Christoph Friedburg

Justus-Liebig-Universität Gießen, Gieben, Hesse, Germany

Are you Christoph Friedburg?

Claim your profile

Publications (32)131.82 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: To develop and test an algorithm to segment intraretinal layers irrespectively of the actual Optical Coherence Tomography (OCT) device used. The developed algorithm is based on the graph theory optimization. The algorithm's performance was evaluated against that of three expert graders for unsigned boundary position difference and thickness measurement of a retinal layer group in 50 and 41 B-scans, respectively. Reproducibility of the algorithm was tested in 30 C-scans of 10 healthy subjects each with the Spectralis and the Stratus OCT. Comparability between different devices was evaluated in 84 C-scans (volume or radial scans) obtained from 21 healthy subjects, two scans per subject with the Spectralis OCT, and one scan per subject each with the Stratus OCT and the RTVue-100 OCT. Each C-scan was segmented and the mean thickness for each retinal layer in sections of the early treatment of diabetic retinopathy study (ETDRS) grid was measured. The algorithm was able to segment up to 11 intraretinal layers. Measurements with the algorithm were within the 95% confidence interval of a single grader and the difference was smaller than the interindividual difference between the expert graders themselves. The cross-device examination of ETDRS-grid related layer thicknesses highly agreed between the three OCT devices. The algorithm correctly segmented a C-scan of a patient with X-linked retinitis pigmentosa. The segmentation software provides device-independent, reliable, and reproducible analysis of intraretinal layers, similar to what is obtained from expert graders. Potential application of the software includes routine clinical practice and multicenter clinical trials.
    Translational vision science & technology. 02/2014; 3(1):1.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in CACNA1F encoding the α1-subunit of the retinal Cav1.4 L-type calcium channel have been linked to Cav1.4 channelopathies including incomplete congenital stationary night blindness type 2A (CSNB2), Åland Island eye disease (AIED) and cone-rod dystrophy type 3 (CORDX3). Since CACNA1F is located on the X chromosome, Cav1.4 channelopathies are typically affecting male patients via X-chromosomal recessive inheritance. Occasionally, clinical symptoms have been observed in female carriers, too. It is currently unknown how these mutations lead to symptoms in carriers and how the retinal network in these females is affected. To investigate these clinically important issues we compared retinal phenotypes in Cav1.4-deficient and Cav1.4 heterozygous mice and in human female carrier patients. Heterozygous Cacna1f carrier mice have a retinal mosaic consistent with differential X-chromosomal inactivation, characterized by adjacent vertical columns of affected and non-affected wild type-like retinal network. Vertical columns in heterozygous mice are well comparable to either the wild type retinal network of normal mice or to the retina of homozygous mice. Affected retinal columns display pronounced rod and cone photoreceptor synaptopathy and cone degeneration. These changes lead to vastly impaired vision-guided navigation under dark and normal light conditions and reduced retinal electroretinography (ERG) responses in Cacna1f carrier mice. Similar abnormal ERG responses were found in five human CACNA1F carriers, four of which had novel mutations. In conclusion, our data on Cav1.4 deficient mice and human female carriers of mutations in CACNA1F are consistent with a phenotype of mosaic CSNB2.
    Human Molecular Genetics 10/2013; · 7.69 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: PURPOSE: To develop and evaluate a method for automated segmentation and quantitative analysis of pathological cavities in the retina visualized by Spectral-Domain (SD)-OCT scans. METHODS: The algorithm is based on the segmentation of the grey-level intensities within a B-Scan by a k-means cluster analysis and subsequent classification by a k-nearest neighbor algorithm. Accuracy was evaluated against three clinical experts using 130 bullous cavities identified on 8 SD-OCT B-scans of 3 patients with wet age-related macular degeneration (AMD) and 5 patients with X-linked retinoschisis, as well as on one volume scan of a patient with X-linked retinoschisis. The algorithm calculated (i) the surface area of the cavities for the B-scans and (ii) the volume of all cavities for the volume scan. In order to validate the applicability of the algorithm in clinical use, 31 volume scans of one AMD patient with a serous retinal detachment taken over the course of 4 years were analyzed. RESULTS: Discrepancies in area measurements between the segmentation results of the algorithm and the experts were within the range of the area deviations among the experts. Volumes interpolated from the b-scan series of the volume scan were comparable among experts and algorithm (0.249 mm³ for the algorithm, 0.271 mm³ for expert #1, 0.239 mm³ for expert #2 and 0.262 mm³ for expert #3). Volume changes of the serous retinal detachment were quantifiable. CONCLUSIONS: The segmentation algorithm represents a method for the automated analysis of large numbers of volume scans during routine diagnostics and in clinical trials.
