A survey of hereditary aspects of pigmentary retinal dystrophies

A study of 707 cases of retinitis pigmentosa and choroideraemia presenting over 12 years were classified according to their modes of inheritance-439 autosomal recessive (62%), 193 autosomal dominant (27%), 75 X-linked (10.7%). The patients with autosomal recessive transmission included 58 Usher syndrome, 12 Laurence-Moon-Bardet-Biedl syndrome and 33 Leber's congenital amaurosis. Another 37 had an early onset with macular degeneration and 31 were of late onset with pericentral dystrophy. Forty two were offspring of consanguineous parents. Of 193 individuals (78 families) with autosomal dominant inheritance, 20% had night blindness from early childhood. With X-linked transmission, 33 males and 31 female carriers comprised the retinitis pigmentosa group and eight males and three carrier females, choroideraemia. Almost all this X-linked group were of British ancestry. Of patients originating from the Mediterranean area, 94% had autosomal recessive disease.     

Prevalence of tapeto-retinal dystrophies among Danish children

Age specific prevalence rates are presented based on 110 cases of pigmentary retinopathy (RP) recorded in the Danish child population of a little over one million individuals on January 1, 1988.A steady and steep rise in age specific prevalences of notified RP throughout infancy and childhood was found. The material consisted in 52 non-systemic and 58 systemic cases. 35 of the systemic cases could be nosologically identified, leaving 23 cases unidentified with respect to known diseases or syndromes.Among the genetic types autosomal recessive inheritance was the most common with 60 cases (55%). Parental consanguinity was less frequent than hitherto reported. On the other hand undetected carrier state for X-linked tapeto-retinal dystrophy played a more significant role than expected. A clear excess of males among the simplex cases indicated that some X-linked cases may still be unrecognized.A significant proportion of non-systemic, early infantile RP with an autosomal recessive or simplex mode of inheritance are clinically and electrophysiologically characterised as cone-rod dystrophies.     

Retinal capillaritis in a CRB1-associated retinal dystrophy

Purpose: To report a case of CRB1-associated retinal dystrophy characterized by vitritis, retinal capillaritis, and cystoid macular edema (CME).

Methods: A case report.

Results: An 8-year-old boy was diagnosed with intermediate uveitis and treated with corticosteroids. He was subsequently diagnosed with retinal dystrophy and found to have two CRB1 mutations.

Conclusions: Retinal capillaritis, vitritis, and CME could be inflammatory features of CRB1 retinal dystrophy in our young patient.     

Reliability of kinetic visual field testing in children with mutation-proven retinal dystrophies: Implications for therapeutic clinical trials

Purpose: Kinetic visual field testing is used to monitor disease course in retinal dystrophy clinical care and treatment response in treatment trials, which are increasingly recruiting children. This study investigates Goldmann visual field (GVF) changes in young children with mutation-proven retinal dystrophies as they age and with progression of the retinal degeneration.

Methods: Retrospective review of children ≤ 17 years old with a mutation-proven retinal dystrophy. Objective clinical disease activity was assessed by a retinal degeneration specialist masked to GVF results. Digital quantification of GVF area was performed.

Results: Twenty-nine children (58 eyes), ages 5–16, were identified. GVF area increased with age despite progression in 20 children and clinical stability in nine children. Mean ± standard error increase in GVF area/year was 333 ± 130 mm² (I4e, p = 0.012), 720 ± 155 mm² (III4e, p < 0.001), and 759 ± 167 mm² (IV4e, p < 0.001), with greater increases at earlier ages. Repeatability coefficients were 7381 mm² (I4e), 9379 mm² (III4e), and 10346 mm² (IV4e), indicating a large variability. At 2.5 years after the baseline GVF the area increased ≥ 20%, the criterion for positive treatment outcome defined in recent published therapeutic trials, in 38% (I4e), 34% (III4e), and 33% (IV4e) of eyes.

Conclusion: In a substantial proportion of children with mutation-proven retinal dystrophies, there is a significant increase in GVF area with age, particularly those < 12 years, despite progression or stability of disease. These findings suggest that change in GVF area in children with retinal dystrophies can be an unreliable measure of response to treatment and on which to base appropriate counseling about visual impairment.     

Pattern dystrophies of the retinal pigment epithelium

Three members of a family in one generation were affected by a pattern dystrophy of the retinal pigment epithelium. The patients present typical hyperpigmented macular RPE lesions in a butterfly-shaped to (macro-)reticular pattern, and were all asymptomatic. Examination of 26 family members in 3 generations suggests autosomal recessive inheritance. The family showed some cases of congenital deutanomaly, and a female subject presented both disorders.     

