The Experts below are selected from a list of 3585 Experts worldwide ranked by ideXlab platform

Graham E. Holder - One of the best experts on this subject based on the ideXlab platform.

  • High-resolution optical coherence tomography imaging in KCNV2 retinopathy
    2020
    Co-Authors: Panagiotis I Sergouniotis, Michel Michaelides, Andrew R. Webster, Anthony G. Robson, Graham E. Holder, Anthony T Moore
    Abstract:

    ABSTRACT Aim To report novel spectral domain optical coherence tomography (SD-OCT) findings and new mutational data in patients with 'Cone Dystrophy with supernormal rod electroretinogram', a recessive childhood onset retinal Dystrophy consequent upon mutation in the KCNV2 gene. Design/methods This was a comparative case series study of 12 patients with clinical and/or electrophysiological findings in keeping with KCNV2 mutation. Clinical examination and electrophysiological testing results were reviewed. Fundus photography and autofluorescence imaging were performed. Retinal layer appearance and thickness were evaluated using SD-OCT. The coding region and introneexon boundaries of KCNV2 were screened by direct sequencing. Results Mutations in KCNV2 were detected in all families; five of these changes were novel. Pattern electroretinograms were undetectable and full-field electroretinograms showed findings specific for the disorder

  • the phenotypic variability of retinal dystrophies associated with mutations in crx with report of a novel macular Dystrophy phenotype
    Investigative Ophthalmology & Visual Science, 2014
    Co-Authors: Sarah Hull, Vincent Plagnol, Anthony G. Robson, Graeme C.m. Black, Gavin Arno, Sarah Chamney, Isabelle Russelleggitt, Dorothy A Thompson, Simon C Ramsden, Graham E. Holder
    Abstract:

    PURPOSE: To present a detailed phenotypic and molecular study of a series of 18 patients from 11 families with retinal dystrophies consequent on mutations in the Cone-rod homeobox (CRX) gene and to report a novel phenotype. METHODS: Families were ascertained from a tertiary clinic in the United Kingdom and enrolled into retinal Dystrophy studies investigating the phenotype and molecular basis of inherited retinal disease. Eleven patients were ascertained from the study cohorts and a further seven from investigation of affected relatives. Detailed phenotyping included electrodiagnostic testing and retinal imaging. Bidirectional Sanger sequencing of all exons and intron-exon boundaries of CRX was performed on all 18 reported patients and segregation confirmed in available relatives. RESULTS: Based on clinical characteristics and electrophysiology, four patients had Leber congenital amaurosis (LCA), two had rod-Cone Dystrophy (RCD), five had Cone-rod Dystrophy (CORD), one had Cone Dystrophy (COD), and six had macular Dystrophy with different phenotypes observed within 5 of 11 families. The macular Dystrophy patients presented between 35 to 50 years of age and had visual acuities at last review ranging from 0.2 to 1.5 logMAR (20/32 to 20/630 Snellen). All 18 patients were heterozygous for a mutation in CRX with seven novel mutations identified. There was no evident association between age of onset and position or type of CRX mutation. De novo mutations were confirmed in three patients. CONCLUSIONS: Mutations in CRX demonstrate significant phenotypic heterogeneity both between and within pedigrees. A novel, adult-onset, macular Dystrophy phenotype is characterized, further extending our knowledge of the etiology of dominant macular dystrophies.

  • pathognomonic diagnostic ergs a review and update
    Retina-the Journal of Retinal and Vitreous Diseases, 2013
    Co-Authors: Ajoy Vincent, Anthony G. Robson, Graham E. Holder
    Abstract:

    Purpose To review three inherited retinal disorders associated with diagnostic or pathognomonic electroretinogram (ERG) abnormalities: Cone Dystrophy with supernormal rod ERG (KCNV2), enhanced S-Cone syndrome (NR2E3), and bradyopsia (RGS9/R9AP). Methods A review of clinical details, genetic basis, and electrophysiological features in these disorders and a brief summary of the standard and nonstandard ERG techniques required to identify the disorders. Results The electrophysiological features in each of these three disorders are pathognomonic such that the responsible gene can be specified. The results from nonstandard electrophysiological testing in excess of international standards are necessary to describe the pathognomonic changes in Cone Dystrophy with supernormal rod ERG and bradyopsia. The clinical phenotype in the disorders can be variable. Mutations in NR2E3 may additionally be associated with phenotypes other than enhanced S-Cone syndrome. Conclusion : Characteristic ERG changes enable the diagnosis of Cone Dystrophy with supernormal rod ERG, enhanced S-Cone syndrome, and bradyopsia and accurate genetic screening. This review highlights the need for additional nonstandard ERGs to make the diagnosis in two of these disorders.