    Investigative ophthalmology & visual science 06/2013; · 3.43 Impact Factor
  • Wadim Bowl, Birgit Lorenz, Melanie Jaeger, Christoph Friedburg
    [Show abstract] [Hide abstract]
    ABSTRACT: PURPOSE: With "standard" stimuli (white, Goldmann size III, 200 ms) the Nidek Microperimeter MP1 underestimates retinal light increment sensitivity (LIS). We thoroughly analyse this problem, suggest alternative settings to improve sensitivity to detect dysfunction, and provide true normal values. METHODS: LIS was tested at 55 positions in the macular region employing a 4-2-1 staircase strategy with 200 ms white or red stimuli on a 1.3 cd m(-2) background. Stimulus size was Goldmann III and I, and additionally II in the healthy subjects. All participants received a complete ophthalmological examination, spectral domain optical coherence tomography (OCT) and fundus autofluorescence (FAF). RESULTS: In normals, distributions of LIS for white Goldmann sizes II and III within the central 6° to 10° were clipped off at 20 dB - the MP1 cannot attenuate them any further. When the stimulus size was reduced to Goldmann I or the color changed to red, median LIS in the fovea (~15 dB) was about 5 dB higher than at 10° eccentricity. Estimated from these results, central LIS for white Goldmann sizes II and III stimuli were 21 dB and 27 dB, respectively. In four patients with either focal or diffuse macular pathology as confirmed by funduscopy, OCT, or FAF, reduced LIS was clearly detected with Goldmann size I stimuli but not III. CONCLUSIONS: In all subjects reported here, central LIS was above the technical limit of the MP1. To measure true thresholds in healthy subjects, either smaller (Goldmann size I) or dimmer stimuli (red) must be used.
    Investigative ophthalmology & visual science 05/2013; · 3.43 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are major causes of blindness. They result from mutations in many genes which has long hampered comprehensive genetic analysis. Recently, targeted next-generation sequencing (NGS) has proven useful to overcome this limitation. To uncover "hidden mutations" such as copy number variations (CNVs) and mutations in non-coding regions, we extended the use of NGS data by quantitative readout for the exons of 55 RP and LCA genes in 126 patients, and by including non-coding 5' exons. We detected several causative CNVs which were key to the diagnosis in hitherto unsolved constellations, e.g. hemizygous point mutations in consanguineous families, and CNVs complemented apparently monoallelic recessive alleles. Mutations of non-coding exon 1 of EYS revealed its contribution to disease. In view of the high carrier frequency for retinal disease gene mutations in the general population, we considered the overall variant load in each patient to assess if a mutation was causative or reflected accidental carriership in patients with mutations in several genes or with single recessive alleles. For example, truncating mutations in RP1, a gene implicated in both recessive and dominant RP, were causative in biallelic constellations, unrelated to disease when heterozygous on a biallelic mutation background of another gene, or even non-pathogenic if close to the C-terminus. Patients with mutations in several loci were common, but without evidence for di- or oligogenic inheritance. Although the number of targeted genes was low compared to previous studies, the mutation detection rate was highest (70%) which likely results from completeness and depth of coverage, and quantitative data analysis. CNV analysis should routinely be applied in targeted NGS, and mutations in non-coding exons give reason to systematically include 5'-UTRs in disease gene or exome panels. Consideration of all variants is indispensable because even truncating mutations may be misleading.
    PLoS ONE 01/2013; 8(11):e78496. · 3.53 Impact Factor
  • Source
  • Source
  • Klinische Monatsblätter für Augenheilkunde 10/2012; 229(10):1009-17. · 0.70 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The aim of the study was to objectively characterize the function of rods, cones, and intrinsic photosensitive retinal ganglion cells (ipRGCs) in patients with RPE65 mutations by using two published protocols for chromatic pupillometry, and to correlate the data with the clinical phenotype. The study group comprised 11 patients with RPE65 mutations, and for control purposes, 32 healthy probands and 2 achromats. A custom-made binocular chromatic pupillometer (Bino I) connected to a ColorDome Ganzfeld stimulator was used to assess changes in pupil diameter in response to red (640 nm) and blue (462 nm) light stimuli. Light intensities, stimulus duration, and background varied depending on the protocol used. Results were compared to the clinical phenotype, that is, visual field (Goldmann perimetry), best corrected visual acuity, and full-field stimulus testing (FST). No significant differences in any of the pupil response parameters were observed in intraday or intervisit variability tests. Pupil responses to rod-weighted stimulation were significantly diminished in all RPE65 patients. Pupil responses to cone-weighted stimuli differed among RPE65 patients and did not always correlate with residual visual field and cone sensitivity loss in FST. Pupil responses to ipRGC-weighted answers were slightly but significantly diminished, and the postillumination pupil response was significantly increased. Chromatic pupillometry represents a highly sensitive and objective test to quantify the function of rods, cones, and ipRGCs in patients with RPE65 mutations.
