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Carel B. Hoyng - One of the best experts on this subject based on the ideXlab platform.

  • Foveal Sparing in Central Retinal Dystrophies
    Investigative ophthalmology & visual science, 2019
    Co-Authors: Nathalie M. Bax, Carel B. Hoyng, Camiel J. F. Boon, B. Jeroen Klevering, Frans P.m. Cremers, Monika Fleckenstein, Dyon Valkenburg, Stanley Lambertus, Frank G. Holz, Moritz Lindner
    Abstract:

    Purpose: To describe foveal sparing (FS) in central retinal dystrophies (RD). Methods: Participants for this retrospective study were identified from the retinal Dystrophy database of the Department of Ophthalmology at Radboud University Medical Center. FS was defined as an intact foveal structure surrounded by at least 180° of chorioretinal atrophy, and a best-corrected visual acuity (BCVA) of 20/200 Snellen). Eligible eyes were identified using fundus autofluorescence (FAF) images, and FS was confirmed using near-infrared reflectance (NIR) imaging and spectral-domain optical coherence tomography when available. Clinical and demographic data were extracted from medical records. We performed quantification of FS and chorioretinal atrophic areas using semiautomated software on fundus autofluorescence and NIR images. We calculated the chronologic change using eye-wise linear regression. Results: We identified 36 patients (56 eyes) with FS. RDs included: Stargardt disease (STGD1;20 patients), central areolar Choroidal Dystrophy (CACD; 7 patients), mitochondrial retinal Dystrophy (MRD; 6 patients), pseudo-Stargardt pattern Dystrophy (PSPD; 3 patients). Median age at first presentation was 60 (interquartile range [IQR] 54-63) years. Median BCVA at first presentation ranged from 20/25 Snellen in STGD1, to 20/38 Snellen in MRD. Progression of the chorioretinal atrophic area ranged from 0.26 (0.25-0.28) mm/year in PSPD, to 0.14 (0.11-0.22) in CACD. Change in FS area over time was similar between the different dystrophies. Conclusions: The presence of FS in different RDs suggests a disease-independent mechanism that prolongs the survival of the fovea. The associated preservation of BCVA is important for the individual prognosis and has implications for the design of therapeutic trials for RDs.

  • Genetic screening for macular dystrophies in patients clinically diagnosed with dry age-related macular degeneration.
    Clinical genetics, 2018
    Co-Authors: Eveline Kersten, Carel B. Hoyng, Maartje J. Geerlings, Marc Pauper, Jordi Corominas, Bjorn Bakker, Lebriz Altay, Sascha Fauser, Eiko K. De Jong, Anneke I. Den Hollander
    Abstract:

    It can be clinically challenging to distinguish dry age-related macular degeneration (AMD) from AMD-mimicking dystrophies, and sometimes misdiagnosis occurs. With upcoming therapies for dry AMD it is important to exclude patients with a different retinal disease from clinical trials. In this study we evaluated the occurrence of AMD-mimicking dystrophies in an AMD cohort. Whole-exome sequencing (WES) was performed in 218 patients with intermediate AMD or geographic atrophy secondary to AMD and 133 control individuals. WES data was analyzed for rare variants in 19 genes associated with autosomal dominant and recessive macular dystrophies mimicking AMD. In three (1.4%) of 218 cases we identified a pathogenic heterozygous variant (PRPH2 c.424C > T; p.R142W) causal for autosomal dominant central areolar Choroidal Dystrophy (CACD). Phenotypically, these patients all presented with geographic atrophy. In 12 (5.5%) of 218 cases we identified a heterozygous variant of unknown clinical significance, but predicted to be highly deleterious, in genes previously associated with autosomal dominant macular dystrophies. The distinction between AMD and AMD-mimicking dystrophies, such as CACD, can be challenging based on fundus examination alone. Genetic screening for genes associated with macular dystrophies, especially PRPH2, can be beneficial to help identify AMD-mimicking dystrophies.

