Publications by authors named "Klaus Rohrschneider"

37 Publications

[How Can the Percentage of Vision in Criminal Law be Handled by the Medical Expert According to the Current State of Medicine?]

Authors:
Frank H W Tost Klaus Rohrschneider

Klin Monbl Augenheilkd 2020 Nov 26. Epub 2020 Nov 26.

Augenklinik, Universitätsklinikum Heidelberg, Deutschland.

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http://dx.doi.org/10.1055/a-1288-1027DOI Listing
November 2020

[The ophthalmological expert opinion in different fields of law].

Authors:
Klaus Rohrschneider Frank Tost

Klin Monbl Augenheilkd 2020 Jun 17;237(6):805-823. Epub 2020 Apr 17.

The ophthalmological appraisal differs significantly in the different areas of law, so there are some different causalities and standards of proof and, above all, the assessment is very different. For the three important sub-areas of private accident insurance, statutory accident insurance as well as disability law and social compensation law, there are abstract tabular guidelines which form the essential basis for a comparable and thus fair assessment. The basics of the assessment in these fields of law are presented in a comparative way, with particular emphasis on causality.
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http://dx.doi.org/10.1055/a-1143-1819DOI Listing
June 2020

[The Bardet-Biedl Syndrome - Diagnosis and Follow-up].

Authors:
Klaus Rohrschneider Hanno Jörn Bolz

Klin Monbl Augenheilkd 2020 Mar 17;237(3):239-247. Epub 2020 Mar 17.

Senckenberg Zentrum für Humangenetik, Frankfurt am Main.

The Bardet-Biedl syndrome (BBS) is a rare inherited ciliopathy, which is accompanied by retinal disease, i.e. rod-cone dystrophy (retinitis pigmentosa, RP) and other symptoms, especially truncal obesity, polydactyly, renal abnormalities as well as reduced intelligence or learning difficulties. 25 BBS genes are currently known, and these are responsible for the structure and function of primary cilia. Because ciliary integrity is crucial for numerous pathways of developmental signaling, their dysfunction may cause multisystemic disorders - like BBS. Physicians benefit greatly from new molecular genetic methods that have made genetically heterogeneous conditions diagnostically accessible: By next-generation sequencing (NGS), all BBS-associated genes can be analysed simultaneously in a gene panel. As regards the retinal phenotype, genotype-phenotype correlations are not significant. Besides classical autosomal recessive inheritance, oligogenic/triallelic traits have been reported, but these seem to play a minor role, if any (as a growing number of large-scale NGS-based studies suggests). In the absence of causal therapy, the mainstay of ophthalmological endeavour is focused on visual rehabilitation with low vision aids, use of the white cane and training to develop everyday life skills.
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http://dx.doi.org/10.1055/a-1118-3748DOI Listing
March 2020

[Comparison of visual acuity measurement with Landolt rings versus numbers].

Authors:
Klaus Rohrschneider Axel R Spittler Michael Bach

Ophthalmologe 2019 Nov;116(11):1058-1063

Klinik für Augenheilkunde, Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Freiburg, Deutschland.

Purpose: Landolt rings are commonly used for the measurement of visual acuity, especially for legal purposes. For multiple reasons, in clinical practice these optotypes are not in use and not practical. Therefore, the difference between visual acuity tested with Landolt rings as opposed to numbers was evaluated.

Methods: Visual acuity measurements of 2335 eyes from 1394 patients (aged 5-98 years, median 51 years) were retrospectively analyzed at the Low Vision Department of the University of Heidelberg. The patients had a broad range of ophthalmological disorders. In all patients the measurement of visual acuity was performed with numbers as well as Landolt rings according to DIN 58220. Visual acuity was determined in LogMAR and compared between the two optotypes.

Results: Correlation between both optotypes was high with r = 0.927 but there was a pronounced mean difference in visual acuity of 0.13 ± 0.14 LogMAR. Using numbers, visual acuity was 0.13 LogMAR higher, somewhat more than one line. These differences were mostly independent of visual acuity and increased slightly with age; however, the variations were greater for lower visual acuity.

Conclusion: Whereas in clinical practice visual acuity is typically determined using numbers and early treatment diabetic retinopathy study (ETDRS) charts are the gold standard for a scientific assessment of visual acuity, only the use of Landolt rings enables an examination without the influence of form recognition. The use of Landolt rings is therefore valid for legal reasons in Europe according to EN ISO 8596 and in Germany according to DIN 58220. Comparing Landolt rings with the Snellen E chart or LEA symbols, these results confirm previous reports that visual acuity measured with Landolt rings results in lower visual acuity. On average visual acuity is approximately one line worse than when tested with numbers, a fact that has to be taken into account when comparing different examination results. This may be explained by incorrect correlation of the used numbers exceeding the allowed difference in eligibility of 0.05 LogMAR. Hence, it is important for legal assessment to measure visual acuity correctly with Landolt rings.
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http://dx.doi.org/10.1007/s00347-019-0879-1DOI Listing
November 2019

The Common ABCA4 Variant p.Asn1868Ile Shows Nonpenetrance and Variable Expression of Stargardt Disease When Present in trans With Severe Variants.

Authors:
Esmee H Runhart Riccardo Sangermano Stéphanie S Cornelis Joke B G M Verheij Astrid S Plomp Camiel J F Boon Dorien Lugtenberg Susanne Roosing Nathalie M Bax Ellen A W Blokland Marlie H M Jacobs-Camps Saskia D van der Velde-Visser Jan-Willem R Pott Klaus Rohrschneider Alberta A H J Thiadens Caroline C W Klaver L Ingeborgh van den Born Carel B Hoyng Frans P M Cremers

Invest Ophthalmol Vis Sci 2018 07;59(8):3220-3231

Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.

Purpose: To assess the occurrence and the disease expression of the common p.Asn1868Ile variant in patients with Stargardt disease (STGD1) harboring known, monoallelic causal ABCA4 variants.

Methods: The coding and noncoding regions of ABCA4 were sequenced in 67 and 63 STGD1 probands respectively, harboring monoallelic ABCA4 variants. In case p.Asn1868Ile was detected, segregation analysis was performed whenever possible. Probands and affected siblings harboring p.Asn1868Ile without additional variants in cis were clinically evaluated retrospectively. Two asymptomatic siblings carrying the same ABCA4 variants as their probands were clinically examined. The penetrance of p.Asn1868Ile was calculated using allele frequency data of ABCA4 variants in non-Finnish European individuals.

Results: The p.Asn1868Ile variant was found in cis with known variants in 14/67 probands. In 27/67 probands, we identified p.Asn1868Ile without additional variants in cis, in combination with known, mainly severe ABCA4 variants. In 23/27 probands, the trans configuration was established. Among 27 probands and 6/7 STGD1 siblings carrying p.Asn1868Ile, 42% manifested late-onset disease (>44 years). We additionally identified four asymptomatic relatives carrying a combination of a severe variant and p.Asn1868Ile; ophthalmologic examination in two persons did not reveal STGD1. Based on ABCA4 allele frequency data, we conservatively estimated the penetrance of p.Asn1868Ile, when present in trans with a severe variant, to be below 5%.

Conclusions: A significant fraction of genetically unexplained STGD1 cases carries p.Asn1868Ile as a second variant. Our findings suggest exceptional differences in disease expression or even nonpenetrance of this ABCA4 variant, pointing toward an important role for genetic or environmental modifiers in STGD1.
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http://dx.doi.org/10.1167/iovs.18-23881DOI Listing
July 2018

[(Neuro-)ophthalmogical aspects of driving ability].

Authors:
Klaus Rohrschneider

Fortschr Neurol Psychiatr 2018 01 17;86(1):28-36. Epub 2018 Jan 17.

