Macular dystrophies: clinical and imaging features, molecular genetics and therapeutic options

Abstract

Macular dystrophies (MDs) consist of a heterogeneous group of disorders that are characterised by bilateral symmetrical central visual loss. Advances in genetic testing over the last decade have led to improved knowledge of the underlying molecular basis. The developments in high-resolution multimodal retinal imaging have also transformed our ability to make accurate and more timely diagnoses and more sensitive quantitative assessment of disease progression, and allowed the design of optimised clinical trial endpoints for novel therapeutic interventions. The aim of this review was to provide an update on MDs, including Stargardt disease, Best disease, X-linked r etinoschisis, pattern dystrophy, Sorsby fundus dystrophy and autosomal dominant drusen. It highlights the range of innovations in retinal imaging, genotype–phenotype and structure–function associations, animal models of disease and the multiple treatment strategies that are currently in clinical trial or planned in the near future, which are anticipated to lead to significant changes in the management of patients with MDs.

Clinical and genetic characteristics of 10 Japanese patients with PROM1‐associated retinal disorder: A report of the phenotype spectrum and a literature review in the Japanese population

“…There are genes that are associated with different phenotypes of CORD/COD/MD and RP; EYS , CRX , PRPH2, GUCY2D , and RP1L1 (Ba‐Abbad et al, 2019; Bouzia et al, 2020; Davidson et al, 2013; Fujinami‐Yokokawa et al, 2019, 2020; Fujinami et al, 2019; Hull et al, 2014; Katagiri et al, 2018; Koyanagi et al, 2019; Liu et al, 2020; Nakamura et al, 2019; Oishi et al, 2014, 2016; L. Yang et al, 2020). Moreover, different inheritances such as autosomal dominant (AD) and autosomal recessive (AR) are associated with differences in phenotypes (Bouzia et al, 2020; Fujinami‐Yokokawa et al, 2020; Gill et al, 2019; Hull et al, 2014; Liu et al, 2020; Rahman et al, 2020).…”

KCNV2 retinopathy: clinical features, molecular genetics and directions for future therapy

“…Phenotypic studies suggest that there is indeed relative structural preservation of retinal architecture and intact phototransduction ( 16 , 20 , 21 , 52 ). Multiple gene therapy trials for IRDs are ongoing ( 48 , 64 – 67 ), with the first approved gene therapy for RPE65- RD now available (NCT00999609). Further pre-clinical work in animal models and iPSC-derived models is needed to explore safety, efficacy and dosing of potential gene or drug therapy to facilitate translation to human clinical trials.…”

Analysis of retinal sublayer thicknesses and rates of change in ABCA4-associated Stargardt disease

“…Further studies using cellular imaging (e.g., adaptive optics) may shed further light onto the sequence of photoreceptor and RPE cell loss in STGD1 48,49 . Numerous clinical trials of gene therapy and stem cell therapy for Stargardt disease are currently underway, and inclusion of easily-acquired, objective measures of disease progression or treatment response remain critically needed [50][51][52][53][54] . Due to the relatively slow progression of STGD1 and the variability in foveal involvement, it is difficult to follow disease progression in clinical trials using best-corrected visual acuity 55 , and measurements are sometimes limited by ability to fixate and by changes in fixation location 56 .…”