  • Central Areolar Choroidal Dystrophy (CACD) and Age-Related Macular Degeneration (AMD): Differentiating Characteristics in Multimodal Imaging
    Investigative ophthalmology & visual science, 2011
    Co-Authors: D. Smailhodzic, Carel B. Hoyng, Camiel J. F. Boon, Thomas Theelen, Anneke I. Den Hollander, Monika Fleckenstein, Ramon A. C. Van Huet, Johannes P. H. Van De Ven, Steffen Schmitz-valckenberg, Bernhard H. F. Weber
    Abstract:

    Purpose. Late-onset central areolar Choroidal Dystrophy (CACD) may easily be confused with geographic atrophy (GA) in AMD. To detect discerning features, the morphologic changes in CACD patients and in AMD patients were assessed with confocal scanning laser ophthalmoscopy (cSLO), fundus autofluorescence (FAF), and spectral-domain optical coherence tomography (SD-OCT). Methods. A total of 30 CACD patients with identified PRPH2 gene mutations were analyzed and compared to 19 patients with early AMD and 13 patients with AMD-associated GA. The presence of drusen and pigment clumping was determined with color fundus photography. High-resolution in vivo imaging was performed with cSLO and SD-OCT. FAF images and SD-OCT volume scans were analyzed in each study eye. Results. On FAF, a speckled FAF pattern occurred significantly more often in CACD (85%) than in early AMD (5.6%; P < 0.0001). There was a significantly higher frequency of sub-RPE deposits in eyes with AMD than in eyes with CACD (36.8% versus 2.1% of scans, P = 0.0019). Reticular drusen could be visualized by SD-OCT and FAF imaging in 52.6% of the eyes with early AMD and in 100% of the eyes with GA, whereas this drusen phenotype did not manifest in eyes with CACD. Conclusions. Although outer retinal atrophy is the clinically common feature in advanced CACD as well as GA, there are microstructural alterations on high-resolution SD-OCT and FAF imaging that allow for the differentiation between CACD and AMD. The findings may help to identify patients in whom a diagnostic PRPH2 screening is warranted. (ClinicalTrials.gov number, NCT00393692.).

  • Early findings in central areolar Choroidal Dystrophy.
    Acta ophthalmologica, 2009
    Co-Authors: Carel B. Hoyng, Alfred J. L. G. Pinckers, August F. Deutman
    Abstract:

    We examined 69 members of two caucasian families with an autosomal dominant form of central areolar Choroidal Dystrophy using ophthalmoscopy and fundus photography. In five members who had a good visual acuity macular lesions were found. In three of them retinal function tests were performed, which turned out to be normal. These 5 patients underwent fluorescein angiography. Early symptoms of central areolar Choroidal Dystrophy are small parafoveal hyperfluorescent areas due to retinal pigmentepithelium loss and areas of pigment mottling in the macula. Until now the early lesions of central areolar Choroidal Dystrophy in patients with a good visual acuity in both eyes have not been described clearly.

  • Central Areolar Choroidal Dystrophy
    Ophthalmology, 2009
    Co-Authors: Camiel J. F. Boon, B. Jeroen Klevering, Frans P.m. Cremers, Marijke N. Zonneveld-vrieling, Thomas Theelen, Anneke I. Den Hollander, Carel B. Hoyng
    Abstract:

    Objective To describe the clinical characteristics, follow-up data and molecular genetic background in a large group of patients with central areolar Choroidal Dystrophy (CACD). Design Retrospective case series study. Participants One hundred three patients with CACD from the Netherlands. Methods Ophthalmologic examination, including color vision testing, fundus photography, fluorescein angiography, fundus autofluorescence (FAF) imaging, optical coherence tomography, full-field electroretinography (ERG), multifocal ERG, and electrooculography. Blood samples were obtained for DNA extraction and subsequent analysis of the peripherin/RDS gene, as well as haplotype analysis. Main Outcome Measures Clinical characteristics, phenotypic range, clinical follow-up data, and FAF findings. Results The mean age at onset of visual loss was 46 years, with subsequent gradual deterioration in visual acuity. Ninety-eight patients carried a p.Arg142Trp mutation in peripherin/RDS , whereas 5 affected members of a CACD family carried a p.Arg172Gln peripherin/RDS mutation. A remarkable variation in disease severity was observed, and nonpenetrance was seen up to the age of 64 years, in up to 21% of mutation carriers. However, most macular lesions in mutation carriers displayed a typical stage of CACD. Substantial changes were seen on FAF imaging after a mean follow-up period of 11 months. Electrophysiologic data were consistent with a central cone Dystrophy. The age at onset and phenotypic characteristics of CACD show considerable overlap with atrophic age-related macular degeneration (AMD). The great majority of p.Arg142Trp-carrying CACD patients originated from the southeast region of the Netherlands, and haplotype analysis strongly suggested a common founder mutation. Conclusions When caused by a p.Arg142Trp mutation in the peripherin/RDS gene, CACD causes a central cone Dystrophy phenotype. This mutation, which most likely originates from a common founder in most patients, is associated with a significant degree of nonpenetrance. In the elderly patient, CACD may be confused with AMD, especially in cases with decreased penetrance. Financial Disclosure(s) The authors have no proprietary or commercial interest in any materials discussed in this article.

August F. Deutman - One of the best experts on this subject based on the ideXlab platform.

  • Early findings in central areolar Choroidal Dystrophy.
    Acta ophthalmologica, 2009
    Co-Authors: Carel B. Hoyng, Alfred J. L. G. Pinckers, August F. Deutman
    Abstract:

    We examined 69 members of two caucasian families with an autosomal dominant form of central areolar Choroidal Dystrophy using ophthalmoscopy and fundus photography. In five members who had a good visual acuity macular lesions were found. In three of them retinal function tests were performed, which turned out to be normal. These 5 patients underwent fluorescein angiography. Early symptoms of central areolar Choroidal Dystrophy are small parafoveal hyperfluorescent areas due to retinal pigmentepithelium loss and areas of pigment mottling in the macula. Until now the early lesions of central areolar Choroidal Dystrophy in patients with a good visual acuity in both eyes have not been described clearly.

  • Central areolar Choroidal Dystrophy and slowly progressive sensorineural hearing loss
    Acta ophthalmologica Scandinavica, 2009
    Co-Authors: C.b. Hoyng, P.m. Van Rijn, August F. Deutman
    Abstract:

    . Central areolar Choroidal Dystrophy (CACD) is a rare hereditary disorder leading to a central scotoma in middle-aged patients. Two cases of CACD in association with perceptive hearing loss are discussed. A 62-year-old male and a 51-year-old female patient complained of visual deterioration and subsequent hearing loss over several years. In addition to routine ophthalmic and otorhinolaryngological examination both patients underwent fluorescein angiography, (electro)physiological examination and audiometry examination. A demarcated area of atrophy of pigment epithelium and choriocapillaris was found in both patients. A slowly progressive sensorineural hearing loss after adolescence was found in both patients. The hearing deteriorated to such a level at middle age that hearing aids were neccessary. These two cases show that CACD may be associated with perceptive hearing loss.

  • Identification of novel locus for autosomal dominant butterfly shaped macular Dystrophy on 5q21.2–q33.2
    Journal of medical genetics, 2004
    Co-Authors: A.i. Den Hollander, Carel B. Hoyng, August F. Deutman, J. J. C. Van Lith-verhoeven, Ferry F.j. Kersten, J G A M Heister, C. G. F. De Kovel, F.p.m. Cremers
    Abstract:

    Butterfly shaped macular Dystrophy was first described by Deutman et al. in 1970.1 It is characterised by bilateral accumulation of pigmented or yellowish material at the level of the retinal pigment epithelium. Lesions consist of 3–5 “wings,” which resemble the wings of a butterfly. Affected patients present with a subnormal electrooculogram and normal or slightly diminished visual acuity. The disease is relatively benign, but it can progress with age to chorioretinal atrophy in the parafoveal and peripapillary regions.2 Butterfly shaped macular Dystrophy shares important similarities with age related macular degeneration—the most common cause of blindness in older patients.3,4 In both diseases, abnormal deposition of lipofuscin like material at the level of the retinal pigment epithelium is found, which results in loss of the overlying photoreceptors.2 Butterfly shaped macular Dystrophy has an autosomal dominant inheritance pattern. To date, it has been associated only with mutations in the peripherin / RDS gene.5–12 We ascertained members of the family with butterfly shaped macular Dystrophy that was described originally by Deutman et al. in 1970,1 and we excluded peripherin / RDS as the causative gene in this family.2 In addition, we excluded the ROM-1 gene; four genes expressed in cone photoreceptors; all known non-syndromic macular, retinal pigment epithelium, and Choroidal Dystrophy loci; all known Leber congenital amaurosis loci; and all known non-syndromic congenital and stationary retinal disease loci.2 This study aimed to identify the locus responsible for butterfly shaped macular Dystrophy in this family with a genomewide linkage scan. ### Patients and ophthalmic examination We previously ascertained 13 members (eight affected and five unaffected) of a Dutch family with butterfly shaped macular Dystrophy that was first described in 1970 by Deutman et al.1,2 Ophthalmic examination of the participating family members included best corrected Snellen visual acuity, slit …

  • Genetic heterogeneity of butterfly-shaped pigment Dystrophy of the fovea.
    Molecular vision, 2003
    Co-Authors: J. J. C. Van Lith-verhoeven, Carel B. Hoyng, F.p.m. Cremers, L.j.m. Van Den Helm, August F. Deutman
    Abstract:

    PURPOSE: Butterfly-shaped macular Dystrophy (BSMD) has so far only been associated with mutations in the peripherin/RDS gene. The initial aim of our study was to investigate the peripherin/RDS gene as the causative gene in a family with BSMD. Subsequently the putative involvement of the ROM-1 gene, 4 genes expressed in cone photoreceptors, all known non-syndromic macular, retinal pigment epithelium and Choroidal Dystrophy loci, all known Leber congenital amaurosis loci and all known non-syndromic congenital and stationary retinal disease loci was examined. METHODS: Thirteen members from the original family with autosomal dominant BSMD were examined. The protein coding exons of the peripherin/RDS gene were screened for mutations by sequence analysis. Linkage analysis was performed using markers flanking the peripherin/RDS gene to rule out the presence of a heterozygous deletion. Likewise, involvement of the ROM-1 gene, four cone genes, 41 non-syndromic retinal disease loci and one syndromic retinal disease locus was investigated. RESULTS: Sequence analysis of the peripherin/RDS gene revealed no mutations. In addition, the BSMD phenotype could not be genetically linked to the peripherin/RDS gene, the ROM-1 gene and the four cone genes nor to any of the 42 retinal disease loci. CONCLUSIONS: This study reveals genetic heterogeneity for BSMD by the identification of a BSMD family, which is not associated with a mutation in the peripherin/RDS gene nor with any other known non-syndromic retinal disease gene.

  • Central areolar Choroidal Dystrophy associated with dominantly inherited drusen.
    The British journal of ophthalmology, 2002
    Co-Authors: B. Jeroen Klevering, Alfred J. L. G. Pinckers, August F. Deutman, Frans P.m. Cremers, Marc A. Van Driel, August J M Van Hogerwou, Dorien J. R. Van De Pol, Carel B. Hoyng
    Abstract:

    Aim: To describe the clinical and genetic aspects of a retinal Dystrophy that combines central areolar Choroidal Dystrophy (CACD) and autosomal dominantly inherited drusen. Methods: The members of three unrelated families who demonstrated the rare combination of CACD and dominant drusen were clinically and angiographically investigated. In addition, DNA samples from the members of these families were screened for the Arg142Trp mutation in the peripherin/retinal degeneration slow (RDS) gene. Results: The severity of the CACD/dominant drusen maculopathy was age related and the expression of the phenotype varied. All affected individuals carried the Arg142Trp mutation in the peripherin/RDS gene. The clinical spectrum ranged from CACD without noticeable drusen in four individuals to the fully expressed phenotype of CACD with drusen in 14 individuals. Conclusion: CACD macular Dystrophy is associated with dominant drusen in most individuals carrying the Arg142Trp mutation in the peripherin/RDS gene in the three families described. There are no individuals with dominant drusen in the absence of the Arg142Trp mutation, suggesting that the Arg142Trp mutation is one of the factors predisposing to drusen development.