Genetic testing for retinal dystrophies and dysfunctions: benefits, dilemmas and solutions

Human retinal dystrophies have unparalleled genetic and clinical diversity and are currently linked to more than 185 genetic loci. Genotyping is a crucial exercise, as human gene-specific clinical trials to study photoreceptor rescue are on their way. Testing confirms the diagnosis at the molecular level and allows for a more precise prognosis of the possible future clinical evolution. As treatments are gene-specific and the 'window of opportunity' is time-sensitive; accurate, rapid and cost-effective genetic testing will play an ever-increasing crucial role. The gold standard is sequencing but is fraught with excessive costs, time, manpower issues and finding non-pathogenic variants. Therefore, no centre offers testing of all currently 132 known genes. Several new micro-array technologies have emerged recently, that offer rapid, cost-effective and accurate genotyping. The new disease chips from Asper Ophthalmics (for Stargardt dystrophy, Leber congenital amaurosis [LCA], Usher syndromes and retinitis pigmentosa) offer an excellent first pass opportunity. All known mutations are placed on the chip and in 4 h a patient's DNA is screened. Identification rates (identifying at least one disease-associated mutation) are currently approximately 70% (Stargardt), approximately 60-70% (LCA) and approximately 45% (Usher syndrome subtype 1). This may be combined with genotype-phenotype correlations that suggest the causal gene from the clinical appearance (e.g. preserved para-arteriolar retinal pigment epithelium suggests the involvement of the CRB1 gene in LCA). As approximately 50% of the retinal dystrophy genes still await discovery, these technologies will improve dramatically as additional novel mutations are added. Genetic testing will then become standard practice to complement the ophthalmic evaluation.     

Pattern dystrophies of the retinal pigment epithelium

We describe a family that shows autosomal dominant pattern dystrophy of the retinal pigment epithelium. There were 10 affected family members encompassing three generations. The various manifestations of these dystrophies, their inheritance characteristics, affects on vision function and their pathogenesis are discussed.     

Tractional retinal detachment in Usher syndrome type II

Retinal detachment is a rare complication in patients with retinitis pigmentosa. A case is reported of tractional retinal detachment in a patient with retinitis pigmentosa and sensorineural hearing loss, which was diagnosed as Usher syndrome type II. Because of the poor visual prognosis, the patient refused surgery in that eye. Tractional retinal detachment should be added to the differential diagnoses of visual loss in patients with retinitis pigmentosa.     

程序性坏死与视网膜疾病相关性的研究进展

程序性坏死是由分子受体相互作用蛋白激酶1、分子受体相互作用蛋白激酶3和混合系激酶区域蛋白介导的一种不同于凋亡及传统坏死的细胞程序性死亡方式,可由肿瘤坏死因子受体或模式识别受体调控启动。越来越多的研究发现,程序性坏死在视网膜疾病发生和发展中起关键作用。本文将对程序性坏死的分子机制及程序性坏死与视网膜疾病相关性的研究进展进行综述,以帮助寻找治疗视网膜疾病的新靶点。     

Dominant ARL3-related retinitis pigmentosa

Purpose: To clinically and genetically characterise a second family with dominant ARL3-related retinitis pigmentosa due to a specific ARL3 missense variant, p.(Tyr90Cys).

Methods: Clinical examination included optical coherence tomography, electroretinography, and ultra-wide field retinal imaging with autofluorescence. Retrospective data were collected from the registry of inherited retinal diseases at Oslo university hospital. DNA was analysed by whole-exome sequencing and Sanger sequencing. The ARL3 missense variant was visualized in a 3D-protein structure.

Results: The phenotype was non-syndromic retinitis pigmentosa with cataract associated with early onset of decreased central vision and central retinal thinning. Sanger sequencing confirmed the presence of a de novo ARL3 missense variant p.(Tyr90Cys) in the index patient and his affected son. We did not find any other cases with rare ARL3 variants in a cohort of 431 patients with retinitis pigmentosa-like disease. By visualizing Tyr90 in the 3D protein structure, it seems to play an important role in packing of the α/β structure of ADP-ribosylation factor-like 3 (ARL3). When changing Tyr90 to cysteine, we observe a loss of interactions in the core of the α/β structure that is likely to affect folding and stability of ARL3.

Conclusion: Our study confirms that the ARL3 missense variant p.(Tyr90Cys) causes retinitis pigmentosa. In 2016, Strom et al. reported the exact same variant in a mother and two children with RP, labelled ?RP83 in the OMIM database. Now the questionmark can be removed, and ARL3 should be added to the list of genes that may cause non-syndromic dominant retinitis pigmentosa.     

