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.     

Novel C8orf37 Mutations in Patients with Early-onset Retinal Dystrophy,Macular Atrophy,Cataracts, and High Myopia

Purpose: More than 50 genes are reported as causative genes of autosomal recessive (ar) retinitis pigmentosa (RP) and cone-rod dystrophy (CRD). It is challenging to identify causative mutations for arRP and arCRD. The purpose of the present study was to investigate clinical and genetic features of two siblings with early-onset retinal dystrophy.

Methods: Whole-exome sequencing was conducted for the two affected siblings and their unaffected brother and mother from a Japanese family. We performed complete ophthalmic examinations, including visual acuity, funduscopy, visual-field testing, electroretinography and optical coherence tomography.

Results: Whole-exome sequencing analysis identified novel compound heterozygous mutations, a splice site mutation (c.374?+?2T?>?C in intron 4) and a deletion mutation (c.575delC [p.T192MfsX28] in exon 6) of chromosome 8 open reading frame 37 (C8orf37) gene, which encodes a ciliary protein, in both patients. The mother carried the truncating mutation, and the brother carried neither mutation. Ophthalmic examinations revealed diffuse retinal degeneration, macular atrophy, non-recordable electroretinography responses, cataracts, and high myopia in both patients, who could not be diagnosed with either RP or CRD because of the severe retinal degeneration and early onset disease. Longitudinal follow-up of the patients revealed highly progressive retinal degeneration, macular atrophy, and visual field loss.

Conclusions: Recessive C8orf37 mutations have been identified in early to adolescent-onset arRP and arCRD with macular involvement. Our study identified two novel truncating mutations of the C8orf37 gene in siblings with early-onset retinal dystrophy, macular atrophy, cataracts, and high myopia.     

CRB1 maculopathy presenting as fenestrated sheen macular dystrophy with 15-year follow-up

Introduction

We present two patients, the proband and the affected sibling, with biallelic CRB1 mutations leading to a macular dystrophy.

Case presentation

We present two patients, the proband and the affected sibling, with biallelic CRB1 mutations leading to a macular dystrophy. With 15 years of follow-up for the proband, we illustrate the natural history of CRB1 maculopathy based on clinical examination, multimodal imaging, and electrophysiology. In addition, we demonstrate the wide phenotypic spectrum of the condition with the affected sister harboring the same variants but with much milder phenotypic manifestations.

Conclusion

In addition to a previously described pathogenic variant, Ile167_Gly169del, one pathogenic missense variant in CRB1, Lys801Ter, not previously associated with macular dystrophy, is reported here. While CRB1 mutations have been more commonly described in retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA), we demonstrate that mutations in CRB1 can cause a maculopathy with initial features similar to fenestrated sheen macular dystrophy (FSMD) that later evolves into severe macular atrophy.

     

C8orf37 is mutated in Bardet-Biedl syndrome and constitutes a locus allelic to non-syndromic retinal dystrophies

Bardet-Biedl syndrome (BBS) is a pleiotropic and clinically and genetically heterogeneous ciliopathy. Primary features are early-onset retinal dystrophy that is typically rod-cone, obesity, polydactyly, renal abnormalities, hypogonadism, and learning difficulties, but most patients do not present with the full clinical picture. In a BBS patient from a consanguineous marriage we performed next-generation sequencing targeting all known BBS genes and other genes known or hypothesized to cause ciliopathies. While no mutation was present in any of the recognized genes for BBS, we were able to identify the homozygous non-conservative mutation c.529C>T (p.Arg177Trp) in C8orf37 that segregated with the phenotype, affects an evolutionarily highly conserved residue, and is bioinformatically predicted to be pathogenic. The same mutation has been described in unrelated patients with non-syndromic cone-rod dystrophy and other C8orf37 changes were found in individuals with retinitis pigmentosa. We conclude that C8orf37 should be added to BBS screening panels as a probable rare cause of the disease and that individuals with C8orf37-related retinal dystrophy should be screened for BBS features.     

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.     

