scholarly journals Hereditäre Netzhautdystrophien aufgrund von RPE65-Varianten: Von der genetischen Diagnostik zur Therapie

2021 ◽  
Vol 7 (3) ◽  
pp. 115-123
Author(s):  
Manar Aoun ◽  
Ilaria Passerini ◽  
Pietro Chiurazzi ◽  
Marianthi Karali ◽  
Irene De Rienzo ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Early Onset ◽  
Retinal Dystrophy ◽  
Molekulare Diagnostik ◽  
Retinal Diseases ◽  
Sind Eine

Die hereditären Netzhautdystrophien (IRD; inherited retinal diseases) sind eine heterogene Gruppe von Krankheiten – unter anderem Retinitis pigmentosa (RP), Lebersche kongenitale Amaurose (LCA) und Netzhautdystrophie mit frühem Krankheitsbeginn (EO[S]RD; early-onset [severe] retinal dystrophy) –, die sich hinsichtlich der Schwere der Krankheit und des Alters bei Krankheitsbeginn unterscheiden. IRD können durch Mutationen in &#x3e;250 verschiedenen Genen hervorgerufen werden. Varianten des <i>RPE65</i>-Gens sind die Ursache für 0,6–6% aller Fälle von RP und für 3–16% der Fälle von LCA/EORD. Voretigen Neparvovec ist eine Gentherapie, die zur Behandlung von Patienten mit autosomal-rezessiver Retinadystrophie infolge biallelischer <i>RPE65</i>-Varianten (<i>RPE65</i>-IRD) zugelassen ist. Die korrekte molekulare Diagnostik ist daher bei <i>RPE65</i>-IRD von entscheidender Bedeutung, um therapeutisch nutzbare, d. h. potenziell von der Therapie profitierende Genotypen zu identifizieren, und sie ist eine tragende Säule des Patientenmanagements. Es sind bereits Hunderte von <i>RPE65</i>-Varianten bekannt, und während ein Teil als pathogen oder wahrscheinlich pathogen identifiziert werden konnte, ist die Signifikanz anderer Varianten noch unklar. In dieser Übersichtsarbeit beschreiben wir das erforderliche gendiagnostische Vorgehen, um diejenigen Patienten auszuwählen, die die Voraussetzungen für die Behandlung mit Voretigen Neparvovec erfüllen. Die sorgfältige klinische Charakterisierung der Patienten durch interdisziplinäre Expertenteams in Kombination mit der Verfügbarkeit von Next-Genera­tion-Sequenzierung kann den Zugang der Patienten zu verfügbaren Therapieoptionen beschleunigen.

scholarly journals Bi-Allelic Pathogenic Variations in MERTK Including Deletions Are Associated with an Early Onset Progressive Form of Retinitis Pigmentosa

Genes ◽  
2020 ◽  
Vol 11 (12) ◽  
pp. 1517
Author(s):  
Cathrine Jespersgaard ◽  
Mette Bertelsen ◽  
Farah Arif ◽  
Helene Gry Gellert-Kristensen ◽  
Mingyan Fang ◽  
...  
Keyword(s):  
Visual Field ◽  
Retinitis Pigmentosa ◽  
Early Onset ◽  
Molecular Genetic ◽  
Retinal Dystrophy ◽  
Genetic Diagnostics ◽  
Substantial Part ◽  
Optic Coherence Tomography ◽  
Molecular Genetic Diagnostics ◽  
Ngs Data

Bi-allelic pathogenic variants in MERTK cause retinitis pigmentosa (RP). Since deletions of more than one exon have been reported repeatedly for MERTK, CNV (copy number variation) analysis of next-generation sequencing (NGS) data has proven important in molecular genetic diagnostics of MERTK. CNV analysis was performed on NGS data of 677 individuals with inherited retinal diseases (IRD) and confirmed by quantitative RT-PCR analysis. Clinical evaluation was based on retrospective records. Clinical re-examination included visual field examination, dark adaption, scotopic and photopic full-field electroretinograms (ffERG), multifocal ERG (mfERG) and optic coherence tomography (OCT). Fourteen variants were detected in MERTK in six individuals, three of which were deletions of more than one exon. Clinical examinations of five out of six individuals revealed a severe phenotype with early-onset generalized retinal dystrophy with night blindness and progressive visual field loss; however, one individual had a milder phenotype. Three individuals had hearing impairments. We show that deletions represent a substantial part of the causative variants in MERTK and emphasize that CNV analysis should be included in the molecular genetic diagnostics of IRDs.