Jan Grøndahl - One of the best experts on this subject based on the ideXlab platform.

Bernhard H. F. Weber - One of the best experts on this subject based on the ideXlab platform.

  • Central Areolar Choroidal Dystrophy (CACD) and Age-Related Macular Degeneration (AMD): Differentiating Characteristics in Multimodal Imaging
    Investigative ophthalmology & visual science, 2011
    Co-Authors: D. Smailhodzic, Carel B. Hoyng, Camiel J. F. Boon, Thomas Theelen, Anneke I. Den Hollander, Monika Fleckenstein, Ramon A. C. Van Huet, Johannes P. H. Van De Ven, Steffen Schmitz-valckenberg, Bernhard H. F. Weber
    Abstract:

    Purpose. Late-onset central areolar Choroidal Dystrophy (CACD) may easily be confused with geographic atrophy (GA) in AMD. To detect discerning features, the morphologic changes in CACD patients and in AMD patients were assessed with confocal scanning laser ophthalmoscopy (cSLO), fundus autofluorescence (FAF), and spectral-domain optical coherence tomography (SD-OCT). Methods. A total of 30 CACD patients with identified PRPH2 gene mutations were analyzed and compared to 19 patients with early AMD and 13 patients with AMD-associated GA. The presence of drusen and pigment clumping was determined with color fundus photography. High-resolution in vivo imaging was performed with cSLO and SD-OCT. FAF images and SD-OCT volume scans were analyzed in each study eye. Results. On FAF, a speckled FAF pattern occurred significantly more often in CACD (85%) than in early AMD (5.6%; P < 0.0001). There was a significantly higher frequency of sub-RPE deposits in eyes with AMD than in eyes with CACD (36.8% versus 2.1% of scans, P = 0.0019). Reticular drusen could be visualized by SD-OCT and FAF imaging in 52.6% of the eyes with early AMD and in 100% of the eyes with GA, whereas this drusen phenotype did not manifest in eyes with CACD. Conclusions. Although outer retinal atrophy is the clinically common feature in advanced CACD as well as GA, there are microstructural alterations on high-resolution SD-OCT and FAF imaging that allow for the differentiation between CACD and AMD. The findings may help to identify patients in whom a diagnostic PRPH2 screening is warranted. (ClinicalTrials.gov number, NCT00393692.).

  • Phenotypic variability and long-term follow-up of patients with known and novel PRPH2/RDS gene mutations.
    American journal of ophthalmology, 2008
    Co-Authors: Agnes B. Renner, Sten Andréasson, Bernhard H. F. Weber, Bernd Wissinger, Britta Fiebig, Andreas Gal, Elke Cropp, Susanne Kohl, Ulrich Kellner
    Abstract:

    Purpose To describe the phenotypic variability in 22 patients with PRPH2 gene mutations and to report six novel mutations. Design Retrospective study. Methods Clinical examinations included color vision testing, perimetry, fundus autofluorescence (FAF), fluorescein angiography, optical coherence tomography (OCT), and full-field and multifocal electroretinography (International Society for Clinical Electrophysiology of Vision standards). Blood samples were taken for deoxyribonucleic acid (DNA) extraction and mutation screening was performed by direct sequencing of polymerase chain reaction amplicons. Results Eleven unrelated patients and four unrelated families each with two affected members as well as one family with three affected members were examined. Diagnoses included central areolar Choroidal Dystrophy (CACD; n = 9), autosomal dominant retinitis pigmentosa (adRP; n = 7), adult vitelliform macular Dystrophy (n = 3), and cone-rod Dystrophy (CRD; n = 3). FAF was abnormal in all patients and showed various retinal pigment epithelial alterations, in CACD with a speckled FAF pattern. OCT revealed reduced retinal thickness, mostly in CACD, subretinal lesions, macula edema, or was normal. Follow-up (n = 12; range, 1.3 to 26 years) showed a slow progression of the retinal dystrophies. DNA testing revealed previously reported PRPH2 mutations in two families and eight individuals of whom two carried the same mutation but had different phenotypes. Novel PRPH2 mutations were detected in two families with adRP, in identical twins with CACD, and in each of an individual with CACD, CRD, and adRP. Conclusions This series describes the broad spectrum of phenotypes associated with PRPH2 mutations. FAF and OCT are helpful tools for diagnosis and evaluation of disease progression. We report novel PRPH2 mutations in patients with CACD, CRD, and adRP.