Mutation Screen of the Membrane-Type Frizzled-Related Protein (MFRP) Gene in Patients with Inherited Retinal Degenerations

MFRP is a member of the frizzled-related protein family and contains a cysteine-rich domain essential for Wnt binding and signaling. MFRP is highly expressed in the retinal pigment epithelial cells of the eye. A splice donor mutation in the mouse ortholog of Mfrp is responsible for photoreceptor degeneration in the rd6 mouse. For these reasons, we investigated MFRP as a candidate gene for a phenotype associated with mutations. We screened 152 patients with inherited retinal degenerations including retinitis pigmentosa, Leber congenital amaurosis and Stargardt macular dystrophy. We identified five polymorphisms in the 5′ untranslated region, four missense changes, six isocoding variants and four intronic changes. None of the sequence variants were interpreted as pathogenic.     

Early-onset retinal dystrophy and chronic dermatitis in a girl with an undiagnosed congenital disorder of glycosylation (SRD5A3-CDG)

Purpose: Early-onset retinal dystrophy is usually isolated but can also be the presenting manifestation of an undiagnosed systemic disease. The purpose of this report is to highlight the initial presentation of a girl with early-onset retinal dystrophy and chronic dermatitis who was found to have an undiagnosed congenital disorder of glycosylation (SRD5A3-CDG).

Methods: Retrospective case report.

Results: A 13-year-old Baluchi girl was referred for evaluation of low vision since soon after birth. Clinical exam confirmed retinal dystrophy. She also had developmental disability and chronic dermatitis. Brain MRI was normal. Whole exome and confirmatory Sanger sequencing uncovered homozygosity for a SRDA3 deletion (p.Gln96delinsX) that was previously reported in two other Baluchi SRDA3-CDG families with ocular coloboma, optic atrophy, atopic dermatitis, cerebellar hypoplasia, and developmental disability. Early-onset retinal dystrophy was not mentioned in those two families but has since been documented in other SRDA3-CDG families harboring different biallelic variants in the gene.

Discussion: Early-onset retinal dystrophy with chronic dermatitis should raise suspicion for biallelic SRDA3 mutations, particularly in the context of developmental disability. Exome sequencing can be a useful analysis in retinal dystrophy patients with multisystem disease. Homozygosity for the SRDA3 deletion p.Gln96delinsX is not always associated with ocular coloboma.     

原发性视网膜色素变性合并血管闭塞的临床特点分析

目的探讨原发性视网膜色素变性(RP)合并视网膜血管闭塞患者的临床特点及预后。方法回顾性分析18例(36只眼)原发性RP合并视网膜血管闭塞患者的临床资料,包括眼底检查、荧光素眼底血管造影、吲哚氰绿血管造影、视网膜电图及视诱发电位等检查结果。对3例患者进行基因筛选。结果原发性RP合并视网膜血管闭塞患者的临床表现有视乳头萎缩、视网膜血管变细、广泛视网膜色素上皮萎缩。视网膜电图检查显示a、b波为无波型或近无波型。患者多有夜盲史。既符合原发性RP的临床表现,又具有血管闭塞的自身特征,如晚期血管可完全或近完全闭塞、视神经明显萎缩、脉络膜血管受累,最终致盲速度较原发性RP快,且无有效疗法。3例患者经基因筛查,在RHO及RLBPI两基因编码区中,未发现基因突变。结论原发性RP合并视网膜血管闭塞可能属于毯层视网膜变性范畴,血管进行性闭塞可能是其合并的临床表现。     

Clinical characteristics of recessive retinal degeneration due to mutations in the CDHR1 gene and a review of the literature

Background: The clinical phenotype of patients presenting with autosomal recessive CDHR1-related retinopathy has not been well described.

Materials and Methods: This is a retrospective case series of patients presenting to a single institution. Clinical data, including age, visual acuity, dilated fundus exam, fundus photos, fundus autofluorescence (FAF), optical coherence tomography, full-field electroretinograms (ERGs), and results of genetic testing, were collected.