Univ.-Augenklinik Heidelberg Ophthalmologische Rehabilitation.

The requirements regarding visual functioning needed for driving ability are stipulated in Annex 6 of the German driving licence regulations: In case of a visual disorder an ophthalmological assessment is essential: It is of crucial importance for the examining ophthalmologist to exhaust all ocular-medical possibilities to enable the applicant to maintain or regain his driving permission. In the overwhelming majority of the cases this is eminently feasible.However, there is no way to attest driving ability in a patient suffering acute one-sided visual loss for a period of 3 months on the basis of legal recommendations. Concerning oculomotor disturbances, the expansion of the diplopic central visual field and the subjective restriction caused thereby are important: the central 20 degree area must be free of diplopia.According to the German driving license regulations, absolute homonymous visual field defects such as hemianopsia or quadrantic defects affecting the visual centre are incompatible with driving an automobile. Even training measures causing the patient to experience a sense of smooth orientation do nothing to mitigate this fact.Dealing with serious disturbances of visual function, as a matter of principle an ophthalmologist should provide an additional expertise before a positive decision on driving ability is made.
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http://dx.doi.org/10.1055/s-0043-122676DOI Listing
January 2018

Next-generation sequencing reveals the mutational landscape of clinically diagnosed Usher syndrome: copy number variations, phenocopies, a predominant target for translational read-through, and mutated in Heimler syndrome.

Authors:
Christine Neuhaus Tobias Eisenberger Christian Decker Sandra Nagl Cornelia Blank Markus Pfister Ingo Kennerknecht Cornelie Müller-Hofstede Peter Charbel Issa Raoul Heller Bodo Beck Klaus Rüther Diana Mitter Klaus Rohrschneider Ute Steinhauer Heike M Korbmacher Dagmar Huhle Solaf M Elsayed Hesham M Taha Shahid M Baig Heidi Stöhr Markus Preising Susanne Markus Fabian Moeller Birgit Lorenz Kerstin Nagel-Wolfrum Arif O Khan Hanno J Bolz

Mol Genet Genomic Med 2017 Sep 6;5(5):531-552. Epub 2017 Jul 6.

Bioscientia Center for Human GeneticsIngelheimGermany.

Background: Combined retinal degeneration and sensorineural hearing impairment is mostly due to autosomal recessive Usher syndrome (USH1: congenital deafness, early retinitis pigmentosa (RP); USH2: progressive hearing impairment, RP).

Methods: Sanger sequencing and NGS of 112 genes (Usher syndrome, nonsyndromic deafness, overlapping conditions), MLPA, and array-CGH were conducted in 138 patients clinically diagnosed with Usher syndrome.

Results: A molecular diagnosis was achieved in 97% of both USH1 and USH2 patients, with biallelic mutations in 97% (USH1) and 90% (USH2), respectively. Quantitative readout reliably detected CNVs (confirmed by MLPA or array-CGH), qualifying targeted NGS as one tool for detecting point mutations and CNVs. CNVs accounted for 10% of identified alleles, often to seemingly monoallelic point mutations. We demonstrate PTC124-induced read-through of the common p.Trp3955* nonsense mutation (13% of detected alleles), a potential therapy target. Usher gene mutations were found in most patients with atypical Usher syndrome, but the diagnosis was adjusted in case of double homozygosity for mutations in and , genes implicated in isolated deafness and RP. Two patients with additional enamel dysplasia had biallelic mutations, for the first time linking this gene to Heimler syndrome.

Conclusion: Targeted NGS not restricted to Usher genes proved beneficial in uncovering conditions mimicking Usher syndrome.
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http://dx.doi.org/10.1002/mgg3.312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5606877PMC
September 2017

Photoreceptor Progenitor mRNA Analysis Reveals Exon Skipping Resulting from the ABCA4 c.5461-10T→C Mutation in Stargardt Disease.

Authors:
Riccardo Sangermano Nathalie M Bax Miriam Bauwens L Ingeborgh van den Born Elfride De Baere Alejandro Garanto Rob W J Collin Angelique S A Goercharn-Ramlal Anke H A den Engelsman-van Dijk Klaus Rohrschneider Carel B Hoyng Frans P M Cremers Silvia Albert

Ophthalmology 2016 06 12;123(6):1375-85. Epub 2016 Mar 12.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute of Molecular Life Sciences, Nijmegen, The Netherlands. Electronic address:

Purpose: To elucidate the functional effect of the ABCA4 variant c.5461-10T→C, one of the most frequent variants associated with Stargardt disease (STGD1).

Design: Case series.

Participants: Seventeen persons with STGD1 carrying ABCA4 variants and 1 control participant.

Methods: Haplotype analysis of 4 homozygotes and 11 heterozygotes for c.5461-10T→C and sequence analysis of the ABCA4 gene for a homozygous proband. Fibroblasts were reprogrammed from 3 persons with STGD1 into induced pluripotent stem cells, which were differentiated into photoreceptor progenitor cells (PPCs). The effect of the c.5461-10T→C variant on RNA splicing by reverse-transcription polymerase chain reaction was analyzed using PPC mRNA. In vitro assays were performed with minigene constructs containing ABCA4 exon 39. We analyzed the natural history and ophthalmologic characteristics of 4 persons homozygous for c.5461-10T→C.

Main Outcome Measures: Haplotype and rare variant data for ABCA4, RNA splice defects, age at diagnosis, visual acuity, fundus appearance, visual field, electroretinography (ERG) results, fluorescein angiography results, and fundus autofluorescence findings.

Results: The frequent ABCA4 variant c.5461-10T→C has a subtle effect on splicing based on prediction programs. A founder haplotype containing c.5461-10T→C was found to span approximately 96 kb of ABCA4 and did not contain other rare sequence variants. Patient-derived PPCs showed skipping of exon 39 or exons 39 and 40 in the mRNA. HEK293T cell transduction with minigenes carrying exon 39 showed that the splice defects were the result of the c.5461-10T→C variant. All 4 subjects carrying the c.5461-10T→C variant in a homozygous state showed a young age of STGD1 onset, with low visual acuity at presentation and abnormal cone ERG results. All 4 demonstrated severe cone-rod dystrophy before 20 years of age and were legally blind by 25 years of age.

Conclusions: The ABCA4 variant c.5461-10T→C is located on a founder haplotype lacking other disease-causing rare sequence variants. In vitro studies revealed that it leads to mRNA exon skipping and ABCA4 protein truncation. Given the severe phenotype in persons homozygous for this variant, we conclude that this variant results in the absence of ABCA4 activity.
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http://dx.doi.org/10.1016/j.ophtha.2016.01.053DOI Listing
June 2016

Mutation Detection in Patients with Retinal Dystrophies Using Targeted Next Generation Sequencing.

Authors:
Nicole Weisschuh Anja K Mayer Tim M Strom Susanne Kohl Nicola Glöckle Max Schubach Sten Andreasson Antje Bernd David G Birch Christian P Hamel John R Heckenlively Samuel G Jacobson Christina Kamme Ulrich Kellner Erdmute Kunstmann Pietro Maffei Charlotte M Reiff Klaus Rohrschneider Thomas Rosenberg Günther Rudolph Rita Vámos Balázs Varsányi Richard G Weleber Bernd Wissinger

PLoS One 2016 14;11(1):e0145951. Epub 2016 Jan 14.

Molecular Genetics Laboratory, Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tuebingen, Tuebingen, Germany.