Ayurvedic management of Retinitis Pigmentosa (Doshandha) - A Case Study

2017 ◽  
Vol 2 (05) ◽  
Author(s):  
Anju D. ◽  
Pushpa Raj Poudel ◽  
Ajoy Viswam ◽  
Ashwini M. J.
Keyword(s):  
Retinitis Pigmentosa ◽  
Low Vision ◽  
Symptomatic Relief ◽  
Retinal Dystrophy ◽  
Treatment Protocol ◽  
Signs And Symptoms ◽  
Photoreceptor Cells ◽  
Rod Photoreceptor ◽  
Night Time ◽  
Initial Symptoms

Retinitis pigmentosa (RP) is an inherited, degenerative eye disease that causes severe vision impairment due to the progressive degeneration of rod photoreceptor cells in retina. This form of retinal dystrophy manifests initial symptoms independentof age; thus, RP diagnosis occurs anywhere from early infancy to late adulthood. This primary pigmentary retinal dystrophy is a hereditary disorder predominantly affecting the rods more than the cones. The main classical triads of retinitis pigmentosa are arteriolar attenuation, Retinal bone spicule pigmentation and Waxy disc pallor. The main treatment of retinitis pigmentosa is by using Low vision aids (LVA) and Genetic counseling. As such a complete cure for retinitis pigmentosa is not present. So a treatment protocol has to be adopted that helps in at least the symptomatic relief. In Ayurveda, the signs and symptoms of this can be compared with the Lakshanas of Doshandha which is one among the Dristigata Roga. It is considered as a diseased condition in which sunset will obliterate the Dristi Mandala and makes the person blind at night time. During morning hours the rising sunrays will disperse the accumulated Dosas from Dristi to clear vision. This disease resembles Kaphajatimira in its pathogenesis, but the night blindness is the special feature. Since the disease is purely Kaphaja, a treatment attempt is planned in Kaphara and Brimhana line. The present paper discusses a case of retinitis pigmentosa and it’s Ayurvedic Treatment.

scholarly journals Novel TTLL5 Variants Associated with Cone-Rod Dystrophy and Early-Onset Severe Retinal Dystrophy

2021 ◽  
Vol 22 (12) ◽  
pp. 6410
Author(s):  
Vasily Smirnov ◽  
Olivier Grunewald ◽  
Jean Muller ◽  
Christina Zeitz ◽  
Carolin D. Obermaier ◽  
...  
Keyword(s):  
Early Onset ◽  
Retinal Dystrophy ◽  
Copy Number Variants ◽  
Cone Dystrophy ◽  
The Novel ◽  
Targeted Next Generation Sequencing ◽  
Large Deletions ◽  
Gene Panels ◽  
Generation Sequencing

Variants of the TTLL5 gene, which encodes tubulin tyrosine ligase-like family member five, are a rare cause of cone dystrophy (COD) or cone-rod dystrophy (CORD). To date, only a few TTLL5 patients have been clinically and genetically described. In this study, we report five patients harbouring biallelic variants of TTLL5. Four adult patients presented either COD or CORD with onset in the late teenage years. The youngest patient had a phenotype of early onset severe retinal dystrophy (EOSRD). Genetic analysis was performed by targeted next generation sequencing of gene panels and assessment of copy number variants (CNV). We identified eight variants, of which six were novel, including two large multiexon deletions in patients with COD or CORD, while the EOSRD patient harboured the novel homozygous p.(Trp640*) variant and three distinct USH2A variants, which might explain the observed rod involvement. Our study highlights the role of TTLL5 in COD/CORD and the importance of large deletions. These findings suggest that COD or CORD patients lacking variants in known genes may harbour CNVs to be discovered in TTLL5, previously undetected by classical sequencing methods. In addition, variable phenotypes in TTLL5-associated patients might be due to the presence of additional gene defects.

scholarly journals Pathogenic STX3 variants affecting the retinal and intestinal transcripts cause an early-onset severe retinal dystrophy in microvillus inclusion disease subjects

2021 ◽  
Author(s):  
Andreas R. Janecke ◽  
Xiaoqin Liu ◽  
Rüdiger Adam ◽  
Sumanth Punuru ◽  
Arne Viestenz ◽  
...  
Keyword(s):  
Early Onset ◽  
Single Nucleotide Polymorphism Array ◽  
Outer Nuclear Layer ◽  
Retinal Dystrophy ◽  
Geographic Origin ◽  
Retinal Disease ◽  
Homozygosity Mapping ◽  
Rod Photoreceptor ◽  
Loss Of Function ◽  
Knockout Mouse Model

AbstractBiallelic STX3 variants were previously reported in five individuals with the severe congenital enteropathy, microvillus inclusion disease (MVID). Here, we provide a significant extension of the phenotypic spectrum caused by STX3 variants. We report ten individuals of diverse geographic origin with biallelic STX3 loss-of-function variants, identified through exome sequencing, single-nucleotide polymorphism array-based homozygosity mapping, and international collaboration. The evaluated individuals all presented with MVID. Eight individuals also displayed early-onset severe retinal dystrophy, i.e., syndromic—intestinal and retinal—disease. These individuals harbored STX3 variants that affected both the retinal and intestinal STX3 transcripts, whereas STX3 variants affected only the intestinal transcript in individuals with solitary MVID. That STX3 is essential for retinal photoreceptor survival was confirmed by the creation of a rod photoreceptor-specific STX3 knockout mouse model which revealed a time-dependent reduction in the number of rod photoreceptors, thinning of the outer nuclear layer, and the eventual loss of both rod and cone photoreceptors. Together, our results provide a link between STX3 loss-of-function variants and a human retinal dystrophy. Depending on the genomic site of a human loss-of-function STX3 variant, it can cause MVID, the novel intestinal-retinal syndrome reported here or, hypothetically, an isolated retinal dystrophy.

