Macular Degeneration: Wissinger B

Renner AB, Fiebig BS, Weber BH, Wissinger B, Andreasson S, Gal A, Cropp E, Kohl S, Kellner U. · Augenklinik, Charité-Universitätsmedizin Berlin, Germany. · Am J Ophthalmol. · Pubmed #19038374 No free full text.

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.

Wissinger B, Dangel S, Jägle H, Hansen L, Baumann B, Rudolph G, Wolf C, Bonin M, Koeppen K, Ladewig T, Kohl S, Zrenner E, Rosenberg T. · Molecular Genetics Laboratory, Institute for Ophthalmic Research, Centre for Ophthalmology, University Clinics Tübingen, Germany. · Invest Ophthalmol Vis Sci. · Pubmed #18235024 links to  free full text

Abstract: PURPOSE: Cone dystrophy with supernormal rod response (CDSRR) is a retinal disorder characterized by reduced visual acuity, color vision defects, and specific alterations of ERG responses that feature elevated scotopic b-wave amplitudes at high luminance intensities. Mutations in PDE6H and in KCNV2 have been described in CDSRR. A combined clinical and genetic study was conducted in a cohort of patients with CDSRR, to substantiate these prior RESULTS: METHODS: Seventeen patients from 13 families underwent a detailed ophthalmic examination including color vision testing, Goldmann visual fields, fundus photography, Ganzfeld and multifocal ERGs, and optical coherence tomography. The coding sequences and flanking intron/UTR sequences of PDE6C and KCNV2 were screened for mutations by means of DHPLC and direct DNA sequencing of PCR-amplified genomic DNA. results. Whereas no mutations were detected in the PDE6H gene, mutations in KCNV2 were identified in all patients, in either the homozygous or compound heterozygous state. Ten of the 11 identified mutations were novel, including three missense and six truncating mutations and one gross deletion. The mutations concordantly segregate in all available families according a recessive mode of inheritance. The CDSRR phenotype was associated with reduced visual acuity of variable degree and color vision defects. Macular defects ranging from mild pigmentary changes to distinct foveal atrophy were present in nine patients. Progression of the disease was observed in only three of seven patients with follow-up data. CONCLUSIONS: The phenotype of cone dystrophy with supernormal rod response is tightly linked with mutations in KCNV2.

Renner AB, Tillack H, Kraus H, Kohl S, Wissinger B, Mohr N, Weber BH, Kellner U, Foerster MH. · Augenklinik, Campus Benjamin Franklin, Charité Universitätsmedizin Berlin, Berlin, Germany. · Retina. · Pubmed #15579992 No free full text.

Abstract: PURPOSE: Detailed morphologic and functional evaluation of adult vitelliform macular dystrophy (AVMD). METHODS: The records of 61 consecutive AVMD patients (inclusion criterion: vitelliform lesion smaller than one disk diameter at least in one eye) were evaluated retrospectively regarding visual acuity, color vision, perimetry, retinal pigment epithelium (RPE) autofluorescence, fluorescein angiography, electro-oculography, full-field and multifocal electroretinography, and molecular genetic evaluation of the VMD2 and RDS/peripherin genes. RESULTS: The mean age of subjects was 54.6 years. Visual loss was variable (median, 0.6; range, 1.25-0.05). Color vision and visual field were normal in about half of the patients but presented defects with high variability in the remaining patients. Autofluorescence findings showed increased fluorescence within the foveal yellow lesion in 76%. In the majority of eyes, the amplitude of the 30 Hz flicker response of the full-field electroretinogram (72%) and the central P1 amplitude of the multifocal electroretinogram (63%) were reduced. Mutational analyses revealed a potentially disease-associated mutation in the RDS/peripherin gene in one patient. CONCLUSION: AVMD is characterized by late onset, slow progression, good prognosis, and high variability of morphologic and functional abnormalities resulting frequently in misdiagnosis. Autofluorescence findings indicate lipofuscin accumulation in the yellow lesion. Electroretinography revealed a generalized cone system dysfunction with increasing severity toward the fovea.

Kellner U, Wissinger B, Tippmann S, Kohl S, Kraus H, Foerster MH. · Department of Ophthalmology Campus Benjamin Franklin, Charité Universitätsmedizin, Berlin, Germany. · Graefes Arch Clin Exp Ophthalmol. · Pubmed #15069569 No free full text.

Abstract: BACKGROUND: X-linked blue cone monochromatism (BCM) has to be differentiated from x-linked cone dystrophy and autosomal recessive rod monochromatism. METHODS: In nine male patients with congenital cone dysfunction (one family, six single cases; age range: 9-55 years), mutations in the red/green opsin gene cluster were confirmed. Clinical findings were analyzed retrospectively. RESULTS: In one family and three single cases, a single red-green hybrid gene was found carrying a Cys203Arg mutation. Two patients had multiple opsin genes, a red/green hybrid gene and at least one green pigment gene, all carrying the Cys203Arg mutation. In one patient, a large deletion of the locus control region and parts of the red pigment gene were detected. Two patients (ages: 45 and 55 years) complained about progression. Two patients presented with nystagmus. Refractive errors (+8.0 and -11.0 D) and visual acuity were variable (0.05-0.3). Only four patients had a visual acuity > or = 0.1. In two patients, visual acuity could be improved using blue filter glasses. Four of five patients > or = 25 years had dystrophic alterations in the macula. Severe color vision defects and relative central scotoma were present in all patients. In the electroretinogram, residual cone responses were detected in 2/8 patients. CONCLUSIONS: Hybrid red/green opsin genes carrying the Cys203Arg mutation are a frequent cause of BCM in German patients. Molecular genetic evaluation is mandatory for adequate diagnosis of patients since from the clinical data only two patients were diagnosed as having BCM. In the other patients, either rod monochromatism or cone-rod dystrophy could not be excluded with certainty. The patients should be cautioned that macular dystrophy may develop in adults older than 30 years.

Scholl HP, Kremers J, Wissinger B. · Laboratories of Electrophysiology, Department of Experimental Ophthalmology, University Eye Hospital Tübingen, Germany. · Curr Eye Res. · Pubmed #11462159 No free full text.

Abstract: PURPOSE: To determine the L- and M-cone driven ERG responses in a male patient with macular dystrophy and a protan phenotype. METHODS: We measured large field ERG thresholds to stimuli which modulated exclusively the L- or the M-cones or the two in various combinations (both in-phase and in counterphase). In none of the stimuli, the S-cones were modulated. Additionally, standard and multifocal ERGs were measured. Analysis of the L- and M-cone pigment genes was performed by means of PCR, RFLP analysis and DNA sequencing techniques. RESULTS: Macular dystrophy was revealed by the markedly abnormal multifocal ERGs in presence of near normal standard ERGs. The large field ERG responses were exclusively driven by the M-cones with enlarged thresholds when compared with otherwise normal protanopes. In addition, the M-cone driven ERG response phases were abnormal. Pigment gene analysis confirmed a protan genotype with the presence of a single 5'red/3'green hybrid pigment gene. CONCLUSIONS: Our novel stimulus technique allows a reliable analysis of the separate cone pathways even in cases with macular dysfunction. The increased thresholds and the abnormal phase behavior of the M-cone driven ERGs reflect altered mechanisms of the retinal physiology in this patient. The data strongly suggest that the macular dystrophy and the protanopia have independent origins.