Retinal dystrophies (RD) constitute a group of blinding diseases that are characterized by clinical variability and pronounced genetic heterogeneity. The different nonsyndromic and syndromic forms of RD can be attributed to mutations in more than 200 genes. Consequently, next generation sequencing (NGS) technologies are among the most promising approaches to identify mutations in RD. We screened a large cohort of patients comprising 89 independent cases and families with various subforms of RD applying different NGS platforms. While mutation screening in 50 cases was performed using a RD gene capture panel, 47 cases were analyzed using whole exome sequencing. One family was analyzed using whole genome sequencing. A detection rate of 61% was achieved including mutations in 34 known and two novel RD genes. A total of 69 distinct mutations were identified, including 39 novel mutations. Notably, genetic findings in several families were not consistent with the initial clinical diagnosis. Clinical reassessment resulted in refinement of the clinical diagnosis in some of these families and confirmed the broad clinical spectrum associated with mutations in RD genes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0145951PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4713063PMC
July 2016

Homozygosity mapping and whole-genome sequencing reveals a deep intronic PROM1 mutation causing cone-rod dystrophy by pseudoexon activation.

Authors:
Anja K Mayer Klaus Rohrschneider Tim M Strom Nicola Glöckle Susanne Kohl Bernd Wissinger Nicole Weisschuh

Eur J Hum Genet 2016 Mar 8;24(3):459-62. Epub 2015 Jul 8.

Molecular Genetics Laboratory, Centre for Ophthalmology, Institute for Ophthalmic Research, University of Tuebingen, Tuebingen, Germany.

Several genes have been implicated in the autosomal recessive form of cone-rod dystrophy (CRD), but the majority of cases remain unsolved. We identified a homozygous interval comprising two known genes associated with the autosomal recessive form of CRD, namely RAB28 and PROM1, in a consanguineous family with clinical evidence of CRD. Both genes proved to be mutation negative upon sequencing of exons and canonical splice sites but whole-genome sequencing revealed a private variant located deep in intron 18 of PROM1. In silico and functional analyses of this variant using minigenes as splicing reporters revealed the integration of a pseudoexon in the mutant transcript, thereby leading to a premature termination codon and presumably resulting in a functional null allele. This is the first report of a deep intronic variant that acts as a splicing mutation in PROM1. The detection of such variants escapes the exon-focused techniques typically used in genetic analyses. Sequencing the entire genomic regions of known disease genes might identify more causal mutations in the autosomal recessive form of CRD.
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http://dx.doi.org/10.1038/ejhg.2015.144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755378PMC
March 2016

Fundus autofluorescence and optical coherence tomography findings in thiamine responsive megaloblastic anemia.

Authors:
Thomas Ach Rüdiger Kardorff Klaus Rohrschneider

Retin Cases Brief Rep 2015 ;9(2):114-6

*Department of Ophthalmology, University of Alabama at Birmingham, Birmingham, Alabama; †Department of Pediatrics, Marien-Hospital Wesel, Wesel, Germany; and ‡Department of Ophthalmology, University Hospital Heidelberg, Heidelberg, Germany.

Background: To report ophthalmologic fundus autofluorescence and spectral domain optical coherence tomography findings in a patient with thiamine responsive megaloblastic anemia (TRMA).

Methods: A 13-year-old girl with genetically proven TRMA was ophthalmologically (visual acuity, funduscopy, perimetry, electroretinogram) followed up over >5 years. Fundus imaging also included autofluorescence and spectral domain optical coherence tomography.

Results: During a 5-year follow-up, visual acuity and visual field decreased, despite a special TRMA diet. Funduscopy revealed bull's eye appearance, whereas fundus autofluorescence showed central and peripheral hyperfluorescence and perifoveal hypofluorescence. Spectral domain optical coherence tomography revealed affected inner segment ellipsoid band and irregularities in the retinal pigment epithelium and choroidea.

Conclusion: Autofluorescence and spectral domain optical coherence tomography findings in a patient with TRMA show retinitis pigmentosa-like retina, retinal pigment epithelium, and choroid alterations. These findings might progress even under special TRMA diet, indispensable to life. Ophthalmologist should consider TRMA in patients with deafness and ophthalmologic disorders.
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http://dx.doi.org/10.1097/ICB.0000000000000106DOI Listing
December 2015

Novel compound heterozygous NMNAT1 variants associated with Leber congenital amaurosis.

Authors:
Anna M Siemiatkowska L Ingeborgh van den Born Maria M van Genderen Mette Bertelsen Ditta Zobor Klaus Rohrschneider Ramon A C van Huet Siska Nurohmah B Jeroen Klevering Susanne Kohl Sultana M H Faradz Thomas Rosenberg Anneke I den Hollander Rob W J Collin Frans P M Cremers

Mol Vis 2014 2;20:753-9. Epub 2014 Jun 2.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands ; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

Purpose: The gene encoding nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) was recently found to be mutated in a subset of patients with Leber congenital amaurosis (LCA) with macular atrophy. The aim of this study was to determine the occurrence and frequency of NMNAT1 mutations and associated phenotypes in different types of inherited retinal dystrophies.

Methods: DNA samples of 161 patients with LCA without genetic diagnosis were analyzed for variants in NMNAT1 using Sanger sequencing. Variants in exon 5 of NMNAT1, which harbors the majority of the previously identified mutations, were screened in 532 additional patients with retinal dystrophies. This cohort encompassed 108 persons with isolated or autosomal recessive cone-rod dystrophy (CRD), 271 with isolated or autosomal recessive retinitis pigmentosa (RP), and 49 with autosomal dominant RP, as well as 104 persons with LCA in whom the causative mutation was previously identified.

Results: Compound heterozygous alterations were found in six patients with LCA and in one person with early-onset RP. All except one carried the common p.E257K variant on one allele. Macular atrophy was absent in one patient, who carried this variant in combination with a truncating mutation on the other allele. The p.E257K alteration was also found in a heterozygous state in five individuals with LCA and one with RP while no mutation was detected on the other allele. Two individuals with LCA carried other NMNAT1 variants in a heterozygous state, whereas no NMNAT1 variants in exon 5 were identified in individuals with CRD. The p.E257K variant was found to be enriched in a heterozygous state in individuals with LCA (0.94%) compared to Caucasian controls (0.18%), although the difference was statistically insignificant (p=0.12).

Conclusions: Although macular atrophy can occur in LCA and CRD, no NMNAT1 mutations were found in the latter cohort. NMNAT1 variants were also not found in a large group of patients with sporadic or autosomal recessive RP. The enrichment of p.E257K in a heterozygous state in patients with LCA versus controls suggests that this allele could act as a modifier in other genetic subtypes of LCA.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4043607PMC
September 2014

Screening of a large cohort of leber congenital amaurosis and retinitis pigmentosa patients identifies novel LCA5 mutations and new genotype-phenotype correlations.

Authors:
Donna S Mackay Arundhati Dev Borman Ruifang Sui L Ingeborgh van den Born Eliot L Berson Louise A Ocaka Alice E Davidson John R Heckenlively Kari Branham Huanan Ren Irma Lopez Maleeha Maria Maleeha Azam Arjen Henkes Ellen Blokland Raheel Qamar Andrew R Webster Frans P M Cremers Anthony T Moore Robert K Koenekoop Sten Andreasson Elfride de Baere Jean Bennett Gerald J Chader Wolfgang Berger Irina Golovleva Jacquie Greenberg Anneke I den Hollander Caroline C W Klaver B Jeroen Klevering Birgit Lorenz Markus N Preising Raj Ramsear Lisa Roberts Ronald Roepman Klaus Rohrschneider Bernd Wissinger

Hum Mutat 2013 Nov 17;34(11):1537-1546. Epub 2013 Sep 17.

Department of Human Genetics, Institute of Ophthalmology, UCL, London, UK.