  • Clinical findings in a multigeneration family with autosomal dominant central areolar Choroidal Dystrophy associated with an Arg195Leu mutation in the peripherin/RDS gene.
    Archives of ophthalmology (Chicago Ill. : 1960), 2006
    Co-Authors: Claudia N. Keilhauer, Thomas Meigen, Bernhard H. F. Weber
    Abstract:

    Objective To characterize clinical findings associated with a mutation in codon 195 (Arg195Leu) of the peripherin/ RDS gene in a large multigeneration family of European decent. Methods Sixteen members from 2 generations underwent ophthalmologic examination, including best-corrected visual acuity, examination of the anterior segments, and inspection of the ocular fundus after pharmacologic mydriasis. All affected family members underwent Farnsworth Panel-D15 color testing. Five selected family members with early stages of the disease underwent multifocal electroretinography. Full-field electroretinography was performed in 2 family members with more advanced fundus changes. Finally, former patients' records and fundus images were analyzed to determine the course of the disease in affected individuals. Results Nine family members in 2 generations were diagnosed as having autosomal dominant central areolar Choroidal Dystrophy. The family demonstrated an age-dependent increase of central granular fundus abnormalities with progressive development of geographic atrophy. Interindividual phenotypic variability was apparent and ranged from predominantly drusenlike depositions to single perifoveal pigment clumps. Age of onset of visual disturbances varied between 27 and 48 years. All individuals who manifested signs of disease were found to carry an Arg195Leu mutation in the peripherin/ RDS gene. Conclusions Age of onset, progression of the disease, and characteristic fundus abnormalities share similarities to previous reports on families with central areolar Choroidal Dystrophy associated with peripherin/ RDS gene mutations in codons 172, 142, and 195, respectively. However, striking variability in individual phenotypic findings and age of onset in our family suggests that additional factors that modify the defined peripherin/ RDS gene mutation Arg195Leu likely influence the severity of the disease. Clinical Relevance Caution should be advised in predicting the clinical course and severity of the disease based solely on a specific mutation in the peripherin/ RDS gene.

  • Late-onset central areolar Choroidal Dystrophy caused by a heterozygous frame-shift mutation affecting codon 307 of the peripherin/RDS gene.
    Ophthalmic genetics, 2006
    Co-Authors: Claudia N. Keilhauer, Thomas Meigen, Heidi Stöhr, Bernhard H. F. Weber
    Abstract:

    Mutations in the peripherin/RDS gene have been identified in families with various retinopathies including those affecting primarily the macula and those restricted to the retinal periphery. Here, we describe the clinical findings of two sisters with late-onset central areolar Choroidal Dystrophy (CACD). The two siblings underwent genetic testing and were found to be carriers of a heterozygous frame-shift mutation 920delT affecting codon 307 of the peripherin/RDS gene and resulting in a truncated, likely functionless, protein with an altered C-terminus (Leu307fsX83). The identical mutation has previously been reported to cause slowly progressive autosomal dominant retinitis pigmentosa. In our two patients, the Leu307fsX83 mutation accounts for an unusually mild form of retinal degeneration.