Results: Four patients were identified to have biallelic mutations in the CDHR1 gene. All four patients were found to have at least one c.783G>A (p.Pro261 = ) mutation. A novel splice site mutation, c.152-2A>G, was identified in two patients. Patients became symptomatic between the fourth and sixth decades of life. Three patients presented initially with nyctalopia and peripheral visual field constriction, and one patient presented with simultaneous onset of photophobia and nyctalopia. The fundus appearance was characterized by macular atrophy with or without peripheral retinal pigment epithelium changes and arteriolar attenuation. FAF showed a hyperautofluorescent ring surrounding a central area of speckled hypoautofluorescence. Full-field electroretinography was available on three patients and showed decreased cone-and-rod responses.

Conclusions: CDHR1-related retinal dystrophy should be considered in adult patients with a retinal dystrophy who present with symptoms of cone-and-rod dysfunction and macular atrophy on ophthalmoscopic examination.     

Screening of the gene encoding the alpha'-subunit of cone cGMP-PDE in patients with retinal degenerations.

PURPOSE: To screen the exons of the gene encoding the alpha'-subunit of cone cyclic guanosine monophosphate (cGMP>phosphodiesterase (PDE6C) for mutations in a group of 456 unrelated patients with various forms of inherited retinal disease, including cone dystrophy, cone-rod dystrophy, macular dystrophy, and simplex/multiplex and autosomal recessive retinitis pigmentosa. METHODS: The 22 exons of the PDE6C gene were screened for mutations either by denaturing gradient gel electrophoresis and single-strand conformation polymorphism electrophoresis (SSCP) or by SSCP alone; variants were sequenced directly. RESULTS: Although many sequence variants were found, none could be associated with disease. CONCLUSIONS: The results show that PDE6C was not the site of the amutations responsible for the types of inherited retinal degenerations analyzed in the large population of patients 'in the present study. The types of degeneration included those that predominantly affect cone-mediated function (cone and cone-rod dystrophies) or rod-mediated function (retinitis pigmentosa) or that have a predilection for disease in the macula (macular dystrophies).     

The retinal ciliopathies

While the functions of many of the proteins located in or associated with the photoreceptor cilia are poorly understood, disruption of the function of these proteins may result in a wide variety of phenotypes ranging from isolated retinal degeneration to more pleiotropic phenotypes. Systemic findings include neurosensory hearing loss, developmental delay, situs-inversus, infertility, disorders of limb and digit development, obesity, kidney disease, liver disease, and respiratory disease. The concept of "retinal ciliopathies" brings to attention the importance of further molecular analysis of this organelle as well as provides a potential common target for therapies for these disorders. The retinal ciliopathies include retinitis pigmentosa, macular degeneration, cone-dystrophy, cone-rod dystrophy, Leber congenital amaurosis, as well as retinal degenerations associated with Usher syndrome, primary ciliary dyskinesia, Senior-Loken syndrome, Joubert syndrome, Bardet-Biedl syndrome, Laurence-Moon syndrome, McKusick-Kaufman syndrome, and Biemond syndrome. Mutations for these disorders have been found in retinitis pigmentosa-1 (RP1), retinitis pigmentosa GTPase regulator (RPGR), retinitis pigmentosa GTPase regulator interacting protein (RPGR-IP), as well as the Usher, Bardet-Biedl, and nephronophthisis genes. Other systemic disorders associated with retinal degenerations that may also involve ciliary abnormalities include: Alstrom, Edwards-Sethi, Ellis-van Creveld, Jeune, Meckel-Gruber, Orofaciodigital Type 9, and Gurrieri syndromes. Understanding these conditions as ciliopathies may help the ophthalmologist to recognize associations between seemingly unrelated diseases and have a high degree of suspicion that a systemic finding may be present.     

Naturally occurring animal models with outer retina phenotypes

Naturally occurring and laboratory generated animal models serve as powerful tools with which to investigate the etiology of human retinal degenerations, especially retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), cone dystrophies (CD) and macular degeneration (MD). Much progress has been made in elucidating gene defects underlying disease, in understanding mechanisms leading to disease, and in designing molecules for translational research and gene-based therapy to interfere with the progression of disease. Key to this progress has been study of naturally occurring murine and canine retinal degeneration mutants. This article will review the history, phenotypes and gene defects of select animal models with outer retina (photoreceptor and retinal pigment epithelium) degeneration phenotypes.     