This study was undertaken to investigate the prevalence of sequence variants in LCA5 in patients with Leber congenital amaurosis (LCA), early-onset retinal dystrophy (EORD), and autosomal recessive retinitis pigmentosa (arRP); to delineate the ocular phenotypes; and to provide an overview of all published LCA5 variants in an online database. Patients underwent standard ophthalmic evaluations after providing informed consent. In selected patients, optical coherence tomography (OCT) and fundus autofluorescence imaging were possible. DNA samples from 797 unrelated patients with LCA and 211 with the various types of retinitis pigmentosa (RP) were screened by Sanger sequence analysis of all LCA5 exons and intron/exon junctions. Some LCA patients were prescreened by APEX technology or selected based on homozygosity mapping. In silico analyses were performed to assess the pathogenicity of the variants. Segregation analysis was performed where possible. Published and novel LCA5 variants were collected, amended for their correct nomenclature, and listed in a Leiden Open Variation Database (LOVD). Sequence analysis identified 18 new probands with 19 different LCA5 variants. Seventeen of the 19 LCA5 variants were novel. Except for two missense variants and one splice site variant, all variants were protein-truncating mutations. Most patients expressed a severe phenotype, typical of LCA. However, some LCA subjects had better vision and intact inner segment/outer segment (IS/OS) junctions on OCT imaging. In two families with LCA5 variants, the phenotype was more compatible with EORD with affected individuals displaying preserved islands of retinal pigment epithelium. One of the families with a milder phenotype harbored a homozygous splice site mutation; a second family was found to have a combination of a stop mutation and a missense mutation. This is the largest LCA5 study to date. We sequenced 1,008 patients (797 with LCA, 211 with arRP) and identified 18 probands with LCA5 mutations. Mutations in LCA5 are a rare cause of childhood retinal dystrophy accounting for ∼2% of disease in this cohort, and the majority of LCA5 mutations are likely null. The LCA5 protein truncating mutations are predominantly associated with LCA. However, in two families with the milder EORD, the LCA5 gene analysis revealed a homozygous splice site mutation in one and a stop mutation in combination with a missense mutation in a second family, suggesting that this milder phenotype is due to residual function of lebercilin and expanding the currently known phenotypic spectrum to include the milder early onset RP. Some patients have remaining foveal cone structures (intact IS/OS junctions on OCT imaging) and remaining visual acuities, which may bode well for upcoming treatment trials.
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http://dx.doi.org/10.1002/humu.22398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4337959PMC
November 2013

Interferon versus methotrexate in intermediate uveitis with macular edema: results of a randomized controlled clinical trial.

Authors:
Friederike Mackensen Eva Jakob Christina Springer Bianca C Dobner Ute Wiehler Petra Weimer Klaus Rohrschneider Christoph Fiehn Regina Max Brigitte Storch-Hagenlocher Matthias D Becker

Am J Ophthalmol 2013 Sep 17;156(3):478-486.e1. Epub 2013 Jun 17.

Department of Ophthalmology, University of Heidelberg, Heidelberg, Germany; Interdisciplinary Uveitis Center, University of Heidelberg, Heidelberg, Germany.

Purpose: To compare interferon (IFN) beta with methotrexate (MTX) in the treatment of intermediate uveitis with macular edema.

Design: Monocentric, prospective, randomized, controlled clinical trial.

Methods:

Setting: Specialized uveitis center at the University of Heidelberg. PATIENT OR STUDY POPULATION: Patients with either primary intermediate uveitis or uveitis associated with multiple sclerosis. MAIN INCLUSION CRITERIA: Visual acuity of 20/30 or worse (0.2 logarithm of the minimal angle of resolution) and macular edema of more than 250 μm (central 1-mm in optical coherence tomography; Stratus). Randomization into either IFN beta 44 μg subcutaneously 3 times weekly or 20 mg MTX subcutaneously once weekly.

Main Outcome Measures: At 3 months, the primary outcome parameter of mean change in visual acuity was evaluated and efficacy was determined. Secondary parameters were macular edema by optical coherence tomography, inflammatory activity, and retinal sensitivity by microperimetry (MP-1; Nidek). In case of treatment failure, switching to the other treatment arm was possible.

Results: Nineteen patients were included. Ten were randomized to MTX, and 9 were randomized to IFN beta. At 3 months, visual acuity improved a mean 0.31 logarithm of the minimal angle of resolution (range, -0.02 to -0.96, 15.6 letters on the Early Treatment Diabetic Retinopathy Study chart) in the IFN beta group versus a mean 0.09 logarithm of the minimal angle of resolution (range, 0.12 to -0.38, 4.7 letters) in the MTX arm (P = .0435, Mann-Whitney U test). Macular thickness decreased by a mean of 206 μm (range, -41 to -416 μm) in the IFN arm, but increased by 47 μm (range, 108 to -28 μm) in the MTX group (P < .0001).

Conclusions: Although the sample size is small, results of the trial support superiority of IFN beta over MTX in the treatment of macular edema in the setting of intermediate uveitis.
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http://dx.doi.org/10.1016/j.ajo.2013.05.002DOI Listing
September 2013

Mutations in RAB28, encoding a farnesylated small GTPase, are associated with autosomal-recessive cone-rod dystrophy.

Authors:
Susanne Roosing Klaus Rohrschneider Avigail Beryozkin Dror Sharon Nicole Weisschuh Jennifer Staller Susanne Kohl Lina Zelinger Theo A Peters Kornelia Neveling Tim M Strom L Ingeborgh van den Born Carel B Hoyng Caroline C W Klaver Ronald Roepman Bernd Wissinger Eyal Banin Frans P M Cremers Anneke I den Hollander

Am J Hum Genet 2013 Jul 6;93(1):110-7. Epub 2013 Jun 6.

Department of Human Genetics, Radboud University Medical Centre, 6500 HB Nijmegen, the Netherlands.

The majority of the genetic causes of autosomal-recessive (ar) cone-rod dystrophy (CRD) are currently unknown. A combined approach of homozygosity mapping and exome sequencing revealed a homozygous nonsense mutation (c.565C>T [p.Glu189*]) in RAB28 in a German family with three siblings with arCRD. Another homozygous nonsense mutation (c.409C>T [p.Arg137*]) was identified in a family of Moroccan Jewish descent with two siblings affected by arCRD. All five affected individuals presented with hyperpigmentation in the macula, progressive loss of the visual acuity, atrophy of the retinal pigment epithelium, and severely reduced cone and rod responses on the electroretinogram. RAB28 encodes a member of the Rab subfamily of the RAS-related small GTPases. Alternative RNA splicing yields three predicted protein isoforms with alternative C-termini, which are all truncated by the nonsense mutations identified in the arCRD families in this report. Opposed to other Rab GTPases that are generally geranylgeranylated, RAB28 is predicted to be farnesylated. Staining of rat retina showed localization of RAB28 to the basal body and the ciliary rootlet of the photoreceptors. Analogous to the function of other RAB family members, RAB28 might be involved in ciliary transport in photoreceptor cells. This study reveals a crucial role for RAB28 in photoreceptor function and suggests that mutations in other Rab proteins may also be associated with retinal dystrophies.
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http://dx.doi.org/10.1016/j.ajhg.2013.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3710761PMC
July 2013

Severe vision and hearing impairment and successful aging: a multidimensional view.

Authors:
Hans-Werner Wahl Vera Heyl Philipp M Drapaniotis Karl Hörmann Jost B Jonas Peter K Plinkert Klaus Rohrschneider

Gerontologist 2013 Dec 7;53(6):950-62. Epub 2013 Mar 7.