Molecular genetics of central retinal dystrophies

A range of chorioretinal dystrophies that principally affect the central retina have recently been associated with either specific genetic mutations or mapped to refined genomic loci. Mutations of two genes, peripherin/RDS (chromosome 6p) and TIMP3 (chromosome 22q) have been shown to be of particular importance to this group of disorders. Other conditions such as Stargardt's disease, Best's disease, pattern dystrophy, cone dystrophy and cone-rod dystrophy have been mapped to different regions of the genome, however the underlying genetic mutations await identification. Molecular genetic diagnostic techniques are now available for a number of central choroidoretinal dystrophies allowing for earlier, accurate diagnosis and laying the groundwork for future studies of potential therapeutic protocols.     

Efficacy of topical brinzolamide in children with retinal dystrophies

ABSTRACT

Background: Inherited retinal dystrophies are a leading cause of irreversible blindness in children in the United States. Topical carbonic anhydrase inhibitors have improved central vision and cystoid macular edema in patients with retinal dystrophies, but few studies have assessed their efficacy in children.

Materials and Methods: A retrospective chart review was performed with Institutional Review Board approval to identify pediatric patients with inherited retinal dystrophies who received topical brinzolamide at a single university center between 2008 and 2015. Serial visual acuity and central macular thicknesses were compared to assess the efficacy of brinzolamide.

Results: Seven subjects were identified who met the inclusion criteria. Four had juvenile X-linked retinoschisis, two had retinitis pigmentosa, and one had Leber congenital amaurosis. All were prescribed brinzolamide thrice daily; however, one patient was completely non-compliant. Four of the six treated patients exhibited a mild decrease in central macular thickness in both eyes during the study with all six treated patients having significantly improved vision at the first endpoint, 33.2 ± 8.2 months after treatment initiation. For treated patients, average visual acuity (LogMAR) ± standard error of the mean improved from 0.5 ± 0.04 pre-treatment to 0.3 ± 0.1 at the second endpoint, 50.2 ± 7.3 months after treatment initiation.

Conclusions: Mild anatomic improvement of macular cysts was seen in pediatric patients using brinzolamide. Visual acuity improvement occurred even without significant reduction in macular cysts. Further studies are needed to determine whether the beneficial effects of carbonic anhydrase inhibitors are sustained in children with inherited retinal degenerations.     

Current Stem-Cell Approaches for the Treatment of Inherited Retinal Degenerations

ABSTRACT

Stem cells provide a promising new therapeutic approach for the treatment of multiple acquired and inherited retinal conditions. While to date, there have been numerous clinical trials examining the ability of stem cells to treat the geographic atrophy found in advanced non-neovascular age-related macular degeneration, fewer clinical trials have specifically examined stem-cell therapy for inherited retinal disease. Moreover, it remains to be seen if human stem cells will be able to regenerate the lost retinal cell populations that represent a final common pathway for most of the inherited retinal diseases, or if stem cells will secrete a neuroprotective paracrine factor that will delay progression of these diseases. Here, we will review a number of the current clinical trials, either completed or in process, that have been designed to specifically treat inherited retinal conditions. There was considerable initial concern that using human stem cells as therapeutic agents might have the potential to form benign tumors or trigger an immune response that would have deleterious effects on the patient’s retina. Currently, the majority of the clinical trials reviewed share the conclusion that intraocular stem-cell approach is generally well tolerated and safe for patients. While there are some efficacy data that have been published for a few of the reviewed trials, none of the completed studies have been empowered to demonstrate statistically significant efficacy in humans.     

Genetic dissection of non-syndromic retinitis pigmentosa

Retinitis pigmentosa (RP) belongs to a group of pigmentary retinopathies. It is the most common form of inherited retinal dystrophy, characterized by progressive degradation of photoreceptors that leads to nyctalopia, and ultimately, complete vision loss. RP is distinguished by the continuous retinal degeneration that progresses from the mid-periphery to the central and peripheral retina. RP was first described and named by Franciscus Cornelius Donders in the year 1857. It is one of the leading causes of bilateral blindness in adults, with an incidence of 1 in 3000 people worldwide. In this review, we are going to focus on the genetic heterogeneity of this disease, which is provided by various inheritance patterns, numerosity of variations and inter-/intra-familial variations based upon penetrance and expressivity. Although over 90 genes have been identified in RP patients, the genetic cause of approximately 50% of RP cases remains unknown. Heterogeneity of RP makes it an extremely complicated ocular impairment. It is so complicated that it is known as “fever of unknown origin”. For prognosis and proper management of the disease, it is necessary to understand its genetic heterogeneity so that each phenotype related to the various genetic variations could be treated.