Electroretinogram and electrooculogram in retinal degeneration

Electroretinogram (ERG) and electrooculogram (EOG) are fundamental for proper early diagnosis of retinal dystrophies and degenerations. The most characteristic changes of ERG and EOG in such retinal dystrophies as Stargardt's disease, Best's disease, fundus flavimaculatus, fundus albipunctatus, retinitis pigmentosa, choroideremia, iuvenile retinoschisis, congenital stationary night blindness, progressive cone dystrophy and in some of retinal degenerations for differential diagnosis were described. Electrophysiological state of retina in retinal dystrophy depends on patient's age and pattern of inheritance. Very often typical for dystrophy changes in ERG and EOG without any visible pathology on eye fundi are found. On the other hand there are some of degenerations similar to dystrophies in clinical examination. In such cases only ERG and EOG allow to be sure which diagnosis should be done.     

Factors associated with visual acuity in patients with cystoid macular oedema and Retinitis Pigmentosa

Purpose: Retinitis pigmentosa is the most common inherited retinal dystrophy. The factors associated with visual acuity in patients with other retinal diseases are well known, but are poorly understood in patients with retinitis pigmentosa. This knowledge is useful for prognosis and to support secondary endpoints in clinical trials.

Methods: We conducted a cross-sectional study of consecutive patients recruited from the inherited retinal disease service from January 2012 to December 2012. Central macular thickness (CMT) was measured using spectral domain optical coherence tomography.

Results: Data were available for 81 patients and 162 eyes. After multivariable analyses, older age, earlier age of onset of symptoms, and thicker CMT were associated with lower visual acuity. Gender and inheritance pattern were not associated with visual acuity. Each decade older age, younger age of onset, and thicker CMT was associated with 0.12, 0.10, and 0.11 worse logarithm of the minimal angle of resolution units of visual acuity, respectively (p < 0.05 for all).

Conclusions: Age, age of onset, and CMT are associated with visual acuity and important factors to measure in studies of retinitis pigmentosa.     

Gene therapy in inherited retinal degenerative diseases,a review

Hereditary diseases of the retina represent a group of diseases with several heterogeneous mutations that have the common end result of progressive photoreceptor death leading to blindness. Retinal degenerations encompass multifactorial diseases such as age-related macular degeneration, Leber congenital amaurosis, Stargardt disease, and retinitis pigmentosa. Although there is currently no cure for degenerative retinal diseases, ophthalmology has been at the forefront of the development of gene therapy, which offers hope for the treatment of these conditions. This article will explore an overview of the clinical trials of gene supplementation therapy for retinal diseases that are underway or planned for the near future.     

Delineating the Clinical Phenotype of Patients With the c.629C>G,p.Pro210Arg Mutation in Peripherin-2

PurposeMore than 200 different mutations in peripherin-2 (PRPH2) are associated with multiple subtypes of inherited retinal diseases (IRDs), including retinitis pigmentosa and cone or macular diseases. Our goal was to understand how the poorly characterized PRPH2 mutation p.Pro210Arg (P210R) affects visual function and retinal structure as well as gain insight into the mechanism driving the clinical pathology.MethodsEleven patients had clinical assessments including best-corrected visual acuity (BCVA), full field and multifocal electroretinography (ERG), static (spot size V) and kinetic perimetry (Octopus 900), and dark-adapted chromatic (DAC; Medmont; spot size V) perimetry. Images were acquired with the Optos ultra-wide field camera and spectral-domain optical coherence tomography (SD-OCT). Molecular characteristics of the P210R mutant protein were evaluated in vitro.ResultsPatients with the P210R mutation had BCVA (Snellen) ranging from 20/15 to 20/80. Perimetry showed a reduction in sensitivity, while ERG findings suggested that cone function was more impaired than rod function. Scotomas were identified corresponding to atrophic retinal lesions. Imaging revealed heterogeneous outer retinal changes such as hyperfluorescent flecks, hypo-autofluorescence (AF) regions of atrophy, and thinning of the photoreceptor layer on SD-OCT. In vitro findings suggested that P210R-Prph2 retains the ability to interact with binding partner Rom1 but abnormally accumulates in the endoplasmic reticulum (ER), suggesting the protein does not fold properly.ConclusionsRod and cone sensitivities were decreased in subjects with the P210R mutation in PRPH2. There was scotomatous vision loss that occurred within the macula, likely due to atrophy that occurs after drusen have formed and have begun to resolve. This suggests that although rod and cone photoreceptors are dependent on PRPH2, preventing blindness in this specific subgroup of patients could involve therapeutics that impede the formation or lifecycle of drusen.     