*Address correspondence to Hans-Werner Wahl, Heidelberg University, Department of Psychological Aging Research, Institute of Psychology, Bergheimer Strasse 20, Heidelberg 69115, Germany. E-mail:

Purpose: Previous research on psychosocial adaptation of sensory-impaired older adults has focused mainly on only one sensory modality and on a limited number of successful aging outcomes. We considered a broad range of successful aging indicators and compared older adults with vision impairment, hearing impairment, and dual sensory impairments and without sensory impairment.

Design And Methods: Data came from samples of severely visually impaired (VI; N = 121), severely hearing-impaired (HI; N = 116), dual sensory-impaired (DI; N = 43), and sensory-unimpaired older adults (UI; N = 150). Participants underwent a wide-ranging assessment, covering everyday competence, cognitive functioning, social resources, self-regulation strategies, cognitive and affective well-being, and 4-year survival status (except the DI group).

Results: The most pronounced difference among groups was in the area of everyday competence (lowest in VI and DI). Multigroup comparisons in latent space revealed both similar and differing relationship strengths among health, everyday competence, social resources, self-regulation, and overall well-being, depending on sensory status. After 4 years, mortality in VI (29%) and HI (30%) was significantly higher than in UI (20%) at the bivariate level, but not after controlling for confounders in a multivariate analysis.

Implications: A multidimensional approach to the understanding of sensory impairment and psychosocial adaptation in old age reveals a complex picture of loss and maintenance.
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http://dx.doi.org/10.1093/geront/gnt013DOI Listing
December 2013

IQCB1 mutations in patients with leber congenital amaurosis.

Authors:
Alejandro Estrada-Cuzcano Robert K Koenekoop Frauke Coppieters Susanne Kohl Irma Lopez Rob W J Collin Elfride B W De Baere Debbie Roeleveld Jonah Marek Antje Bernd Klaus Rohrschneider L Ingeborgh van den Born Françoise Meire Irene H Maumenee Samuel G Jacobson Carel B Hoyng Eberhart Zrenner Frans P M Cremers Anneke I den Hollander

Invest Ophthalmol Vis Sci 2011 Feb 11;52(2):834-9. Epub 2011 Feb 11.

Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

Purpose: Leber congenital amaurosis (LCA) is genetically heterogeneous, with 15 genes identified thus far, accounting for ∼70% of LCA patients. The aim of the present study was to identify new genetic causes of LCA.

Methods: Homozygosity mapping in >150 LCA patients of worldwide origin was performed with high-density SNP microarrays to identify new disease-causing genes.

Results: In three isolated LCA patients, the authors identified large homozygous regions on chromosome 3 encompassing the IQCB1 gene, which has been associated with Senior-Loken syndrome (SLSN), characterized by nephronophthisis and retinal degeneration. Mutation analysis of IQCB1 in these three patients and a subsequent cohort of 222 additional LCA patients identified frameshift and nonsense mutations in 11 patients diagnosed with LCA. On re-inspection of the patient's disease status, seven were found to have developed SLSN, but four maintained the diagnosis of LCA as the kidney function remained normal.

Conclusions: Results show that the onset of renal failure in patients with IQCB1 mutations is highly variable, and that mutations are also found in LCA patients without nephronophthisis, rendering IQCB1 a new gene for LCA. However, these patients are at high risk for developing renal failure, which in early stages is often not recognized and can cause sudden death from fluid and electrolyte imbalance. It is therefore recommended that all LCA patients be screened for IQCB1 mutations, to follow them more closely for kidney disease.
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http://dx.doi.org/10.1167/iovs.10-5221DOI Listing
February 2011

Homozygosity mapping in patients with cone-rod dystrophy: novel mutations and clinical characterizations.

Authors:
Karin W Littink Robert K Koenekoop L Ingeborgh van den Born Rob W J Collin Luminita Moruz Joris A Veltman Susanne Roosing Marijke N Zonneveld Amer Omar Mahshad Darvish Irma Lopez Hester Y Kroes Maria M van Genderen Carel B Hoyng Klaus Rohrschneider Mary J van Schooneveld Frans P M Cremers Anneke I den Hollander

Invest Ophthalmol Vis Sci 2010 Nov 16;51(11):5943-51. Epub 2010 Jun 16.

The Rotterdam Eye Hospital, Rotterdam, The Netherlands.

Purpose: To determine the genetic defect and to describe the clinical characteristics in a cohort of mainly nonconsanguineous cone-rod dystrophy (CRD) patients.

Methods: One hundred thirty-nine patients with diagnosed CRD were recruited. Ninety of them were screened for known mutations in ABCA4, and those carrying one or two mutations were excluded from further research. Genome-wide homozygosity mapping was performed in the remaining 108. Known genes associated with autosomal recessive retinal dystrophies located within a homozygous region were screened for mutations. Patients in whom a mutation was detected underwent further ophthalmic examination.

Results: Homozygous sequence variants were identified in eight CRD families, six of which were nonconsanguineous. The variants were detected in the following six genes: ABCA4, CABP4, CERKL, EYS, KCNV2, and PROM1. Patients carrying mutations in ABCA4, CERKL, and PROM1 had typical CRD symptoms, but a variety of retinal appearances on funduscopy, optical coherence tomography, and autofluorescence imaging.

Conclusions: Homozygosity mapping led to the identification of new mutations in consanguineous and nonconsanguineous patients with retinal dystrophy. Detailed clinical characterization revealed a variety of retinal appearances, ranging from nearly normal to extensive retinal remodeling, retinal thinning, and debris accumulation. Although CRD was initially diagnosed in all patients, the molecular findings led to a reappraisal of the diagnosis in patients carrying mutations in EYS, CABP4, and KCNV2.
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http://dx.doi.org/10.1167/iovs.10-5797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3061516PMC
November 2010

A novel nonsense mutation in CEP290 induces exon skipping and leads to a relatively mild retinal phenotype.

Authors:
Karin W Littink Jan-Willem R Pott Rob W J Collin Hester Y Kroes Joke B G M Verheij Ellen A W Blokland Marta de Castro Miró Carel B Hoyng Caroline C W Klaver Robert K Koenekoop Klaus Rohrschneider Frans P M Cremers L Ingeborgh van den Born Anneke I den Hollander

Invest Ophthalmol Vis Sci 2010 Jul 3;51(7):3646-52. Epub 2010 Feb 3.

Rotterdam Eye Hospital, Rotterdam, The Netherlands.

PURPOSE. To identify the genetic defect in a family with variable retinal phenotypes. The proband had a diagnosis of Leber congenital amaurosis (LCA), whereas her two cousins had an early-onset severe retinal dystrophy (EOSRD) with useful vision. A distant family member had retinitis pigmentosa (RP). METHODS. DNA samples of the affected family members were genotyped with 250 K genome-wide SNP microarrays. Genetic defects were localized by linkage analysis and homozygosity mapping, and candidate genes were analyzed by sequencing. Patients underwent a full ophthalmic examination. RESULTS. Compound heterozygous mutations in CEP290 were identified in the proband and her two cousins: the frequent c.2991+1655A>G founder mutation and a novel nonsense mutation in exon 7 (c.451C>T, p.Arg151X). The proband had nystagmus, hyperopia, a flat electroretinogram (ERG), and decreased visual acuity (20/250) from birth. The two cousins had minimal scotopic ERG responses at the age of 2. In one of these patients, visual acuity had reached a level of 20/32 at age 5, which is high for patients with CEP290 mutations. Analysis of the CEP290 mRNA in affected individuals revealed altered splice forms in which either exon 7 or exons 7 and 8 were skipped. In both mutant cDNA products, the open reading frame was not disrupted. Furthermore, homozygosity mapping and mutation analysis in the distant family member affected by RP revealed a homozygous mutation in MERTK, but no CEP290 mutations. This MERTK mutation was heterozygously present in the most severely affected (LCA) patient, but was absent in the two more mildly affected cousins. CONCLUSIONS. A novel nonsense mutation in CEP290 results in nonsense-associated altered splicing. That the remaining open reading frame is intact may explain the less severe phenotype observed in the two affected cousins. The additional heterozygous mutation in MERTK may clarify the more severe phenotype in the proband. This study extends the phenotypic spectrum of CEP290-associated diseases at the mild end.
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http://dx.doi.org/10.1167/iovs.09-5074DOI Listing
July 2010

A novel homozygous nonsense mutation in CABP4 causes congenital cone-rod synaptic disorder.