    Investigative ophthalmology & visual science 07/2012; 53(9):5641-52. · 3.43 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The correct segmentation of blood vessels in optical coherence tomography (OCT) images may be an important requirement for the analysis of intra-retinal layer thickness in human retinal diseases. We developed a shape model based procedure for the automatic segmentation of retinal blood vessels in spectral domain (SD)-OCT scans acquired with the Spectralis OCT system. The segmentation procedure is based on a statistical shape model that has been created through manual segmentation of vessels in a training phase. The actual segmentation procedure is performed after the approximate vessel position has been defined by a shadowgraph that assigns the lateral vessel positions. The active shape model method is subsequently used to segment blood vessel contours in axial direction. The automated segmentation results were validated against the manual segmentation of the same vessels by three expert readers. Manual and automated segmentations of 168 blood vessels from 34 B-scans were analyzed with respect to the deviations in the mean Euclidean distance and surface area. The mean Euclidean distance between the automatically and manually segmented contours (on average 4.0 pixels respectively 20 µm against all three experts) was within the range of the manually marked contours among the three readers (approximately 3.8 pixels respectively 18 µm for all experts). The area deviations between the automated and manual segmentation also lie within the range of the area deviations among the 3 clinical experts. Intra reader variability for the experts was between 0.9 and 0.94. We conclude that the automated segmentation approach is able to segment blood vessels with comparable accuracy as expert readers and will provide a useful tool in vessel analysis of whole C-scans, and in particular in multicenter trials.
    Biomedical Optics Express 07/2012; 3(7):1478-91. · 3.18 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To identify the underlying mutation and describe the phenotype in a consanguineous Kurdish family with Leber's congenital amaurosis (LCA)/early onset severe retinal dystrophy (EOSRD). Members of the index family were followed up to 22 years by ophthalmological examinations, including best corrected visual acuity (BCVA), Goldmann visual field (GVF), two-color-threshold perimetry (2CTP) and Ganzfeld electroretinogram (ERG), fundus photographs, fundus autofluorescence (FAF), and optical coherence tomography (OCT). After excluding seven of nine known LCA/EOSRD genes in the index patient, linkage analysis was performed in the family using a microarray followed by microsatellite fine mapping and direct sequencing of candidate genes. RD3 was screened by direct sequencing of 85 independent patients with LCA/EOSRD presenting with a BCVA ≥ 1.0 LogMAR before the age of 2 years to assess the prevalence of RD3 mutations in LCA/EOSRD. Since RD3 and RetGC1 have a functional relation, study authors screened for a modifying effect of RD3 mutations in 17 independent patients with mutations in GUCY2D. BCVA was severely reduced from the earliest examinations (as early as 3 months), never exceeding 1.3 LogMAR. The disease presented as cone-rod dystrophy with dystrophic changes in the macula and bone spicules in the periphery on progression. Linkage analysis narrowed the region of interest towards the LCA12 locus. Direct sequencing of RD3 revealed a homozygous nonsense mutation (c.180C > A) in all affected members tested. Screening of additional unrelated LCA/EOSRD patients revealed only polymorphisms in RD3. This is the second family reported so far with mutations in RD3. Mutations in RD3 are a very rare cause of LCA associated with an extremely severe form of retinal dystrophy.