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.     

Progressive sector retinitis pigmentosa due to c.440G>T mutation in SAG in an Australian family

ABSTRACT

Background

Heterozygous c.440 G > T mutation in the S-antigen visual arrestin (SAG) gene has been described as a cause of autosomal dominant retinitis pigmentosa (adRP) in a series of patients of Hispanic origin. This study presents the early and late clinical features and disease progression rates in an Australian family with SAG adRP.     

Analysis of the Arg345Trp disease-associated allele of the EFEMP1 gene in individuals with early onset drusen or familial age-related macular degeneration

Background: A single base change within the EFEMP1 gene has been associated with malattia leventinese and Doyne honeycomb retinal dystrophy, two dominantly inherited macular diseases with early onset drusen. The aim of this study was to determine whether the same disease allele was also associated with other forms of early onset drusen or familial cases of age‐related macular degeneration. Methods: Thirteen index cases of early onset drusen together with 15 other family members were examined. In addition, 54 familial cases of age‐related macular degeneration were examined. Blood was taken for DNA analysis and screened for the Arg345Trp disease‐associated allele of the EFEMP1 gene. Twenty‐four cases of malattia leventinese or Doyne honeycomb retinal dystrophy were also screened as positive controls. Another 150 ethnicity‐ and age‐matched individuals acted as controls. Results: The Arg345Trp disease‐associated allele in the EFEMP1 gene was confirmed in individuals with malattia leventinese and Doyne honeycomb retinal dystrophy. However, involvement of this allele was not evident in either early onset drusen or familial age‐related macular degeneration. Conclusions: The Arg345Trp disease‐associated allele of the EFEMP1 gene does not appear to be associated with cases of early onset drusen that fall outside the diagnosis of malattia leventinese or Doyne honeycomb retinal dys­trophy, nor does it appear to play a role in familial age‐related macular degeneration. These findings do not exclude the involvement of other alleles of the EFEMP1 gene in either phenotype. The genetic mechanisms involved in the hetero­geneous group of early onset drusen remain to be elucidated but should lead to insights into the genetic causes of macular diseases.     

Autosomal dominant pericentral retinal dystrophy caused by a novel missense mutation in the TOPORS gene

Purpose: This study aimed to identify the genetic cause of autosomal dominant pericentral retinal dystrophy (adPRD) in a large Norwegian family with 35 affected members. Methods: The family was characterized by clinical ophthalmological examination along with fundus photography, dark adaptometry and electroretinography. We performed a genome‐wide linkage analysis followed by sequencing of a candidate gene to identify the mutation causing the disease. Results: The ophthalmological examinations revealed an atypical form of retinitis pigmentosa (RP), which we prefer to call adPRD. Compared with classical RP, this phenotype has a favourable prognosis. Linkage analysis showed a linkage peak covering the most recently reported adRP gene TOPORS. This gene was sequenced in 19 family members and a novel missense mutation, c.1205a>c, resulting in an amino acid substitution p.Q402P, was detected in all affected members. The mutation showed complete co‐segregation with the disease in this family, with a LOD score of 7.3. It is located in a highly conserved region and alignment with the appropriate DNA sequence from other species shows complete conservation of this amino acid. The mutation was not detected in 207 healthy, unrelated controls of Norwegian origin. Conclusions: We present a novel mutation in the TOPORS gene co‐segregating with a distinct phenotype of adPRD in a large Norwegian family.