Authors:
Karin W Littink Maria M van Genderen Rob W J Collin Susanne Roosing Arjan P M de Brouwer Frans C C Riemslag Hanka Venselaar Alberta A H J Thiadens Carel B Hoyng Klaus Rohrschneider Anneke I den Hollander Frans P M Cremers L Ingeborgh van den Born

Invest Ophthalmol Vis Sci 2009 May 13;50(5):2344-50. Epub 2008 Dec 13.

Rotterdam Eye Hospital, Rotterdam, The Netherlands.

Purpose: The purpose of this study was to identify the causative gene defect in two siblings with an uncharacterized cone-rod dysfunction and to describe the clinical characteristics.

Methods: Genome-wide homozygosity mapping, with a 250K SNP-array followed by a search for candidate genes, was performed. The patients underwent ophthalmic examination, including elaborate electroretinography.

Results: In a Dutch sib pair, a shared 9-Mb homozygous region was found on 11q13.1-q13.5 that encompasses the CABP4 gene, previously implicated in autosomal recessive incomplete congenital stationary night blindness (CSNB2) in two small families. A novel homozygous p.Arg216X mutation in CABP4 was detected in the sib pair. Quantitative RT-PCR on RNA isolated from patient lymphoblast cells showed no nonsense-mediated degradation of mutant CABP4 mRNA. Clinically, patients presented with reduced visual acuity, photophobia, and abnormal color vision, but they did not experience night blindness. Electroretinograms showed electronegative mixed rod-cone responses and severely reduced cone responses, as in CSNB2. Isolated rod responses, however, were (sub)normal.

Conclusions: A novel homozygous nonsense mutation in CABP4 in two siblings resulted in a phenotype with severely reduced cone function and only negligibly reduced rod function on electroretinography and psychophysical testing. Since these patients and two of three previously described patients do not experience night blindness, the name CSNB2 is confusing for patients as well as clinicians. Therefore, the authors propose to name the phenotype congenital cone-rod synaptic disorder.
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http://dx.doi.org/10.1167/iovs.08-2553DOI Listing
May 2009

Use of fundus perimetry (microperimetry) to quantify macular sensitivity.

Authors:
Klaus Rohrschneider Stefan Bültmann Christina Springer

Prog Retin Eye Res 2008 Sep 3;27(5):536-48. Epub 2008 Aug 3.

Department of Ophthalmology, University of Heidelberg, Im Neuenheimer Feld 400, D-69120 Heidelberg, Germany.

The advances in retinal imaging technologies have led to enormous innovation towards diagnostic in current ophthalmology, enabling the practitioner to detect early retinal changes and to document treatment effects. While, in the past, retinoscopy, visual acuity testing and perimetry played the major role in functional diagnostics, today, laser-based systems like laser scanning imaging systems especially for fluorescein-angiography, optical coherence tomography, electrodiagnostic systems and the analysis of retinal vessels may be used as well. However, the challenge to correlate subjective alterations or clinical changes with visual function, still remains. Micro- or fundus perimetry offers the option to test retinal sensitivity while directly observing the fundus. In this paper, we review the literature encompassing the results of more than 25 years of fundus perimetry, i.e. perimetry under simultaneous visualization of the fundus. During this time, results on known diseases and reproducibility of the technique were published, but a lot of work was also performed on the combination of different examination methods, allowing a synopsis of long-term results and new approaches by combining different methods and improving each of them. The first part of this review attends to improvements of the method. The second part addresses the clinical and diagnostic values. The final part is dedicated to diagnostic and long-term observation of fundus perimetric results beginning with common and rare diseases like age-related macular degeneration, macular holes and diabetic retinopathy, various types of macular dystrophies ending with challenges in conventional perimetry like glaucoma and malingering. Due to the experience and progress in the field of fundus perimetry and retinal imaging, the method has long passed its role of observing and has all the potential for prediction, early detection and treatment-monitoring of macular diseases.
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http://dx.doi.org/10.1016/j.preteyeres.2008.07.003DOI Listing
September 2008

Identification of novel mutations in patients with Leber congenital amaurosis and juvenile RP by genome-wide homozygosity mapping with SNP microarrays.

Authors:
Anneke I den Hollander Irma Lopez Suzanne Yzer Marijke N Zonneveld Irene M Janssen Tim M Strom Jayne Y Hehir-Kwa Joris A Veltman Maarten L Arends Thomas Meitinger Maria A Musarella L Ingeborgh van den Born Gerald A Fishman Irene H Maumenee Klaus Rohrschneider Frans P M Cremers Robert K Koenekoop

Invest Ophthalmol Vis Sci 2007 Dec;48(12):5690-8

Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.

Purpose: Leber congenital amaurosis (LCA) and juvenile retinitis pigmentosa (RP) cause severe visual impairment early in life. Thus far, mutations in 13 genes have been associated with autosomal recessive LCA and juvenile RP. The purpose of this study was to use homozygosity mapping to identify mutations in known LCA and juvenile RP genes.

Methods: The genomes of 93 consanguineous and nonconsanguineous patients with LCA and juvenile RP were analyzed for homozygous chromosomal regions by using SNP microarrays. This patient cohort was highly selected, as mutations in the known genes had been excluded with the LCA mutation chip, or a significant number of LCA genes had been excluded by comprehensive mutation analysis. Known LCA and juvenile RP genes residing in the identified homozygous regions were analyzed by sequencing. Detailed ophthalmic examinations were performed on the genotyped patients.

Results: Ten homozygous mutations, including seven novel mutations, were identified in the CRB1, LRAT, RPE65, and TULP1 genes in 12 patients. Ten patients were from consanguineous marriages, but in two patients no consanguinity was reported. In 10 of the 12 patients, the causative mutation was present in the largest or second largest homozygous segment of the patient's genome.

Conclusions: Homozygosity mapping using SNP microarrays identified mutations in a significant proportion (30%) of consanguineous patients with LCA and juvenile RP and in a small number (3%) of nonconsanguineous patients. Significant homozygous regions which did not map to known LCA or juvenile RP genes and may be instrumental in identifying novel disease genes were detected in 33 patients.
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http://dx.doi.org/10.1167/iovs.07-0610DOI Listing
December 2007

Microperimetric assessment of patients with type 2 idiopathic macular telangiectasia.

Authors:
Peter Charbel Issa Hans-Martin Helb Klaus Rohrschneider Frank G Holz Hendrik P N Scholl

Invest Ophthalmol Vis Sci 2007 Aug;48(8):3788-95

Department of Ophthalmology, University of Bonn, Bonn, Germany.

Purpose: To assess changes of the light increment sensitivity (LIS) of the macular area in patients with type 2 idiopathic macular telangiectasia (IMT).

Methods: Fifty-eight eyes of 30 patients were examined in a cross-sectional study. All eyes were assigned to group A (early disease stages) or group B (late disease stages with retinal pigment clumping or vascular membranes). Investigation of visual function included visual acuity and fundus-related microperimetry.