  • A Novel Missense Mutation in Both OPN1LW and OPN1MW Cone Opsin Genes Causes X-Linked Cone Dystrophy (XLCOD5)
    Retinal Degenerative Diseases, 2011
    Co-Authors: Jessica C Gardner, Naheed Kanuga, Tom R. Webb, Anthony G. Robson, Graham E. Holder, Andrew Stockman, Caterina Ripamonti, Neil D. Ebenezer, Olufunmilola A. Ogun, Sophie Devery
    Abstract:

    X-linked Cone and Cone-rod dystrophies (XLCOD and XLCORD) are an inherited group of retinal disorders primarily involving Cone photoreceptors. The most common cause is mutation of RPGR. In a British family with XLCOD, we mapped the disorder to Xq26.1-qter, excluding RPGR and other known retinal degeneration genes. The Cone opsin gene array on Xq28 was a positional candidate locus. A novel missense mutation (c.529T > C; p.W177R) was identified in exon 3 of both the long wavelength-sensitive (OPN1LW; LW, red) and medium wavelength-sensitive (OPN1MW; MW, green) Cone opsin genes, which segregated with disease. Exon 3 sequences of both genes were identical, derived from the OPN1MW gene by partial gene conversion. The amino acid W177 is conserved in all opsins across species. We have shown that W177R in MW opsin results in protein misfolding and retention in the endoplasmic reticulum (ER). Mutations in the OPN1LW /OPN1MW Cone opsin gene array can therefore cause a spectrum of phenotypes, from colour blindness to progressive Cone Dystrophy (XLCOD5).

  • Cone Dystrophy with supernormal rod electroretinogram a comprehensive genotype phenotype study including fundus autofluorescence and extensive electrophysiology
    Retina-the Journal of Retinal and Vitreous Diseases, 2010
    Co-Authors: Anthony G. Robson, Michel Michaelides, Anthony T Moore, Andrew R. Webster, Susan M. Downes, David M. Hunt, Ja Cowing, Graham E. Holder
    Abstract:

    Purpose: The purpose of this study was to characterize the clinical, electrophysiologic, and genetic features in "Cone Dystrophy with supernormal rod electroretinogram (ERG)."Methods: Twenty-four cases between 5 and 59 years of age were ascertained. Full-field ERGs, incorporating the international standards, were used to derive intensity-ERG response functions. ON-OFF ERGs were performed. Fundus autofluorescence imaging was performed on 15 subjects. Deoxyribonucleic acid was available in 18 cases and was screened for a mutation in KCNV2.Results: Photophobia and nyctalopia were common. Autofluorescence was variable but often showed a ring-like area of high density that in middle-aged individuals, usually surrounded by an area of macular retinal pigment epithelial atrophy. Scotopic ERG amplitudes overlapped with the normal range but had characteristic a-and b-wave intensity-response functions; all had a broadened a-wave to the brightest flash. Photopic ERGs were abnormal; there was a delay in some ON and most OFF responses. Mutations in KCNV2 were detected in 18 cases, including 4 with novel mutations.Conclusion: Individuals with mutations in KCNV2 manifest a wide range of macular and autofluorescence abnormalities. A ring-like area of parafoveal high density autofluorescence is common. ERG amplitudes are variable, but the intensity-ERG response functions and bright flash ERG waveforms are pathognomonic. RETINA 30:51-62,2010

Michel Michaelides - One of the best experts on this subject based on the ideXlab platform.

  • High-resolution optical coherence tomography imaging in KCNV2 retinopathy
    2020
    Co-Authors: Panagiotis I Sergouniotis, Michel Michaelides, Andrew R. Webster, Anthony G. Robson, Graham E. Holder, Anthony T Moore
    Abstract:

    ABSTRACT Aim To report novel spectral domain optical coherence tomography (SD-OCT) findings and new mutational data in patients with 'Cone Dystrophy with supernormal rod electroretinogram', a recessive childhood onset retinal Dystrophy consequent upon mutation in the KCNV2 gene. Design/methods This was a comparative case series study of 12 patients with clinical and/or electrophysiological findings in keeping with KCNV2 mutation. Clinical examination and electrophysiological testing results were reviewed. Fundus photography and autofluorescence imaging were performed. Retinal layer appearance and thickness were evaluated using SD-OCT. The coding region and introneexon boundaries of KCNV2 were screened by direct sequencing. Results Mutations in KCNV2 were detected in all families; five of these changes were novel. Pattern electroretinograms were undetectable and full-field electroretinograms showed findings specific for the disorder

  • Cone opsins, colour blindness and Cone Dystrophy: Genotype-phenotype correlations.
    South African Medical Journal, 2016
    Co-Authors: Jessica C Gardner, Michel Michaelides, Alison J. Hardcastle
    Abstract:

    X-linked Cone photoreceptor disorders caused by mutations in the OPN1LW (L) and OPN1MW (M) Cone opsin genes on chromosome Xq28 include a range of conditions from mild stable red-green colour vision deficiencies to severe Cone dystrophies causing progressive loss of vision and blindness. Advances in molecular genotyping and functional analyses of causative variants, combined with deep retinal phenotyping, are unravelling genetic mechanisms underlying the variability of Cone opsin disorders.