    Investigative ophthalmology & visual science 04/2012; 53(7):3463-72. · 3.43 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Congenital stationary night blindness (CSNB) is a heterogeneous retinal disorder characterized by visual impairment under low light conditions. This disorder is due to a signal transmission defect from rod photoreceptors to adjacent bipolar cells in the retina. Two forms can be distinguished clinically, complete CSNB (cCSNB) or incomplete CSNB; the two forms are distinguished on the basis of the affected signaling pathway. Mutations in NYX, GRM6, and TRPM1, expressed in the outer plexiform layer (OPL) lead to disruption of the ON-bipolar cell response and have been seen in patients with cCSNB. Whole-exome sequencing in cCSNB patients lacking mutations in the known genes led to the identification of a homozygous missense mutation (c.1807C>T [p.His603Tyr]) in one consanguineous autosomal-recessive cCSNB family and a homozygous frameshift mutation in GPR179 (c.278delC [p.Pro93Glnfs(∗)57]) in a simplex male cCSNB patient. Additional screening with Sanger sequencing of 40 patients identified three other cCSNB patients harboring additional allelic mutations in GPR179. Although, immunhistological studies revealed Gpr179 in the OPL in wild-type mouse retina, Gpr179 did not colocalize with specific ON-bipolar markers. Interestingly, Gpr179 was highly concentrated in horizontal cells and Müller cell endfeet. The involvement of these cells in cCSNB and the specific function of GPR179 remain to be elucidated.
    The American Journal of Human Genetics 02/2012; 90(2):321-30. · 11.20 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To provide an up to 14-year overview of the early ocular phenotype in siblings with a homozygous p.G461R mutation in the KCNV2 gene. Two brothers and their sister were followed-up clinically from ages 5 years, 4 years, and 2 months, respectively, including complete ophthalmological examinations. Goldmann visual fields, two-color-threshold (2CT) perimetry, color vision testing, optical coherence tomography (OCT), fundus autofluorescence (FAF), and Ganzfeld electroretinograms (ERGs) were performed according to age-related capabilities. Genetic analyses included whole genome linkage analysis, homozygosity mapping, and candidate gene sequencing. All three siblings were homozygous for the p.G461R mutation. At 5 months, the younger brother had no nystagmus and Teller-acuity of 3.2 cyc/deg. At older age, all three presented nystagmus, increased light sensitivity, reduced color discrimination, and relative central scotomas. Visual acuities ranged from 20/200 to 20/70. The macula developed minor irregularities of the RPE, thinning in optical coherence tomography, and a ring of increased FAF. Scotopic (rod) sensitivity was reduced by 2 log and photopic sensitivity by 1 log in two-color-threshold perimetry. ERG responses were markedly delayed. Photopic amplitudes were severely reduced. Scotopic b-waves rose steeply with flash intensity, but for the standard flash supernormal amplitudes were only reached in the girl. FAF was similar to that in cone-rod dystrophy. Although cone dysfunction was accompanied by rod dysfunction, and scotopic ERGs in patient 2 deteriorated, no patient demonstrated any unequivocal sign of rod degeneration. Grossly delayed b-waves with a steep response-versus-intensity relationship rather than supernormal amplitudes should remind clinicians of this specific condition.
    Investigative ophthalmology & visual science 09/2011; 52(12):8621-9. · 3.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Acute zonal occult outer retinopathy (AZOOR) is a rare disease and is part of the white dot syndrome occurring bilaterally and often asymmetrically in young healthy myopic women. Characteristic findings are distinct focal lesions of the outer segments (OS) of the photoreceptor (PR) layer and abnormalities in fundus autofluorescence (FAF) within the lesions. Currently there is a lack of defined disease criteria, such as specific laboratory findings. Also no effective therapy is known which makes it difficult to diagnose, differentiate and treat AZOOR. Supplementation of antioxidants may become part of therapeutic options in AZOOR. A 19-year-old myopic woman presented with unilaterally reduced visual acuity. Due to the clinical features and with the help of FAF, spectral domain optical coherence tomography (SD-OCT) and perimetry the diagnosis of blind spot enlargement syndrome in AZOOR was made. Identification of autoantibodies specific for two retinal antigens (CRALBP and S-Ag) supports the concept of an autoimmunological origin of the disease. Systemic steroids were given but stopped almost 6 weeks later as no improvement was seen. In follow-up controls over 12 months the clinical picture remained unchanged without any further therapy.
    Der Ophthalmologe 09/2011; 108(11):1045-9. · 0.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cone dystrophy with supernormal rod response (CDSRR) is considered to be a very rare autosomal recessive retinal disorder. CDSRR is associated with mutations in KCNV2, a gene that encodes a modulatory subunit (Kv8.2) of a voltage-gated potassium channel. In this study, we found that KCNV2 mutations are present in a substantial fraction (2.2-4.3%) of a sample of 367 independent patients with a variety of initial clinical diagnoses of cone malfunction, indicating that CDSRR is underdiagnosed and more common than previously thought. In total, we identified 20 different KCNV2 mutations; 15 of them are novel. A new finding of this study is the substantial proportion of large deletions at the KCNV2 locus that accounts for 15.5% of the mutant alleles in our sample. We determined the breakpoints and size of all five different deletions, which ranged between 10.9 and 236.8 kb. Two deletions encompass the entire KCNV2 gene and one also includes the adjacent VLDLR gene. Furthermore, we investigated N-terminal amino acid substitution mutations for its effect on interaction with Kv2.1 using yeast two-hybrid technology. We found that these mutations dramatically reduce or abolish this interaction suggesting a lack of assembly of heteromeric Kv channels as one underlying pathomechanism of CDSRR.