Results: Thirty-seven and 16 eyes were assigned to group A and group B, respectively. Temporal to the fovea, each eye of group B had an absolute scotoma. Topographically, the areas with reduced LIS correlated well with the angiographically hyperfluorescent areas or retinal pigmentations and showed a sharp demarcation from areas with normal LIS. However, within areas with angiographic alterations, at least some test locations exhibited preserved LIS in group B eyes; in 51% of group A eyes, none of those test locations showed abnormal LIS. Group A eyes that showed marked LIS reduction revealed common abnormalities: either hyporeflective spaces between the neurosensory retina and the retinal pigment epithelium in OCT imaging or atrophic areas, both topographically related to the scotoma. Visual acuity was correlated with foveal LIS but not with the LIS temporal to the fovea.

Conclusions: Long-standing morphologic macular alterations from type 2 IMT are associated with topographically related functional impairment. Eyes with profound parafoveal scotomas can exhibit relatively preserved visual acuity. Therefore, testing for retinal light sensitivity should be included as an additional outcome measure for future interventional studies.
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http://dx.doi.org/10.1167/iovs.06-1272DOI Listing
August 2007

Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis.

Authors:
Anneke I den Hollander Robert K Koenekoop Suzanne Yzer Irma Lopez Maarten L Arends Krysta E J Voesenek Marijke N Zonneveld Tim M Strom Thomas Meitinger Han G Brunner Carel B Hoyng L Ingeborgh van den Born Klaus Rohrschneider Frans P M Cremers

Am J Hum Genet 2006 Sep 11;79(3):556-61. Epub 2006 Jul 11.

Department of Human Genetics, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands.

Leber congenital amaurosis (LCA) is one of the main causes of childhood blindness. To date, mutations in eight genes have been described, which together account for approximately 45% of LCA cases. We localized the genetic defect in a consanguineous LCA-affected family from Quebec and identified a splice defect in a gene encoding a centrosomal protein (CEP290). The defect is caused by an intronic mutation (c.2991+1655A-->G) that creates a strong splice-donor site and inserts a cryptic exon in the CEP290 messenger RNA. This mutation was detected in 16 (21%) of 76 unrelated patients with LCA, either homozygously or in combination with a second deleterious mutation on the other allele. CEP290 mutations therefore represent one of the most frequent causes of LCA identified so far.
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http://dx.doi.org/10.1086/507318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1559533PMC
September 2006

Autologous translocation of the choroid and retinal pigment epithelium in age-related macular degeneration.

Authors:
Antonia M Joussen Florian M A Heussen Sandra Joeres Helene Llacer Beate Prinz Klaus Rohrschneider Kristel J M Maaijwee Jan van Meurs Bernd Kirchhof

Am J Ophthalmol 2006 Jul;142(1):17-30

Department of Vitreoretinal Surgery, Center for Ophthalmology, University of Cologne, Cologne, Germany.

Purpose: To evaluate the autologous translocation of peripheral choroid and retinal pigment epithelium (RPE) in 45 eyes of 43 patients with age-related macular degeneration (AMD).

Design: Prospective nonrandomized study.

Methods: All patients had visual loss due to AMD (n = 5 classic membranes, n = 14 occult, n = 2 mixed, n = 16 pigment epithelial detachment (PED), n = 5 subretinal hemorrhage, n = 3 geographic atrophy). After extraction of the neovascular complex, an autologous peripheral full-thickness explant of RPE, Bruch membrane, and choroid was translocated from the midperiphery to the macula.

Results: Preoperative distant visual acuity ranged from 20/800 to 20/40. Reading vision ranged from 1.4 logarithm of reading acuity determination (logRAD) to 0.5 logRAD (0.04 to 0.32 Snellen equivalent). Revision surgery was required in 22 eyes as a result of proliferative vitreoretinopathy (PVR), retinal detachment, macular pucker, or vitreous hemorrhage. In eight patients, the patch was renewed. At six months, distant visual acuity ranged from light perception to 20/50 (increase of 15 letters in four eyes). Reading vision ranged from 1.4 to 0.4 logRAD. Visual outcome was unrelated to the type of AMD. Vascularization of the transplant was visible on indocyanine green (ICG) angiography in 40 of 42 eyes. In most patients, autofluorescence of the pigment epithelium was coincident with revascularization of the graft. Fixation on the patch was positively related to visual acuity.

Conclusions: Autologous translocation of a full-thickness transplant of choroid and RPE usually results in a vascularized and functioning graft. Vascularization was even achieved in patients with geographic atrophy. Fixation stability and microperimetry before the patch translocation may be helpful in selecting patients who will profit from surgery.
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http://dx.doi.org/10.1016/j.ajo.2006.01.090DOI Listing
July 2006

Microarray-based mutation detection and phenotypic characterization of patients with Leber congenital amaurosis.

Authors:
Suzanne Yzer Bart P Leroy Elfride De Baere Thomy J de Ravel Marijke N Zonneveld Krysta Voesenek Ulrich Kellner Jose P Martinez Ciriano Jan-Tjeerd H N de Faber Klaus Rohrschneider Ronald Roepman Anneke I den Hollander Johannes R Cruysberg Françoise Meire Ingele Casteels Norka G van Moll-Ramirez Rando Allikmets L Ingeborgh van den Born Frans P M Cremers

Invest Ophthalmol Vis Sci 2006 Mar;47(3):1167-76

The Rotterdam Eye Hospital, Rotterdam, The Netherlands.

Purpose: To test the efficiency of a microarray chip as a diagnostic tool in a cohort of northwestern European patients with Leber congenital amaurosis (LCA) and to perform a genotype-phenotype analysis in patients in whom pathologic mutations were identified.

Methods: DNAs from 58 patients with LCA were analyzed using a microarray chip containing previously identified disease-associated sequence variants in six LCA genes. Mutations identified by chip analysis were confirmed by sequence analysis. On identification of one mutation, all protein coding exons of the relevant genes were sequenced. In addition, sequence analysis of the RDH12 gene was performed in 22 patients. Patients with mutations were phenotyped.

Results: Pathogenic mutations were identified in 19 of the 58 patients with LCA (32.8%). Four novel sequence variants were identified. Mutations were most frequently found in CRB1 (15.5%), followed by GUCY2D (10.3%). The p.R768W mutation was found in 8 of 10 GUCY2D alleles, suggesting that it is a founder mutation in the northwest of Europe. In early childhood, patients with AIPL1 or GUCY2D mutations show normal fundi. Those with AIPL1-associated LCA progress to an RP-like fundus before the age of 8, whereas patients with GUCY2D-associated LCA still have relatively normal fundi in their mid-20s. Patients with CRB1 mutations present with distinct fundus abnormalities at birth and consistently show characteristics of RP12. Pathogenic GUCY2D mutations result in the most severe form of LCA.

Conclusions: Microarray-based mutation detection allowed the identification of 32% of LCA sequence variants and represents an efficient first-pass screening tool. Mutations in CRB1, and to a lesser extent, in GUCY2D, underlie most LCA cases in this cohort. The present study establishes a genotype-phenotype correlation for AIPL1, CRB1, and GUCY2D.
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http://dx.doi.org/10.1167/iovs.05-0848DOI Listing
March 2006

Late-onset retinal dystrophy in alpha-mannosidosis.

Authors:
Christina Springer Alexander Gutschalk Hans-Michael Meinck Klaus Rohrschneider

Graefes Arch Clin Exp Ophthalmol 2005 Dec 17;243(12):1277-9. Epub 2005 Jun 17.