  • Progressive Cone Dystrophy Associated with Mutation in CNGB3
    2015
    Co-Authors: Michel Michaelides, Anthony T Moore, Irene A. Aligianis, John R. Ainsworth, Peter Good, John D. Mollon, Eamonn R. Maher, David M. Hunt
    Abstract:

    PURPOSE. To determine the molecular basis for phenotypic variability in a three-generation consanguineous family contain-ing a single individual with complete achromatopsia and three individuals with progressive Cone Dystrophy. METHODS. Four affected individuals underwent ophthalmic ex-amination, electrophysiological assessment, color fundus pho-tography, and psychophysical testing. Blood samples were obtained for DNA extraction and mutation screening of the Cone-specific cGMP-gated (CNG) channel protein gene CNGB3 was undertaken. RESULTS. The clinical findings in one family member were consistent with a diagnosis of complete achromatopsia, with nystagmus, photophobia, and poor visual acuity from early infancy and complete color-blindness, normal fundi, and ab-sent Cone responses with normal rod responses on electroreti-nography (ERG). Mutation analysis revealed her to be homozy-gous for the common CNGB3 achromatopsia mutation, 1148delC (Thr383fs). In contrast, the three other symptomatic individuals in the family had findings consistent with progres-sive Cone Dystrophy. Their visual problems began later in childhood (ranging from 3 to 14 years of age) and there was evidence of progressive deterioration in Cone function. All three had a marked tritanopic color vision defect and fundos-copy revealed bilateral macular atrophy. Electrophysiological testing of these three subjects demonstrated clear evidence of progressive deterioration of Cone responses over time; rod responses were normal. All three individuals with this progres-sive phenotype were found to be compound heterozygotes for the 1148delC (Thr383fs) frameshift mutation and a novel Arg403Gln missense mutation in CNGB3. CONCLUSIONS. Mutations in CNGB3, which have been shown to cause achromatopsia, are now shown to be associated with autosomal recessive progressive Cone Dystrophy. In this study, a novel Arg403Gln mutation was identified, located in the middle of the pore domain of the Cone CNG cation channel -subunit, which when associated with the nonsense mutation Thr383fs, resulted in progressive Cone Dystrophy. (Invest Oph

  • Cone Dystrophy with supernormal rod erg psychophysical testing shows comparable rod and Cone temporal sensitivity losses with no gain in rod function
    Investigative Ophthalmology & Visual Science, 2014
    Co-Authors: Andrew Stockman, Michel Michaelides, Anthony T Moore, Andrew R. Webster, Bruce G Henning, Jocelyn Cammack, Caterina Ripamonti
    Abstract:

    Purpose: We report a psychophysical investigation of five observers with the retinal disorder "Cone Dystrophy with supernormal rod ERG", caused by mutations in the gene KCNV2 that encodes a voltage-gated potassium channel found in rod and Cone photoreceptors. We compare losses for rod- and for Cone-mediated vision to further investigate the disorder and to assess whether the supernormal ERG is associated with any visual benefit. Methods: L-Cone, S-Cone and rod temporal acuity (critical flicker fusion frequency-cff) was measured as a function of target irradiance; L-Cone temporal contrast-sensitivity was measured as a function of temporal frequency. Results: Temporal acuity measures reveal that losses for vision mediated by rods, S-Cones and L-Cones are roughly equivalent. Further, the gain in rod function implied by the supernormal ERG provides no apparent benefit to near-threshold rod-mediated visual performance. The L-Cone temporal contrast-sensitivity function in affected observers is similar in shape to the mean normal function but only after the mean function has been compressed by halving the logarithmic sensitivities. Conclusions: The name of this disorder is potentially misleading because the comparable losses found across rod and Cone vision suggest that the disorder is a generalized Cone-rod Dystrophy. Temporal acuity and temporal contrast-sensitivity measures are broadly consistent with the defect in the voltage-gated potassium channel producing a nonlinear distortion of the photoreceptor response but after otherwise normal transduction processes.

  • dominant Cone rod Dystrophy a mouse model generated by gene targeting of the gcap1 guca1a gene
    PLOS ONE, 2011
    Co-Authors: Prateek K Buch, Michel Michaelides, Marija Mihelec, Phillippa Cottrill, Susan E Wilkie, Rachael A Pearson, Y Duran, Emma L West, Robin R Ali, David M. Hunt
    Abstract:

    Cone Dystrophy 3 (COD3) is a severe dominantly inherited retinal degeneration caused by missense mutations in GUCA1A, the gene encoding Guanylate Cyclase Activating Protein 1 (GCAP1). The role of GCAP1 in controlling cyclic nucleotide levels in photoreceptors has largely been elucidated using knock-out mice, but the disease pathology in these mice cannot be extrapolated directly to COD3 as this involves altered, rather than loss of, GCAP1 function. Therefore, in order to evaluate the pathology of this dominant disorder, we have introduced a point mutation into the murine Guca1a gene that causes an E155G amino acid substitution; this is one of the disease-causing mutations found in COD3 patients. Disease progression in this novel mouse model of Cone Dystrophy was determined by a variety of techniques including electroretinography (ERG), retinal histology, immunohistochemistry and measurement of cGMP levels. It was established that although retinal development was normal up to 3 months of age, there was a subsequent progressive decline in retinal function, with a far greater alteration in Cone than rod responses, associated with a corresponding loss of photoreceptors. In addition, we have demonstrated that accumulation of cyclic GMP precedes the observed retinal degeneration and is likely to contribute to the disease mechanism. Importantly, this knock-in mutant mouse has many features in common with the human disease, thereby making it an excellent model to further probe disease pathogenesis and investigate therapeutic interventions.