  • Evaluation of the gene encoding the tissue inhibitor of metalloproteinases-3 in various maculopathies.
    Investigative ophthalmology & visual science, 1997
    Co-Authors: Ute Felbor, Eberhart Zrenner, D. Doepner, U. Schneider, Bernhard H. F. Weber
    Abstract:

    Purpose. Mutations in the gene encoding the tissue inhibitor of metalloproteinases-3 (TIMP3) have been shown previously to cause Sorsby's fundus Dystrophy, an autosomal-dominant disorder characterized by extracellular matrix irregularities in Bruch's membrane. To assess the involvement of TIMP3 in a variety of other macular dystrophies, the authors have screened this gene for disease-causing mutations in age-related macular degeneration (AMD), adult vitelliform macular Dystrophy (AVMD), central areolar Choroidal Dystrophy (CACD), syndrome-associated macular dystrophies, cone-rod Dystrophy, and a group with unspecified macular degeneration. Methods. Single-stranded conformational analysis of the entire coding region was performed using the polymerase chain reaction and oligonucleotide primers flanking the five exons of the TIMP3 gene as well as the putative promotor region and a highly conserved fragment of the 3'-untranslated region. The authors analyzed a total of 217 patients, including 143 patients with AMD, 28 patients with AVMD, 21 patients with CACD, and 25 patients with other forms of macular Dystrophy. Results. In the 217 patients analyzed, the authors have identified one sequence alteration (a G-to-C base change) in the 5'-untranslated region in a patient with AMD. However, the functional consequences of this mutation are not clear. No other disease-causing mutations were found. The authors have characterized a frequent intragenic polymorphism in exon 3 of the TIMP3 gene (heterozygosity = 0.57) that will be useful for genetic linkage or allele sharing analyses or both. Conclusions. The authors' results suggest that TIMP3 is not a major factor in the cause of AMD, AVMD, and CACD. Thus far, Sorsby's fundus Dystrophy appears to be the only phenotype known to be associated with mutations in TIMP3.

Anneke I. Den Hollander - One of the best experts on this subject based on the ideXlab platform.

  • Genetic screening for macular dystrophies in patients clinically diagnosed with dry age-related macular degeneration.
    Clinical genetics, 2018
    Co-Authors: Eveline Kersten, Carel B. Hoyng, Maartje J. Geerlings, Marc Pauper, Jordi Corominas, Bjorn Bakker, Lebriz Altay, Sascha Fauser, Eiko K. De Jong, Anneke I. Den Hollander
    Abstract:

    It can be clinically challenging to distinguish dry age-related macular degeneration (AMD) from AMD-mimicking dystrophies, and sometimes misdiagnosis occurs. With upcoming therapies for dry AMD it is important to exclude patients with a different retinal disease from clinical trials. In this study we evaluated the occurrence of AMD-mimicking dystrophies in an AMD cohort. Whole-exome sequencing (WES) was performed in 218 patients with intermediate AMD or geographic atrophy secondary to AMD and 133 control individuals. WES data was analyzed for rare variants in 19 genes associated with autosomal dominant and recessive macular dystrophies mimicking AMD. In three (1.4%) of 218 cases we identified a pathogenic heterozygous variant (PRPH2 c.424C > T; p.R142W) causal for autosomal dominant central areolar Choroidal Dystrophy (CACD). Phenotypically, these patients all presented with geographic atrophy. In 12 (5.5%) of 218 cases we identified a heterozygous variant of unknown clinical significance, but predicted to be highly deleterious, in genes previously associated with autosomal dominant macular dystrophies. The distinction between AMD and AMD-mimicking dystrophies, such as CACD, can be challenging based on fundus examination alone. Genetic screening for genes associated with macular dystrophies, especially PRPH2, can be beneficial to help identify AMD-mimicking dystrophies.