    Human Mutation 08/2011; 32(12):1398-406. · 5.21 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Congenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous retinal disease. Although electroretinographic (ERG) measurements can discriminate clinical subgroups, the identification of the underlying genetic defects has been complicated for CSNB because of genetic heterogeneity, the uncertainty about the mode of inheritance, and time-consuming and costly mutation scanning and direct sequencing approaches. To overcome these challenges and to generate a time- and cost-efficient mutation screening tool, the authors developed a CSNB genotyping microarray with arrayed primer extension (APEX) technology. To cover as many mutations as possible, a comprehensive literature search was performed, and DNA samples from a cohort of patients with CSNB were first sequenced directly in known CSNB genes. Subsequently, oligonucleotides were designed representing 126 sequence variations in RHO, CABP4, CACNA1F, CACNA2D4, GNAT1, GRM6, NYX, PDE6B, and SAG and spotted on the chip. Direct sequencing of genes known to be associated with CSNB in the study cohort revealed 21 mutations (12 novel and 9 previously reported). The resultant microarray containing oligonucleotides, which allow to detect 126 known and novel mutations, was 100% effective in determining the expected sequence changes in all known samples assessed. In addition, investigation of 34 patients with CSNB who were previously not genotyped revealed sequence variants in 18%, of which 15% are thought to be disease-causing mutations. This relatively inexpensive first-pass genetic testing device for patients with a diagnosis of CSNB will improve molecular diagnostics and genetic counseling of patients and their families and gives the opportunity to analyze whether, for example, more progressive disorders such as cone or cone-rod dystrophies underlie the same gene defects.
    Investigative ophthalmology & visual science 08/2009; 50(12):5919-26. · 3.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To describe fundus autofluorescence (FAF) in carriers of choroideremia (CHM), and to compare FAF findings with ophthalmoscopy and electrophysiologic and psychophysical data. Prospective, observational case series and systematic review. Six unrelated carriers of CHM. Clinical examination included a comprehensive ophthalmic examination, fundus photography, FAF, kinetic perimetry, 2-color threshold perimetry (2CTP), full-field electroretinography (ERG), and multifocal ERG (mfERG). All 6 carriers (33-60 years of age) were screened for mutations in the coding region of Rab Escort Protein 1 gene (REP1) including close flanking intronic sequence and deletions within 2160 bp of 5' untranslated sequence. Intensity and distribution of FAF, rod sensitivity loss, cone sensitivity loss in 2CTP, amplitude and latency in full-field ERG, amplitude in mfERG, and correlation of all 3 parameters. Mutations in the coding region of REP1 were identified in 3 of 6 carriers. All 6 carriers had good visual acuity. Three carriers complained of photophobia and 1 of impaired vision in dim light. Ophthalmoscopy revealed peripapillary atrophy and retinal pigment epithelium (RPE) mottling mainly in the macular region, and additional RPE clumping and flecks of atrophy in the periphery. A very irregular pattern of low- and high-density FAF speckles was seen. Low-density FAF surrounding the optic nerve head corresponded with the peripapillary atrophy. In areas of major FAF changes, mfERG was deteriorated. The 2CTP images revealed functional disturbances in rods and cones. No general pattern was observed. On MfERG, reduced amplitudes in areas with normal cone sensitivity in 2CTP were seen. All 6 carriers of CHM showed a characteristic FAF pattern that can guide mutation analysis. Even when other functional testing is inconspicuous, FAF is a rapid, noninvasive indicator. The authors have no proprietary or commercial interest in any of the materials discussed in this article.