Andrew R. Webster - One of the best experts on this subject based on the ideXlab platform.

  • High-resolution optical coherence tomography imaging in KCNV2 retinopathy
    2020
    Co-Authors: Panagiotis I Sergouniotis, Michel Michaelides, Andrew R. Webster, Anthony G. Robson, Graham E. Holder, Anthony T Moore
    Abstract:

    ABSTRACT Aim To report novel spectral domain optical coherence tomography (SD-OCT) findings and new mutational data in patients with 'Cone Dystrophy with supernormal rod electroretinogram', a recessive childhood onset retinal Dystrophy consequent upon mutation in the KCNV2 gene. Design/methods This was a comparative case series study of 12 patients with clinical and/or electrophysiological findings in keeping with KCNV2 mutation. Clinical examination and electrophysiological testing results were reviewed. Fundus photography and autofluorescence imaging were performed. Retinal layer appearance and thickness were evaluated using SD-OCT. The coding region and introneexon boundaries of KCNV2 were screened by direct sequencing. Results Mutations in KCNV2 were detected in all families; five of these changes were novel. Pattern electroretinograms were undetectable and full-field electroretinograms showed findings specific for the disorder

  • Identification and characterization of the VAX2 p.Leu139Arg variant: possible involvement of VAX2 in Cone Dystrophy
    2018
    Co-Authors: Giovanna Alfano, Andrew R. Webster, Naushin H. Waseem, Shomi S. Bhattacharya
    Abstract:

    Objective: This study was undertaken with the objective to investigate the potential involvement of VAX2 in retinal degeneration. Methods: A cohort of macular and Cone Dystrophy patients (n = 70) was screened for variant identification. Polymerase chain reaction (PCR) products were purified using ExoSAP-IT. Direct sequencing of PCR products was performed using BigDye 3.1 on the ABI 3730 DNA Analyzer and analyzed using DNASTAR software tool. Search for known variant was performed using the following platforms: 1000 Genomes Project, Ensembl, UCSC, ExAc, and dbSNP. The VAX2 mutants were generated using the GeneArt® Site-Directed Mutagenesis kit. In vitro analysis was performed in hTERTRPE-1 (RPE-1) cell line. Cells were photographed using a Zeiss AXIOVERT S100 microscope. Images were analyzed using Photoshop CS4 software. Results: Here, we report the identification of a heterozygous non-synonymous variant (c.416T>G; p.Leu139Arg) in one Cone Dystrophy proband. Functional characterization of this variant in vitro revealed an aberrant phenotype seen as protein mislocalization to cytoplasm/nucleus and aggregates undergoing degradation or forming aggresomes. The cellular phenotype suggests protein loss-of-function. Analysis of the VAX2 p.Leu139Met, a variant present in the normal population, showed a phenotype similar to the wild-type, further supporting the hypothesis for the Leucine 139 to Arginine change to be damaging. Conclusions: This study raises the interesting possibility for evaluating VAX2 as a candidate gene for Cone Dystrophy.

  • Cone Dystrophy with supernormal rod erg psychophysical testing shows comparable rod and Cone temporal sensitivity losses with no gain in rod function
    Investigative Ophthalmology & Visual Science, 2014
    Co-Authors: Andrew Stockman, Michel Michaelides, Anthony T Moore, Andrew R. Webster, Bruce G Henning, Jocelyn Cammack, Caterina Ripamonti
    Abstract:

    Purpose: We report a psychophysical investigation of five observers with the retinal disorder "Cone Dystrophy with supernormal rod ERG", caused by mutations in the gene KCNV2 that encodes a voltage-gated potassium channel found in rod and Cone photoreceptors. We compare losses for rod- and for Cone-mediated vision to further investigate the disorder and to assess whether the supernormal ERG is associated with any visual benefit. Methods: L-Cone, S-Cone and rod temporal acuity (critical flicker fusion frequency-cff) was measured as a function of target irradiance; L-Cone temporal contrast-sensitivity was measured as a function of temporal frequency. Results: Temporal acuity measures reveal that losses for vision mediated by rods, S-Cones and L-Cones are roughly equivalent. Further, the gain in rod function implied by the supernormal ERG provides no apparent benefit to near-threshold rod-mediated visual performance. The L-Cone temporal contrast-sensitivity function in affected observers is similar in shape to the mean normal function but only after the mean function has been compressed by halving the logarithmic sensitivities. Conclusions: The name of this disorder is potentially misleading because the comparable losses found across rod and Cone vision suggest that the disorder is a generalized Cone-rod Dystrophy. Temporal acuity and temporal contrast-sensitivity measures are broadly consistent with the defect in the voltage-gated potassium channel producing a nonlinear distortion of the photoreceptor response but after otherwise normal transduction processes.