Retinal Transplantation, Stem Cell and Gene Therapy in Retinitis Pigmentosa

2021 ◽  
pp. 131-139
Keyword(s):  
Gene Therapy ◽  
Stem Cell ◽  
Retinitis Pigmentosa ◽  
Retinal Dystrophy ◽  
Gene Replacement ◽  
Disease Genes ◽  
Functional Roles ◽  
Tunnel Vision ◽  
Hereditary Retinal Dystrophy ◽  
Cell And Gene Therapy

Retinitis pigmentosa is the most common hereditary retinal dystrophy which has marked clinical and genetic heterogeneity. Common presentations among this disorder include night blindness, tunnel vision, and subsequent progression to complete blindness respectively. The known causative disease genes have a variety of developmental and functional roles, with mutations in more than 120 genes shown to be responsible for the phenotypes. In addition, mutations within the same gene have been shown to cause different disease phenotypes, even within the same family, highlighting further levels of complexity. In recent years significant advancements have been made in the understanding of the pathogenesis of the disease and stem cell and gene replacement treatments have been proposed as potentially efficacious therapies. This review summarizes the clinical development of retinal stem cell and gene therapy.

scholarly journals Molecular Screening of 43 Brazilian Families Diagnosed with Leber Congenital Amaurosis or Early-Onset Severe Retinal Dystrophy

Genes ◽  
2017 ◽  
Vol 8 (12) ◽  
pp. 355 ◽  
Author(s):  
Fernanda Porto ◽  
Evan Jones ◽  
Justin Branch ◽  
Zachry Soens ◽  
Igor Maia ◽  
...  
Keyword(s):  
Early Onset ◽  
Retinal Dystrophy ◽  
Molecular Screening ◽  
Leber Congenital Amaurosis

scholarly journals New Compound Heterozygous CYP4V2 Mutations in Bietti Crystalline Corneoretinal Dystrophy

2020 ◽  
Author(s):  
Ting Wang ◽  
Qingshan Chen ◽  
Longhao Kuang ◽  
Jiantao Wang ◽  
Xiaohe Yan
Keyword(s):  
Autosomal Recessive ◽  
Frameshift Mutation ◽  
Retinal Dystrophy ◽  
Genetic Diagnosis ◽  
Compound Heterozygous ◽  
Retinal Diseases ◽  
Sequence Capture ◽  
Pathogenic Genes ◽  
Compound Heterozygous Mutations ◽  
Targeted Sequence Capture

Abstract Background: Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessive retinal dystrophy which is caused by the mutations of CYP4V2.Here we identified new CYP4V2compound heterozygous mutations in BCD.Methods:381 pathogenic genes related to retinal diseases were screened by targeted sequence capture array techniques and confirmed by Sanger sequencing.Results:Two female siblings with BCD carry two compound heterozygous mutations in CYP4V2. One was missense mutation c.1198C>T (p.R400C) and the other was frameshift mutation c.802-8_810delinsGC (p.V268_E329del).Optical coherence tomography (OCT) showed that the ellipsoid zone was absent in the macular regions and electroretinogram (ERG) revealed poor cone and rod responses. Conclusions:Newcompound heterozygous mutations in CYP4V2 are related to the BCD.Our study expands our knowledge of heterogenic phenotypes and genotypes through genetic diagnosis of the BCD patients.

scholarly journals Rare Co-Occurrence of Visual Snow in a Female Carrier With RPGRORF15-Associated Retinal Disorder

2021 ◽  
Vol 12 ◽  
Author(s):  
Aekkachai Tuekprakhon ◽  
Aulia Rahmi Pawestri ◽  
Ragkit Suvannaboon ◽  
Ketwarin Thongyou ◽  
Adisak Trinavarat ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Disease Onset ◽  
Retinal Dystrophy ◽  
Female Carrier ◽  
Ophthalmological Examination ◽  
Early Disease ◽  
Rare Form ◽  
Inactivation Pattern ◽  
Retinal Disorder ◽  
Female Carriers

X-linked retinitis pigmentosa (XLRP), a rare form of retinitis pigmentosa (RP), is predominantly caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene. Affected males often present with severe phenotypes and early disease onset. In contrast, female carriers are usually asymptomatic or show stationary phenotypes. Herein, we reported an 8-year-old female carrier, a daughter of a confirmed RP father with RPGR mutation, with an early onset of progressive cone-rod pattern retinal dystrophy. Additionally, the carrier experienced visual snow-like symptom as long as she recalled. Ophthalmological examination showed the reduction of visual acuity and attenuation of photoreceptor functions since the age of 5 years. Further analysis revealed a heterozygous pathogenic variant of the RPGR gene and a random X-inactivation pattern. Although she harboured an identical RPGR variant as the father, there were phenotypic intrafamilial variations. The information on the variety of genotypic and phenotypic presentations in XLRP carriers is essential for further diagnosis, management, and monitoring of these cases, including the design of future gene therapy trials.

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