    Ophthalmology 05/2009; 116(6):1201-9.e1-2. · 5.56 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels contribute to pacemaker activity, and co-determine the integrative behaviour of neurons and shape their response to synaptic stimulation. Four channel isoforms, HCN1-4, have been described in mammals. Recent studies showed particularly strong expression of HCN1 channels in rods and cones of the rat retina, suggesting that HCN1 channels are involved in the shaping of light responses in both types of photoreceptors. Therefore, the loss of HCN1 channels should lead to pronounced changes in light-induced electrical responses under both scotopic and photopic conditions. This was tested using a mouse transgenic approach. We used immunohistochemistry and patch-clamp recording to study the distribution of HCN1 channels in the mouse retina. HCN1 channels were strongly expressed in rod and cone photoreceptors, as well as in some bipolar, amacrine and ganglion cell types. In electroretinograms (ERGs) from animals in which the HCN1 channel gene had been knocked out, the b-wave amplitudes were unaltered (scotopic conditions) or somewhat reduced (photopic conditions), whereas the duration of both scotopic and photopic ERG responses was strikingly prolonged. Our data suggest that in visual information processing, shortening and shaping of light responses by activation of HCN1 at the level of the photoreceptors is an important step in both scotopic and photopic pathways.
    European Journal of Neuroscience 12/2008; 28(11):2221-30. · 3.75 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Later onset and progression of retinal dystrophy occur with some RPE65 missense mutations. The functional consequences of the novel P25L RPE65 mutation was correlated with its early-childhood phenotype and compared with other pathogenic missense mutations. In addition to typical clinical tests, fundus autofluorescence (FAF), optical coherence tomography (OCT), and two-color threshold perimetry (2CTP) were measured. RPE65 mutations were screened by SSCP and direct sequencing. Isomerase activity of mutant RPE65 was assayed in 293F cells and quantified by HPLC analysis of retinoids. A very mild phenotype was detected in a now 7-year-old boy homozygous for the P25L mutation in RPE65. Although abnormal dark adaptation was noticed early, best corrected visual acuity was 20/20 at age 5 years and 20/30 at age 7 years. Nystagmus was absent. Cone electroretinogram (ERG) was measurable, rod ERG severely reduced, and FAF very low. 2CTP detected mainly cone-mediated responses in scotopic conditions, and light-adapted cone responses were approximately 1.5 log units below normal. High-resolution spectral domain OCT revealed morphologic changes. Isomerase activity in 293F cells transfected with RPE65/P25L was reduced to 7.7% of wild-type RPE65-transfected cells, whereas RPE65/L22P-transfected cells had 13.5%. The mild clinical phenotype observed is consistent with the residual activity of a severely hypomorphic mutant RPE65. Reduction to <10% of wild-type RPE65 activity by homozygous P25L correlates with almost complete rod function loss and cone amplitude reduction. Functional survival of cones is possible in patients with residual RPE65 isomerase activity. This patient should profit most from gene therapy.
    Investigative ophthalmology & visual science 07/2008; 49(12):5235-42. · 3.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Leber congenital amaurosis (LCA) usually describes patients with severely reduced vision due to a retinal dystrophy in early childhood. In 135 families in a case series with severely reduced vision due to a retinal dystrophy in early childhood a complete ophthalmologic examination was extended by two-color threshold perimetry, fundus autofluorescence (FAF), und optical coherence tomography (OCT). Mutation screening included AIPL1, CRB1, CRX, GUCY2D, LRAT, RPE65, RPGRIP, and TULP1. GUCY2D mutations caused the most severe phenotype with severely reduced vision from birth but unremarkable fundus appearance. RPE65 mutations were correlated with an obvious lack of FAF. CRB1 mutations showed a significantly thickened retina on OCT. CRX mutations were associated with a progressive form of cone-rod dystrophy. A genotype-phenotype correlation for selected genes allows an optimized strategy for the molecular genetic work-up.
    Der Ophthalmologe 07/2007; 104(6):490-8. · 0.53 Impact Factor

Publication Stats

458 Citations
131.82 Total Impact Points

Institutions

  • 2011–2013
    • Justus-Liebig-Universität Gießen
      Gieben, Hesse, Germany
  • 2009–2013
    • Universitätsklinikum Gießen und Marburg
      Marburg, Hesse, Germany
  • 2002–2011
    • University of Tuebingen
      • Institute for Ophthalmic Research
      Tübingen, Baden-Wuerttemberg, Germany
  • 2007
    • Universität Regensburg
      Ratisbon, Bavaria, Germany
  • 2004
    • Universitätsmedizin Göttingen
      Göttingen, Lower Saxony, Germany
  • 2002–2004
    • Georg-August-Universität Göttingen
      Göttingen, Lower Saxony, Germany
  • 2001
    • University of Cambridge
      Cambridge, England, United Kingdom
  • 1998–1999
    • Universitätsklinikum Tübingen
      Tübingen, Baden-Württemberg, Germany