  • a detailed phenotypic description of autosomal dominant Cone Dystrophy due to a de novo mutation in the gucy2d gene
    Eye, 2014
    Co-Authors: Rajarshi Mukherjee, Anthony T Moore, Anthony G. Robson, Andrew Stockman, G E Holder, Catherine A Egan, Andrew R. Webster
    Abstract:

    The purpose of this study is to describe the phenotype of a family with de novo mutation in the GUCY2D. Five subjects, including two monozygotic twins, underwent ophthalmic clinical examination while some had autofluorescence imaging (AF) and optical coherence tomography (OCT). Symptomatic individuals underwent electrophysiological testing. The youngest subject (21 years) was also evaluated psychophysically. DNA obtained from the individuals was screened for mutations in GUCY2D. Microsatellite markers were used to determine the haplotype of 17p surrounding the GUCY2D gene. The youngest subject had 6/18 visual acuity, an annulus of hyper-autofluorescence in the perifoveal region, and a subfoveal absence of outer segments on OCT. In the older individuals, severe thinning of inner retina and a patchy loss of photoreceptors and retinal pigment epithelium were observed in the perifoveal region. All three showed generalised Cone system dysfunction with preserved rod function on electrophysiology. Psychophysical evaluation was consistent with poor Cone function. Screening of the GUCY2D gene revealed the mutation p.R838H in all the affected individuals and was absent in the asymptomatic patients. Haplotyping showed that the mutation originated from the unaffected mother. Autosomal dominant Cone Dystrophy due to GUCY2D can occur without a history in the antecedents due to a de novo mutation. This is important to consider in any simplex case with a similar phenotype. The phenotype description of this disorder is expanded with detailed description of the OCT findings. This paper describes the concordance of the phenotypic findings in the monozygotic twins.

  • A homozygous mutation in the TUB gene associated with retinal Dystrophy and obesity.
    Human mutation, 2013
    Co-Authors: Arundhati Dev Borman, Andrew R. Webster, Donna S. Mackay, Robert H. Henderson, Naushin Waseem, Laura R. Pearce, Kerstin Nagel-wolfrum, Alice E. Davidson, Sumedha Garg, Vincent Plagnol
    Abstract:

    Inherited retinal dystrophies are a major cause of childhood blindness. Here, we describe the identification of a homozygous frameshift mutation (c.1194_1195delAG, p.Arg398Serfs*9) in TUB in a child from a consanguineous UK Caucasian family investigated using autozygosity mapping and whole-exome sequencing. The proband presented with obesity, night blindness, decreased visual acuity, and electrophysiological features of a rod Cone Dystrophy. The mutation was also found in two of the proband's siblings with retinal Dystrophy and resulted in mislocalization of the truncated protein. In contrast to known forms of retinal Dystrophy, including those caused by mutations in the tubby-like protein TULP-1, loss of function of TUB in the proband and two affected family members was associated with early-onset obesity, consistent with an additional role for TUB in energy homeostasis.

Anthony G. Robson - One of the best experts on this subject based on the ideXlab platform.

  • High-resolution optical coherence tomography imaging in KCNV2 retinopathy
    2020
    Co-Authors: Panagiotis I Sergouniotis, Michel Michaelides, Andrew R. Webster, Anthony G. Robson, Graham E. Holder, Anthony T Moore
    Abstract:

    ABSTRACT Aim To report novel spectral domain optical coherence tomography (SD-OCT) findings and new mutational data in patients with 'Cone Dystrophy with supernormal rod electroretinogram', a recessive childhood onset retinal Dystrophy consequent upon mutation in the KCNV2 gene. Design/methods This was a comparative case series study of 12 patients with clinical and/or electrophysiological findings in keeping with KCNV2 mutation. Clinical examination and electrophysiological testing results were reviewed. Fundus photography and autofluorescence imaging were performed. Retinal layer appearance and thickness were evaluated using SD-OCT. The coding region and introneexon boundaries of KCNV2 were screened by direct sequencing. Results Mutations in KCNV2 were detected in all families; five of these changes were novel. Pattern electroretinograms were undetectable and full-field electroretinograms showed findings specific for the disorder

  • the phenotypic variability of retinal dystrophies associated with mutations in crx with report of a novel macular Dystrophy phenotype
    Investigative Ophthalmology & Visual Science, 2014
    Co-Authors: Sarah Hull, Vincent Plagnol, Anthony G. Robson, Graeme C.m. Black, Gavin Arno, Sarah Chamney, Isabelle Russelleggitt, Dorothy A Thompson, Simon C Ramsden, Graham E. Holder
    Abstract:

    PURPOSE: To present a detailed phenotypic and molecular study of a series of 18 patients from 11 families with retinal dystrophies consequent on mutations in the Cone-rod homeobox (CRX) gene and to report a novel phenotype. METHODS: Families were ascertained from a tertiary clinic in the United Kingdom and enrolled into retinal Dystrophy studies investigating the phenotype and molecular basis of inherited retinal disease. Eleven patients were ascertained from the study cohorts and a further seven from investigation of affected relatives. Detailed phenotyping included electrodiagnostic testing and retinal imaging. Bidirectional Sanger sequencing of all exons and intron-exon boundaries of CRX was performed on all 18 reported patients and segregation confirmed in available relatives. RESULTS: Based on clinical characteristics and electrophysiology, four patients had Leber congenital amaurosis (LCA), two had rod-Cone Dystrophy (RCD), five had Cone-rod Dystrophy (CORD), one had Cone Dystrophy (COD), and six had macular Dystrophy with different phenotypes observed within 5 of 11 families. The macular Dystrophy patients presented between 35 to 50 years of age and had visual acuities at last review ranging from 0.2 to 1.5 logMAR (20/32 to 20/630 Snellen). All 18 patients were heterozygous for a mutation in CRX with seven novel mutations identified. There was no evident association between age of onset and position or type of CRX mutation. De novo mutations were confirmed in three patients. CONCLUSIONS: Mutations in CRX demonstrate significant phenotypic heterogeneity both between and within pedigrees. A novel, adult-onset, macular Dystrophy phenotype is characterized, further extending our knowledge of the etiology of dominant macular dystrophies.

  • a detailed phenotypic description of autosomal dominant Cone Dystrophy due to a de novo mutation in the gucy2d gene
    Eye, 2014
    Co-Authors: Rajarshi Mukherjee, Anthony T Moore, Anthony G. Robson, Andrew Stockman, G E Holder, Catherine A Egan, Andrew R. Webster
    Abstract:

    The purpose of this study is to describe the phenotype of a family with de novo mutation in the GUCY2D. Five subjects, including two monozygotic twins, underwent ophthalmic clinical examination while some had autofluorescence imaging (AF) and optical coherence tomography (OCT). Symptomatic individuals underwent electrophysiological testing. The youngest subject (21 years) was also evaluated psychophysically. DNA obtained from the individuals was screened for mutations in GUCY2D. Microsatellite markers were used to determine the haplotype of 17p surrounding the GUCY2D gene. The youngest subject had 6/18 visual acuity, an annulus of hyper-autofluorescence in the perifoveal region, and a subfoveal absence of outer segments on OCT. In the older individuals, severe thinning of inner retina and a patchy loss of photoreceptors and retinal pigment epithelium were observed in the perifoveal region. All three showed generalised Cone system dysfunction with preserved rod function on electrophysiology. Psychophysical evaluation was consistent with poor Cone function. Screening of the GUCY2D gene revealed the mutation p.R838H in all the affected individuals and was absent in the asymptomatic patients. Haplotyping showed that the mutation originated from the unaffected mother. Autosomal dominant Cone Dystrophy due to GUCY2D can occur without a history in the antecedents due to a de novo mutation. This is important to consider in any simplex case with a similar phenotype. The phenotype description of this disorder is expanded with detailed description of the OCT findings. This paper describes the concordance of the phenotypic findings in the monozygotic twins.

  • pathognomonic diagnostic ergs a review and update
    Retina-the Journal of Retinal and Vitreous Diseases, 2013
    Co-Authors: Ajoy Vincent, Anthony G. Robson, Graham E. Holder
    Abstract:

    Purpose To review three inherited retinal disorders associated with diagnostic or pathognomonic electroretinogram (ERG) abnormalities: Cone Dystrophy with supernormal rod ERG (KCNV2), enhanced S-Cone syndrome (NR2E3), and bradyopsia (RGS9/R9AP). Methods A review of clinical details, genetic basis, and electrophysiological features in these disorders and a brief summary of the standard and nonstandard ERG techniques required to identify the disorders. Results The electrophysiological features in each of these three disorders are pathognomonic such that the responsible gene can be specified. The results from nonstandard electrophysiological testing in excess of international standards are necessary to describe the pathognomonic changes in Cone Dystrophy with supernormal rod ERG and bradyopsia. The clinical phenotype in the disorders can be variable. Mutations in NR2E3 may additionally be associated with phenotypes other than enhanced S-Cone syndrome. Conclusion : Characteristic ERG changes enable the diagnosis of Cone Dystrophy with supernormal rod ERG, enhanced S-Cone syndrome, and bradyopsia and accurate genetic screening. This review highlights the need for additional nonstandard ERGs to make the diagnosis in two of these disorders.

