. Previously, the recurrence risk of STGD1 was estimated by analyzing variants in patient data and using their population variant frequencies in which white patients are overrepresented. Furthermore, assuming that variant effects are independent of genetic ancestry, estimates were made for each gnomAD population. In this article, the effects of missing heritability, de novo variants, reduced penetrance of variants and sex/gender are incorporated and discussed.

Age-related macular degeneration (AMD) is a leading cause of visual impairment with the risk of developing the disease influenced by a combination of genetic and environmental factors. With the recent expansion of treatment options, enhancing diagnostic accuracy and improving access to treatment are increasingly becoming the focus of interest. By using data from genome-wide association studies (GWAS) to generate polygenic risk scores (PRS), an assessment of an individual’s genetic risk for AMD is feasible. While the predictive accuracy of the AMD-PRS is most robust for individuals at very high genetic risk, genetic diagnostic testing is warranted due to the large number of affected individuals resulting from the high prevalence of AMD. Early genetic confirmation of AMD-related pathology can facilitate timely treatment initiation, potentially improving patient outcomes.

Visual impairment is a severe global health problem. Underlying ocular diseases can affect both the anterior and posterior eye. Unfortunately, the efficient delivery of drug molecules to the posterior eye, especially the retina, is still a major challenge. This review provides an overview of the difficulties and limitations of current delivery options for the treatment of eye diseases in the light of drug nanotherapy. Furthermore, ocular changes that are relevant for nanotherapeutic approaches are illustrated using the example of diabetic retinopathy (DR). The therapeutic focus is on promising approaches of using nanoparticles (NP) for the therapy of the posterior segment of the human eye. The overall aim of this review is to scrutinize how NP could fill gaps in the field of ocular drug therapy.

RPE65 biallelic mutation-associated inherited retinal degeneration (IRD) is currently the only IRD for which gene therapy is approved. This narrative review provides a brief overview of the disease and an update of the current literature on outcomes following the approval of treatment with voretigene neparvovec (LuxturnaTM) in 2017 (USA) and Europe (2018). Post-marketing results confirm a significant therapeutic effect of this gene augmentation on rod function similar to that seen in the phase 1 to 3 clinical trials. The full-field chromatic light sensitivity test is an appropriate test to demonstrate early and sustained effects of treatment. Visual acuity and visual fields may improve in less advanced disease. Accelerated chorioretinal atrophy (CRA) is a previously unrecognised adverse effect that is now reported in 13 % to 50 % of treated eyes. If central, visual acuity loss and paracentral visual field defects may occur. Further studies are needed to identify patients at risk of CRA in order to maximize patient benefit from a costly intervention.

Leber’s hereditary optic neuropathy (LHON) is the most common mitochondrial disease, and was the first to be linked to mitochondrial DNA (mtDNA) variations. Recently, autosomal recessive forms of LHON were described in addition to the classical mtDNA-associated forms. Clinically, LHON manifests with subacute and painless loss of central visual acuity, in most cases starting unilaterally, and involving the second eye a few weeks later. Almost all LHON cases are caused by pathogenic variants in genes that code for proteins relevant for function of Complex I of the respiratory chain. The Complex I dysfunction in LHON leads to decreased ATP synthesis and to increased production of reactive oxygen species which ultimately initiates dysfunction and apoptosis of retinal ganglion cells and their axons, the optic nerve. Idebenone, a synthetic CoQ derivative, is a potent intramitochondrial antioxidant and can shuttle electrons directly to complex III of the respiratory chain, thereby bypassing complex I deficiency. On the basis of several clinical trials, it has been approved as a treatment for LHON in 2015 (in the EU). In addition, direct intravitreal gene replacement therapy is being investigated, with several late-stage clinical trials already completed. In the future, gene editing of mtDNA variants may also become a therapeutic option.