Diversity of familial exudative vitreoretinopathy / 中华眼底病杂志

Familial exudative vitreoretinopathy (FEVR) is a hereditary retinal vascular dysplasia. So far, 6 genes have been found to be associated with FEVR: Wnt receptor Frizzled Protein 4, Norrie's disease, co-receptor low-density lipoprotein receptor-related protein 5, tetraspanin 12, zinc finger protein 408, and kinesin family members 11 genes. Its clinical manifestations, pathological processes and genetic patterns are diverse, and it shows the relationship between gene polymorphism and clinical manifestation diversity. It is characterized by different symptoms between the same individual, the same family, and the same gene mutation; different clinical stages and gene mutation types of parents or unilateral genetic children; different clinical characteristics and gene mutation patterns of full-term and premature infant; combined with other eye disease and systemic diseases;double gene mutations and single gene mutations have different clinical manifestations and gene mutation characteristics. A comprehensive understanding of the different clinical manifestations and diverse genetics of FEVR can provide better guidance for the treatment of FEVR.

Advances in the genetics of familial exudative vitreoretinopathy / 中华眼底病杂志

Familial exudative vitreoretinopathy (FEVR) is a hereditary disease with high geneticheterogeneity,including autosomal dominant inheritance,autosomal recessive inheritance,snd X-linked recessive inheritance.So far,six genes have been found to be associated with FEVR:Wnt receptor fizzled protein (FZD4),Norrie disease (NDP),co-receptor low-densitylipoprotein receptor-related protein 5 (LRP5),and tetrasin 12 (TSPANI2),zinc finger protein408 (ZNF408),kinesin family member 11 (KIF11) gene.Among them,FZD4,NDP,LRPS,TSPANI2 and other four genes play an important role in the Norrin/Frizzled 4 signaling pathway.In retinal capillary endothelial cells,Norrin specifically controls the occurrence of ocular capillaries by activating the Norrin/Frizzled 4 signaling pathway.ZNT408 and KIF11 are newly discovered pathogenic genes related to FEVR in the past 5 years.ZNF408 encodes the transcription factor that plays an important role in retinal angiogenesis.KIF 11 plays a role in eye development and maintenance of retinal morphology and function.

Clinical features and identification of gene mutation in families with familial exudative vitreoretinopathy / 中华眼底病杂志

Objective To identify mutations in NDP,FZD4,LRPS,TSPAN12 in Chinese families with familial exudative vitreoretinopathy (FEVR) and observe the clinical features.Methods Retrospective case series study.The 9 patients (18 eyes) and 5 normal members from 4 unrelated families were included in the study.The patients medical history and family history were collected in detail.All patients underwent best corrected visual acuity (BCVA),slit-lamp biomicroscopy,fundus colorized photography,fundus fluorescein angiography (FFA).Genomic DNA were collected from all the patients.Mutations were detected by directly sequencing to the whole coding region and exon-intron boundaries ofNDP,FZD4,LRP5 and TSPAN12 gene.Polyphen and SWT programs were used to predict the effects on the structure and functional properties of mutant protein.Results There were two affected individuals in the family 2 carried LRP5 gene mutation [c.1330C＞T (p.R444C)] in exon 6 by sequence analysis.A score of 0.882 was acquired by Polyphen program analysis.And the missense change was predicted to be pathogenic by SIFT.Fundus changes of the proband showed angioplasia,tortuosity of peripheral vessels.And temporal dragging of the optic disc,peripheral avascular zone,neovascularization were found in FFA.Brush-like and straight of peripheral vessels were found in I 1.No variant was found in NDP,FZD4 and TSPAN12 gene.Conclusion Our study supports the gene mutation c.1330C＞T (p.R444C) of LRP5 is pathogenesis of FEVR.Patients with the same mutation could have variable phenotypic characteristics.

Genotype and clinical phenotype analysis in patients with retinitis pigmentosa and cone rod dystrophy / 中华眼底病杂志