  • A Novel Missense Mutation in Both OPN1LW and OPN1MW Cone Opsin Genes Causes X-Linked Cone Dystrophy (XLCOD5)
    Retinal Degenerative Diseases, 2011
    Co-Authors: Jessica C Gardner, Naheed Kanuga, Tom R. Webb, Anthony G. Robson, Graham E. Holder, Andrew Stockman, Caterina Ripamonti, Neil D. Ebenezer, Olufunmilola A. Ogun, Sophie Devery
    Abstract:

    X-linked Cone and Cone-rod dystrophies (XLCOD and XLCORD) are an inherited group of retinal disorders primarily involving Cone photoreceptors. The most common cause is mutation of RPGR. In a British family with XLCOD, we mapped the disorder to Xq26.1-qter, excluding RPGR and other known retinal degeneration genes. The Cone opsin gene array on Xq28 was a positional candidate locus. A novel missense mutation (c.529T > C; p.W177R) was identified in exon 3 of both the long wavelength-sensitive (OPN1LW; LW, red) and medium wavelength-sensitive (OPN1MW; MW, green) Cone opsin genes, which segregated with disease. Exon 3 sequences of both genes were identical, derived from the OPN1MW gene by partial gene conversion. The amino acid W177 is conserved in all opsins across species. We have shown that W177R in MW opsin results in protein misfolding and retention in the endoplasmic reticulum (ER). Mutations in the OPN1LW /OPN1MW Cone opsin gene array can therefore cause a spectrum of phenotypes, from colour blindness to progressive Cone Dystrophy (XLCOD5).

Anthony T Moore - One of the best experts on this subject based on the ideXlab platform.

  • High-resolution optical coherence tomography imaging in KCNV2 retinopathy
    2020
    Co-Authors: Panagiotis I Sergouniotis, Michel Michaelides, Andrew R. Webster, Anthony G. Robson, Graham E. Holder, Anthony T Moore
    Abstract:

    ABSTRACT Aim To report novel spectral domain optical coherence tomography (SD-OCT) findings and new mutational data in patients with 'Cone Dystrophy with supernormal rod electroretinogram', a recessive childhood onset retinal Dystrophy consequent upon mutation in the KCNV2 gene. Design/methods This was a comparative case series study of 12 patients with clinical and/or electrophysiological findings in keeping with KCNV2 mutation. Clinical examination and electrophysiological testing results were reviewed. Fundus photography and autofluorescence imaging were performed. Retinal layer appearance and thickness were evaluated using SD-OCT. The coding region and introneexon boundaries of KCNV2 were screened by direct sequencing. Results Mutations in KCNV2 were detected in all families; five of these changes were novel. Pattern electroretinograms were undetectable and full-field electroretinograms showed findings specific for the disorder

  • Progressive Cone Dystrophy Associated with Mutation in CNGB3
    2015
    Co-Authors: Michel Michaelides, Anthony T Moore, Irene A. Aligianis, John R. Ainsworth, Peter Good, John D. Mollon, Eamonn R. Maher, David M. Hunt
    Abstract:

    PURPOSE. To determine the molecular basis for phenotypic variability in a three-generation consanguineous family contain-ing a single individual with complete achromatopsia and three individuals with progressive Cone Dystrophy. METHODS. Four affected individuals underwent ophthalmic ex-amination, electrophysiological assessment, color fundus pho-tography, and psychophysical testing. Blood samples were obtained for DNA extraction and mutation screening of the Cone-specific cGMP-gated (CNG) channel protein gene CNGB3 was undertaken. RESULTS. The clinical findings in one family member were consistent with a diagnosis of complete achromatopsia, with nystagmus, photophobia, and poor visual acuity from early infancy and complete color-blindness, normal fundi, and ab-sent Cone responses with normal rod responses on electroreti-nography (ERG). Mutation analysis revealed her to be homozy-gous for the common CNGB3 achromatopsia mutation, 1148delC (Thr383fs). In contrast, the three other symptomatic individuals in the family had findings consistent with progres-sive Cone Dystrophy. Their visual problems began later in childhood (ranging from 3 to 14 years of age) and there was evidence of progressive deterioration in Cone function. All three had a marked tritanopic color vision defect and fundos-copy revealed bilateral macular atrophy. Electrophysiological testing of these three subjects demonstrated clear evidence of progressive deterioration of Cone responses over time; rod responses were normal. All three individuals with this progres-sive phenotype were found to be compound heterozygotes for the 1148delC (Thr383fs) frameshift mutation and a novel Arg403Gln missense mutation in CNGB3. CONCLUSIONS. Mutations in CNGB3, which have been shown to cause achromatopsia, are now shown to be associated with autosomal recessive progressive Cone Dystrophy. In this study, a novel Arg403Gln mutation was identified, located in the middle of the pore domain of the Cone CNG cation channel -subunit, which when associated with the nonsense mutation Thr383fs, resulted in progressive Cone Dystrophy. (Invest Oph

  • Cone Dystrophy with supernormal rod erg psychophysical testing shows comparable rod and Cone temporal sensitivity losses with no gain in rod function
    Investigative Ophthalmology & Visual Science, 2014
    Co-Authors: Andrew Stockman, Michel Michaelides, Anthony T Moore, Andrew R. Webster, Bruce G Henning, Jocelyn Cammack, Caterina Ripamonti
    Abstract:

    Purpose: We report a psychophysical investigation of five observers with the retinal disorder "Cone Dystrophy with supernormal rod ERG", caused by mutations in the gene KCNV2 that encodes a voltage-gated potassium channel found in rod and Cone photoreceptors. We compare losses for rod- and for Cone-mediated vision to further investigate the disorder and to assess whether the supernormal ERG is associated with any visual benefit. Methods: L-Cone, S-Cone and rod temporal acuity (critical flicker fusion frequency-cff) was measured as a function of target irradiance; L-Cone temporal contrast-sensitivity was measured as a function of temporal frequency. Results: Temporal acuity measures reveal that losses for vision mediated by rods, S-Cones and L-Cones are roughly equivalent. Further, the gain in rod function implied by the supernormal ERG provides no apparent benefit to near-threshold rod-mediated visual performance. The L-Cone temporal contrast-sensitivity function in affected observers is similar in shape to the mean normal function but only after the mean function has been compressed by halving the logarithmic sensitivities. Conclusions: The name of this disorder is potentially misleading because the comparable losses found across rod and Cone vision suggest that the disorder is a generalized Cone-rod Dystrophy. Temporal acuity and temporal contrast-sensitivity measures are broadly consistent with the defect in the voltage-gated potassium channel producing a nonlinear distortion of the photoreceptor response but after otherwise normal transduction processes.

  • a detailed phenotypic description of autosomal dominant Cone Dystrophy due to a de novo mutation in the gucy2d gene
    Eye, 2014
    Co-Authors: Rajarshi Mukherjee, Anthony T Moore, Anthony G. Robson, Andrew Stockman, G E Holder, Catherine A Egan, Andrew R. Webster
    Abstract:

    The purpose of this study is to describe the phenotype of a family with de novo mutation in the GUCY2D. Five subjects, including two monozygotic twins, underwent ophthalmic clinical examination while some had autofluorescence imaging (AF) and optical coherence tomography (OCT). Symptomatic individuals underwent electrophysiological testing. The youngest subject (21 years) was also evaluated psychophysically. DNA obtained from the individuals was screened for mutations in GUCY2D. Microsatellite markers were used to determine the haplotype of 17p surrounding the GUCY2D gene. The youngest subject had 6/18 visual acuity, an annulus of hyper-autofluorescence in the perifoveal region, and a subfoveal absence of outer segments on OCT. In the older individuals, severe thinning of inner retina and a patchy loss of photoreceptors and retinal pigment epithelium were observed in the perifoveal region. All three showed generalised Cone system dysfunction with preserved rod function on electrophysiology. Psychophysical evaluation was consistent with poor Cone function. Screening of the GUCY2D gene revealed the mutation p.R838H in all the affected individuals and was absent in the asymptomatic patients. Haplotyping showed that the mutation originated from the unaffected mother. Autosomal dominant Cone Dystrophy due to GUCY2D can occur without a history in the antecedents due to a de novo mutation. This is important to consider in any simplex case with a similar phenotype. The phenotype description of this disorder is expanded with detailed description of the OCT findings. This paper describes the concordance of the phenotypic findings in the monozygotic twins.

  • Cone Dystrophy with supernormal rod electroretinogram a comprehensive genotype phenotype study including fundus autofluorescence and extensive electrophysiology
    Retina-the Journal of Retinal and Vitreous Diseases, 2010
    Co-Authors: Anthony G. Robson, Michel Michaelides, Anthony T Moore, Andrew R. Webster, Susan M. Downes, David M. Hunt, Ja Cowing, Graham E. Holder
    Abstract:

    Purpose: The purpose of this study was to characterize the clinical, electrophysiologic, and genetic features in "Cone Dystrophy with supernormal rod electroretinogram (ERG)."Methods: Twenty-four cases between 5 and 59 years of age were ascertained. Full-field ERGs, incorporating the international standards, were used to derive intensity-ERG response functions. ON-OFF ERGs were performed. Fundus autofluorescence imaging was performed on 15 subjects. Deoxyribonucleic acid was available in 18 cases and was screened for a mutation in KCNV2.Results: Photophobia and nyctalopia were common. Autofluorescence was variable but often showed a ring-like area of high density that in middle-aged individuals, usually surrounded by an area of macular retinal pigment epithelial atrophy. Scotopic ERG amplitudes overlapped with the normal range but had characteristic a-and b-wave intensity-response functions; all had a broadened a-wave to the brightest flash. Photopic ERGs were abnormal; there was a delay in some ON and most OFF responses. Mutations in KCNV2 were detected in 18 cases, including 4 with novel mutations.Conclusion: Individuals with mutations in KCNV2 manifest a wide range of macular and autofluorescence abnormalities. A ring-like area of parafoveal high density autofluorescence is common. ERG amplitudes are variable, but the intensity-ERG response functions and bright flash ERG waveforms are pathognomonic. RETINA 30:51-62,2010