  • Central Areolar Choroidal Dystrophy (CACD) and Age-Related Macular Degeneration (AMD): Differentiating Characteristics in Multimodal Imaging
    Investigative ophthalmology & visual science, 2011
    Co-Authors: D. Smailhodzic, Carel B. Hoyng, Camiel J. F. Boon, Thomas Theelen, Anneke I. Den Hollander, Monika Fleckenstein, Ramon A. C. Van Huet, Johannes P. H. Van De Ven, Steffen Schmitz-valckenberg, Bernhard H. F. Weber
    Abstract:

    Purpose. Late-onset central areolar Choroidal Dystrophy (CACD) may easily be confused with geographic atrophy (GA) in AMD. To detect discerning features, the morphologic changes in CACD patients and in AMD patients were assessed with confocal scanning laser ophthalmoscopy (cSLO), fundus autofluorescence (FAF), and spectral-domain optical coherence tomography (SD-OCT). Methods. A total of 30 CACD patients with identified PRPH2 gene mutations were analyzed and compared to 19 patients with early AMD and 13 patients with AMD-associated GA. The presence of drusen and pigment clumping was determined with color fundus photography. High-resolution in vivo imaging was performed with cSLO and SD-OCT. FAF images and SD-OCT volume scans were analyzed in each study eye. Results. On FAF, a speckled FAF pattern occurred significantly more often in CACD (85%) than in early AMD (5.6%; P < 0.0001). There was a significantly higher frequency of sub-RPE deposits in eyes with AMD than in eyes with CACD (36.8% versus 2.1% of scans, P = 0.0019). Reticular drusen could be visualized by SD-OCT and FAF imaging in 52.6% of the eyes with early AMD and in 100% of the eyes with GA, whereas this drusen phenotype did not manifest in eyes with CACD. Conclusions. Although outer retinal atrophy is the clinically common feature in advanced CACD as well as GA, there are microstructural alterations on high-resolution SD-OCT and FAF imaging that allow for the differentiation between CACD and AMD. The findings may help to identify patients in whom a diagnostic PRPH2 screening is warranted. (ClinicalTrials.gov number, NCT00393692.).

  • Central Areolar Choroidal Dystrophy
    Ophthalmology, 2009
    Co-Authors: Camiel J. F. Boon, B. Jeroen Klevering, Frans P.m. Cremers, Marijke N. Zonneveld-vrieling, Thomas Theelen, Anneke I. Den Hollander, Carel B. Hoyng
    Abstract:

    Objective To describe the clinical characteristics, follow-up data and molecular genetic background in a large group of patients with central areolar Choroidal Dystrophy (CACD). Design Retrospective case series study. Participants One hundred three patients with CACD from the Netherlands. Methods Ophthalmologic examination, including color vision testing, fundus photography, fluorescein angiography, fundus autofluorescence (FAF) imaging, optical coherence tomography, full-field electroretinography (ERG), multifocal ERG, and electrooculography. Blood samples were obtained for DNA extraction and subsequent analysis of the peripherin/RDS gene, as well as haplotype analysis. Main Outcome Measures Clinical characteristics, phenotypic range, clinical follow-up data, and FAF findings. Results The mean age at onset of visual loss was 46 years, with subsequent gradual deterioration in visual acuity. Ninety-eight patients carried a p.Arg142Trp mutation in peripherin/RDS , whereas 5 affected members of a CACD family carried a p.Arg172Gln peripherin/RDS mutation. A remarkable variation in disease severity was observed, and nonpenetrance was seen up to the age of 64 years, in up to 21% of mutation carriers. However, most macular lesions in mutation carriers displayed a typical stage of CACD. Substantial changes were seen on FAF imaging after a mean follow-up period of 11 months. Electrophysiologic data were consistent with a central cone Dystrophy. The age at onset and phenotypic characteristics of CACD show considerable overlap with atrophic age-related macular degeneration (AMD). The great majority of p.Arg142Trp-carrying CACD patients originated from the southeast region of the Netherlands, and haplotype analysis strongly suggested a common founder mutation. Conclusions When caused by a p.Arg142Trp mutation in the peripherin/RDS gene, CACD causes a central cone Dystrophy phenotype. This mutation, which most likely originates from a common founder in most patients, is associated with a significant degree of nonpenetrance. In the elderly patient, CACD may be confused with AMD, especially in cases with decreased penetrance. Financial Disclosure(s) The authors have no proprietary or commercial interest in any materials discussed in this article.