Objective To observe the gene mutation and clinical phenotype of patients with retinitis pigmentosa (RP) and cone rod dystrophy (CORD).Methods Thirty-seven patients with RP and 6 patients with CORD and 95 family members were enrolled in the study.The patient's medical history and family history were collected.All the patients and family members received complete ophthalmic examinations to determine the phenotype,including best corrected visual acuity,slit lamp microscope,indirect ophthalmoscopy,color fundus photography,optical coherence tomography,full-field electroretinogram,and fluorescein fundus angiography.DNA was abstracted from patients and family members.Using target region capture sequencing combined with next-generation sequencing to screen the 232 candidate pathogenic mutations.Polymerase chain reaction and direct sequencing were used to confirm the pathogenic pathogenic mutations and Co-segregation is performed among members in the family to determine pathogenic mutation sites.The relationship between genotype and clinical phenotype of RP and CORD was analyzed.Results Of the 37 patients with RP,13 were from 6 families,including 4 families with autosomal dominant inheritance,2 families with autosomal recessive inheritance,and 3 in 6 families were detected pathogenic gene mutations.24 cases were scattered RP.Six patients with CORD were from four families,all of which were autosomal recessive.Of the 43 patients,21 patients were detected the pathogenic gene mutation,and the positive rate was 48.8％.Among them,15 patients with RP were detected 10 pathogenic gene mutations including USH2A,RP1,MYO7A,C8orf37,RPGR,SNRNP200,CRX,PRPF31,C2orf71,IMPDH1,and the clinical phenotype included 10 typical RP,2 cases of RPSP,3 cases of Usher syndrome type 2 and 6 cases of CORD patients were all detected pathogenic gene mutations,including 2 cases of ABCA4,2 mutations of RIMS 1 gene,1 case of CLN3 gene mutation,and 1 case of CRB 1 and RPGR double gene mutation.Conclusions RP and CORD are clinically diverse in genotype and clinically phenotypically similar.For patients with early RP and CORD,clinical phenotype combined with genetic analysis is required to determine the diagnosis of RP and CORD.

Progress and opportunities of gene and stem cell therapy on hereditary ocular fundus diseases / 中华眼底病杂志

Hereditary ocular fundus disease is an important cause of irreversible damage to patients' visual acuity.It has attracted much attention due to its poor prognosis and lack of effective clinical interventions.With the discovery of a large number of hereditary ocular fundus genes and the development of gene editing technology and stem cell technology,gene and stem cell therapy emerged as the new hope for curing such diseases.Gene therapy is more directed at early hereditary ocular fundus diseases,using wild-type gene fragments to replace mutant genes to maintain existing retinal cell viability.Stem cell therapy is more targeted at advanced hereditary ocular fundus diseases,replacing and filling the disabled retinal cell with healthy stem cells.Although gene and stem cell therapy still face many problems such as gene off-target,differentiation efficiency,cell migration and long-term efficacy,the results obtained in preclinical and clinical trials should not be underestimated.With the emergence of various new technologies and new materials,it is bound to further assist gene and stem cell therapy,bringing unlimited opportunities and possibilities for the clinical cure of hereditary ocular fundus diseases.

Analysis of BEST1 gene mutations and clinical features in multifocal vitelliform retinopathy patients / 中华眼底病杂志

Objective To analyze the BEST1 gene mutations and clinical features in patients with multifocal vitelliform retinopathy (MVR).Methods This is a retrospective case series study.Five MVR families with MVR,including 9 patients and 10 healthy family members were recruited.Clinical evaluations were performed in all MVR patients and their family members,including best-corrected visual acuity (BCVA),intraocular pressure (IOP),refraction,slit-lamp examination,90 D preset lens examination,gonioscopy,color fundus photography,optical coherence tomography (OCT),fundus autofluorescence (AF),ultrasound biomicroscopy (UBM) and axial length measurement.Electro-oculogram (EOG) was performed in 12 eyes and visual field were performed in 13 eyes.Peripheral blood samples were collected in all subjects to extract genomic DNA.Coding exons and flanking intronic regions of BEST 1 were amplified by polymerase chain reaction and analyzed by Sanger sequencing.Results Among the 5 MVR families,3 probands from three families had family history,including 1 family had autosomal dominant inheritance pattern.Two patients from 2 families were sporadic cases.Screening of BEST1 gene identified four mutations,including three missense mutations (c.140G＞T,p.R47L;c.232A＞T,p.I78F;c.698C＞T,p.P233L) and 1 deletion mutation (c.910_912del,p.D304del).Two mutations (p.R47L and p.I78F) were novel.The BCVA of affected eyes ranged from hand motion to 1.0.The mean IOP was (30.39± 11.86) mmHg (1 mmHg=0.133 kPa).The mean refractive diopter was (-0.33 ± 1.68) D.Twelve eyes had angle-closure glaucoma (ACG) and 4 eyes had angle closure (AC).EOG Arden ratio was below 1.55 in all patients.The mean anterior chamber depth was (2.17± 0.29) mm.Visual field showed defects varied from paracentral scotoma to diffuse defects.The mean axial length was (21.87± 0.63) mm.All MVR patients had multifocal vitelliform lesions in the posterior poles of retina.ACG eyes demonstrated pale optic disc with increased cup-to-disc ratio.OCT showed retinal edema,extensive serous retinal detachment and subretinal hyper-reflective deposits which had high autofluorescence in AF.The genetic testing and clinical examination were normal in 10 family members.Conclusions MVR patients harbored heterozygous mutation in the BEST1 gene.Two novel mutations (p.R47L and p.I78F) were identified.These patients had clinical features of multifocal vitelliform retinopathy and abnormal EOG.Most patients suffered from AC/ACG.