Department of Ophthalmology, University of Heidelberg, Germany.

alpha-Mannosidosis is a rare lysosomal storage disease that is caused by an inherited deficiency of the lysosomal alpha-mannosidase. Clinical symptoms include coarse facial features, skeletal involvement (dysostosis multiplex), hearing disabilities, mental retardation and hepatosplenomegaly. Only few cases with ocular symptoms have been reported, mainly with lenticular opacities. We report on two brothers with complex neurological symptoms who presented with late-onset retinal dystrophy and were followed up for 6 years.
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http://dx.doi.org/10.1007/s00417-004-1084-7DOI Listing
December 2005

Fundus perimetry with the Micro Perimeter 1 in normal individuals: comparison with conventional threshold perimetry.

Authors:
Christina Springer Stefan Bültmann Hans E Völcker Klaus Rohrschneider

Ophthalmology 2005 May;112(5):848-54

Department of Ophthalmology, University of Heidelberg, Heidelberg, Germany.

Purpose: To determine differential light threshold values obtained with the Micro Perimeter 1 (MP1) in healthy volunteers and to correlate them with conventional automated static threshold perimetry using the Octopus 101 Perimeter.

Design: Prospective comparative observational study.

Participants: Thirty healthy volunteers.

Methods: In 30 eyes of 30 healthy volunteers, static threshold perimetry was performed with the MP1 Micro Perimeter (Nidek Inc., Italy) and the Octopus 101 (Haag-Streit AG, Switzerland) in the same eye in random order.

Main Outcome Measures: Differential light threshold values obtained with the MP1 and their difference to differential light threshold values with the Octopus. Differential light sensitivity was compared for 21 matching points in a rectangular test grid using similar examination settings with Goldmann III stimuli, stimulus presentation time of 100 msec, and white background illumination (1.27 cd/m2).

Results: For the 21 matching locations, mean differential light thresholds with the MP 1 and the Octopus were 15.5+/-0.8 decibels (dB) (range, 13.0-17.1) and 30.2+/-1.2 dB (range, 27.7-32.0), respectively. On the average, the Octopus showed higher threshold values for all test locations than the MP1. The mean difference between both examinations was 14.6+/-1.8 dB for all locations and 14.8+/-1.7 dB excluding the test locations at the blind spot. With a considerably high grade of variation according to the test point location, the difference between the 2 devices varied from 11.4 to 18.3 dB, showing a vertical asymmetry with a larger difference in the lower part of the visual field. Linear regression of the perimetric results for each test point location, excluding the area of the blind spot and the lower line of the test grid, showed significant correlation (r = 0.56; P = 0.036).

Conclusions: The results show that the MP1 provides reproducible threshold values with a systematic difference compared with standard Octopus perimetry of approximately 15 dB. With a larger difference in the lower part of the visual field, differential light sensitivity values in microperimetry with the MP1 are comparable to the threshold values obtained with the Octopus 101 using a correction factor of 11.4 to 18.3 dB according to stimulus location.
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http://dx.doi.org/10.1016/j.ophtha.2004.11.051DOI Listing
May 2005

Characterization of the Crumbs homolog 2 (CRB2) gene and analysis of its role in retinitis pigmentosa and Leber congenital amaurosis.

Authors:
José A J M van den Hurk Penny Rashbass Ronald Roepman Jason Davis Krysta E J Voesenek Maarten L Arends Marijke N Zonneveld Marga H G van Roekel Karen Cameron Klaus Rohrschneider John R Heckenlively Robert K Koenekoop Carel B Hoyng Frans P M Cremers Anneke I den Hollander

Mol Vis 2005 Apr 15;11:263-73. Epub 2005 Apr 15.

Department of Human Genetics, Radboud Univerisity Nijmegen Medical Center, Nijmegen, The Netherlands.

Purpose: Mutations in the Crumbs homolog 1 (CRB1) gene cause autosomal recessive retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA). Database searches reveal two other Crumbs homologs on chromosomes 9q33.3 and 19p13.3. The purpose of this study was to characterize the Crumbs homolog 2 (CRB2) gene on 9q33.3, to analyze its expression pattern, and to determine whether mutations in CRB2 are associated with RP and LCA.

Methods: The CRB2 mRNA and its expression pattern in human tissues were analyzed by reverse transcription-polymerase chain reaction (RT-PCR). The cellular expression of Crb2 in the mouse eye was determined by mRNA in situ hybridizations. The open reading frame and splice junctions of CRB2 were analyzed for mutations by single-strand conformation analysis and direct nucleotide sequencing in 85 RP patients and 79 LCA patients.

Results: The CRB2 gene consists of 13 exons and encodes a 1285 amino acid transmembrane protein. CRB2 is mainly expressed in retina, brain, and kidney. In mouse retina Crb2 expression was detected in all cell layers. Mutation analysis of the CRB2 gene revealed 11 sequence variants leading to an amino acid substitution. Three of them were not identified in control individuals and affect conserved amino acid residues. However, the patients that carry these sequence variants do not have a second sequence variant on the other allele, excluding autosomal recessive inheritance of CRB2 sequence variants as a cause of their disease.

Conclusions: This study shows that CRB2 sequence variants are not a common cause of autosomal recessive RP and LCA. It is possible that a more complex clinical phenotype is associated with the loss or altered function of CRB2 in humans due to its expression in tissues other than the retina.
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April 2005

Microperimetry--comparison between the micro perimeter 1 and scanning laser ophthalmoscope--fundus perimetry.

Authors:
Klaus Rohrschneider Christina Springer Stefan Bültmann Hans E Völcker

Am J Ophthalmol 2005 Jan;139(1):125-34

Department of Ophthalmology, University of Heidelberg, Germany.

Purpose: To compare microperimetry using the scanning laser ophthalmoscope (SLO, Rodenstock, Germany) and the recently introduced Micro Perimeter 1 (Nidek Technologies, Italy).

Design: Prospective comparative observational study.

Methods: Fundus perimetry with static threshold perimetry was performed using the SLO and the MP1 in 68 eyes of 40 consecutive patients with different retinal diseases for example, central serous chorioretinopathy, macular dystrophy, and age-related macular degeneration. With both instruments, an automated 4-2-1 staircase strategy with Goldmann III stimuli and a comparable number of stimuli were applied. The depth and size of the detected scotomata as well as the location and stability of fixation were compared between both instruments.

Results: There was good concordance of results, with 75% (51 of 68 eyes) showing an equal defect. Whereas the MP1 showed larger defects (depth and size) in 23.5% (16/68) of eyes studied than the SLO, the defects appeared larger with the SLO in 1 eye. Concerning fixation analysis, similar results were found for fixation stability with stable fixation in 47.1% (MP1: 32/68) and 48.5% (SLO: 33/68) and likewise for the location of fixation with foveal fixation in 54.4% (37/68) with the MP1 and the SLO. Whereas the average number of stimuli was similar for both instruments (MP1 56.8 +/-16.1, SLO 62.9 +/- 17.0), examination time was prolonged with the MP1 (MP1: 11m 35s +/- 3m 47s, SLO: 10m 29s +/- 3m 23s). Throughout all examinations, fundus visualization with the SLO was superior to the MP1.

Conclusions: For automated threshold microperimetry the MP1 provides results comparable to our SLO perimetry. Both instruments enable detection of sensitivity loss of the central visual field and an analysis of fixation behavior during microperimetry. Nevertheless, the MP1, with its automated real-time image alignment, facilitates examination. Additionally, the enlarged field allows testing in an area of 44 x 36 degrees instead of the 33 x 21 degree-area of the SLO. However, in comparison to our SLO-software, the current software of the MP1 requires improvements before exact measurements of defined retinal diseases are possible.
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http://dx.doi.org/10.1016/j.ajo.2004.08.060DOI Listing
January 2005