Benign familial fleck retina: multimodal imaging including optical coherence tomography angiography / Benign familial fleck retina: estudo multimodal incluindo OCT angiography

ABSTRACT This report presents multimodal imaging of a 27-year-old woman diagnosed with benign familial fleck retina (OMIM 228980), an uncommon disorder. Fundus photographs revealed retinal flecks that affected her post-equatorial retina but spared the macular area. Fundus autofluorescence and infrared imaging demonstrated a symmetrical pattern of yellow-white fleck lesions that affected both eyes. Her full-field electroretinogram and electrooculogram were normal. An optical coherence tomography B-scan was performed for both eyes, revealing increased thickness of the retinal pigmented epithelium leading to multiple small pigmented epithelium detachments. The outer retina remained intact in both eyes. Spectral-domain optical coherence tomography angiography with split-spectrum amplitude decorrelation algorithm and 3 × 3 mm structural en face optical coherence tomography did not show macular lesions. Benign familial fleck retina belongs to a heterogenous group of so-called flecked retina syndromes, and should be considered in patients with yellowish-white retinal lesions without involvement of the macula.

RESUMO O objetivo do presente relato é demonstrar um estudo multimodal de um paciente com diagnóstico de Benign Familial Fleck Retina (BFFR) (OMIM 228980), uma alteração retinana muito rara. Retinografia colorida demonstrou "flecks" na retina posterior ao equador, poupando mácula. Tanto autofluorescência quando imagem "infrared," nota-se padrão simétrico de lesões amareladas em ambos os olhos. Eletrorretinograma padrão de campo total e EOG não evidenciaram alterações. SD OCT B-scan demostrou pequenos e múltiplos descolamentos do epitélio pigmentado (EPR), com retina externa intacta em ambos os olhos. Angiografia por OCT com "split-spectrum amplitude decorrelation algorithm" e "structural" "en face" OCT 3 x 3 mm não apontaram anormalidades na mácula. BFFR pertence ao heterogêneo grupo chamado "flecked retina syndromes," devendo ser considerada em pacientes com flecks retinianos poupando mácula.

An association between subclinical familial exudative vitreoretinopathy and rod-cone dystrophy / Associação entre vitreorretinopatia exsudativa familiar subclínica e distrofia de cones e bastonetes

A 21-year-old Caucasian man presented with a complaint of nyctalopia. Visual acuity in both eyes was 20/20 and anterior segment biomicroscopy results were unremarkable. Fundoscopy revealed peripheral avascular zones, minimal peripheral retinal exudation from the retinal vessels, peripheral retinal telangiectasias and anastomosis in both eyes, and retinal vascular dragging toward the temporal periphery in both eyes. Full field electroretinography showed that rod responses were almost absent and that cone responses were reduced. Macular optical coherence tomography showed normal structure in both eyes. Vascular changes were attributed to a subclinical form of familial exudative vitreoretinopathy. This was an interesting case due to the association of familial exudative vitreoretinopathy with rod-cone dystrophy.

Um homem caucasiano de 21 anos foi avaliado com queixa de nictalopia. A acuidade visual era 20/20 em ambos os olhos. Biomicroscopia do segmento anterior era normal. A fundoscopia revelava zonas avasculares periféricas, exsudação mínima dos vasos retinianos periféricos da retina, telangiectasias da retina periférica com anastomoses em ambos os olhos e deslocamento vascular da retina em direção a periferia temporal em ambos os olhos. O eletrorretinograma (ERG) de campo total apresentava respostas de bastonetes praticamente indetectáveis e redução das respostas de cones. A tomografia de coerência óptica (OCT) macular mostrava estrutura normal em AO. As alterações vasculares foram atribuídas à forma subclínica da vitreorretinopatia exsudativa familiar. Este é um caso interessante com a associação de vitreoretinopatia exsudativa familiar e distrofia de cones e bastonetes (RCD).

Progress in mechanism of CYP4V2 gene mutations for Bietti crystalline corneoretinal dystrophy / 中华实验眼科杂志

Bietti crystalline corneoretinal dystrophy (BCD) is a common form of hereditary retinal degeneration in Chinese.Mutation of the cytochrome P450 4V2 (CYP4V2) gene,a novel family member of the cytochrome P450 genes on chromosome 4q35,has been identified in BCD patients,with the common mutation locus at c.802-8 _ 810dell7insGC (Exon7del),c.992A ＞ C (p.H331 P) and c.1091-2A ＞ G (Exon 9del).CYP4V2 is responsible for oxidation of various substrates in the metabolic pathway,especially ω-hydroxylase activity towards ω-3 polyunsaturated fatty acids (PUFAs).CYP4V2 appears to be the only CYP4 memeber at significant levels in retinal cells,and it may be a prominent contributor to local metabolism of PUFAs,mainly DHA (C22:6n-3),in retinal cells.To understand and investigate the main mechanism of CYP4V2 gene mutation causing BCD is important in the study of genetic diagnosis and genetic management of BCD.This review summarized the current advance in the genetic mechanism of BCD and function of CYP4V2 gene,elucidated the substrate specificity and unraveled the biochemical pathways that may impact function of CYP4V2 in BCD patients.