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Biomedical subjects

E Zrenner

Publications and source records attributed to E Zrenner.

At least 37 records · Page 2Linked to original sources
PubMed2001

[Clinical findings in autosomal recessive syndrome of blue cone hypersensitivity].

BACKGROUND: Intrafamilial variability of the syndrome of night blindness, maculopathy, and enhanced S-cone hypersensitivity was examined. PATIENTS AND METHODS: Siblings with a history of night blindness and reduced visual acuity were examined clinically, psychophysically, electroretinographically (ERG), and electro-oculographically (EOG). RESULTS: The siblings had had night blindness since early childhood and reduced visual acuity since the age of 20 years. Ophthalmoscopy showed degenerative, pigmented changes and subretinal spots, while one sibling had cystic lesions in the fovea. Scotopic ERG showed no rod-driven responses, while large, slow waveforms were detected in response to bright flashes. Photopic ERG induced responses similar in time, amplitude, and configuration to those of the dark-adapted ERG. The b-wave configuration was unchanged in response to chromatic stimuli. However, photopic ERG was more sensitive to blue and white than to red stimuli. The light peak on EOG was reduced. CONCLUSIONS: The enhanced S-cone sensitivity syndrome was expressed to a different degree of severity and probably inherited in an autosomal recessive mode. These unusual ERG findings may be due to a depressed rod system and an increased number of S-cone photoreceptors, postreceptoral circuits, and S-cone sensitive ganglion cells.

Adult↗
PubMed2001

Clinical electrophysiology of two rod pathways: normative values and clinical application.

BACKGROUND: The scotopic 15-Hz flicker electroretinogram (ERG) has two limbs (slow and fast ERG rod signals), and these have been attributed to two retinal rod pathways (the ON rod bipolar and AII amacrine pathway and the rodcone gap-junction pathway). The aim of this study was to provide normative values of the scotopic 15-Hz flicker ERG, to estimate the inter-individual variability, and to apply this method to a clinical setting. METHODS: Twenty-two normal subjects, one patient with retinitis pigmentosa (RP), and two patients with Stargardt's mascular dystrophy (SMD) participated in the study. The SMD patients were screened for mutations in the 50 exons of the ABCA4 (formerly ABCR) gene. We measured ERG response amplitudes and phases to flicker intensities ranging from -3.37 to -0.57 log scotopic trolands s at a flicker frequency of 15 Hz. RESULTS: The normal scotopic 15-Hz flicker ERG showed a biphasic amplitude pattern with a minimum at about-1.57 log scotopic trolands s, where there was an abrupt phase shift of about 180 deg. The inter-individual variability in ERG amplitude ranged from 47% to 67% for the slow and from 41% to 64% for the fast rod signal. Both the RP patient and the SMD patients (who were compound heterozygotes for mutations in the ABCA4 gene) showed reduced amplitudes for the two rod ERG pathways. CONCLUSION: The inter-individual variability might be explained by anatomical differences between individual retinae. In the RP patient, the amplitude reductions corresponded well with the standard rod ERG. In the SMD patients, however, the scotopic 15-Hz flicker ERG revealed rod dysfunction, whereas the standard rod ERG was within normal limits. The scotopic 15-Hz flicker method may be more sensitive than the standard rod ERG.

ATP-Binding Cassette Transporters↗
PubMed2001

Studies on the feasibility of a subretinal visual prosthesis: data from Yucatan micropig and rabbit.

BACKGROUND: To estimate the feasibility of the subretinal concept of a visual prosthesis, animal models and prototypes, each representing a certain aspect of the final prosthesis, were utilised to test for requirements for such a medical device: (1) the ability to elicit--by electrical stimulation--event-related central activity in the central visual system, and (2) the long-term biocompatibility and biostability of the implant within the subretinal space. METHODS: (1) In rabbit and Yucatan minipig, cortical evoked potentials were recorded with chronically implanted epidural electrodes during stimulation with light flashes as well as during electrical stimulation in the subretinal space. Voltage pulses ranging from -3 V to +3 V were applied via an acutely implanted electrode array on a wired prototype. (2) For biocompatibility studies a silicon-based micro-photodiode array (MPDA) was used that closely resembled the design and composition of the final prosthesis. Fourteen months after implantation, angiography was performed and the histological findings of the retina in the immediate vicinity of the implant were evaluated. RESULTS: (1) In both rabbit and minipig, subretinal electrical stimulation resulted in evoked cortical potentials that were comparable to visual evoked potentials. The lowest threshold levels for the subretinal stimulation were 0.6 V for rabbits and 2 V for minipigs. (2) Long-term stability of an implanted MPDA and its biocompatibility were proven for a postoperative period of 14 months. CONCLUSIONS: Data from animal experiments with certain prototypes of the final prosthesis suggest the feasibility of the concept of a subretinal visual prosthesis: Both requirements were met: (1) the functioning of the subretinal stimulation and (2) the biocompatibility of the MPDA implant.

Animals↗
PubMed2001

New views on RPE65 deficiency: the rod system is the source of vision in a mouse model of Leber congenital amaurosis.

Leber congenital amaurosis (LCA) is the most serious form of the autosomal recessive childhood-onset retinal dystrophies. Mutations in the gene encoding RPE65, a protein vital for regeneration of the visual pigment rhodopsin in the retinal pigment epithelium, account for 10-15% of LCA cases. Whereas previous studies of RPE65 deficiency in both animal models and patients attributed remaining visual function to cones, we show here that light-evoked retinal responses in fact originate from rods. For this purpose, we selectively impaired either rod or cone function in Rpe65-/- mice by generating double- mutant mice with models of pure cone function (rhodopsin-deficient mice; Rho-/-) and pure rod function (cyclic nucleotide-gated channel alpha3-deficient mice; Cnga3-/-). The electroretinograms (ERGs) of Rpe65-/- and Rpe65-/-Cnga3-/- mice were almost identical, whereas there was no assessable response in Rpe65-/-Rho-/- mice. Thus, we conclude that the rod system is the source of vision in RPE65 deficiency. Furthermore, we found that lack of RPE65 enables rods to mimic cone function by responding under normally cone-isolating lighting conditions. We propose as a mechanism decreased rod sensitivity due to a reduction in rhodopsin content to less than 1%. In general, the dissection of pathophysiological processes in animal models through the introduction of additional, selective mutations is a promising concept in functional genetics.

Animals↗
PubMed2001

[Automated swinging flashlight test in patients with optic nerve diseases].

AIM OF THE STUDY: The swinging flashlight test is an objective method to diagnose a lesion of the anterior visual pathways. However, errors and faults may easily alter the test's results. Hence, the value of the swinging flashlight test depends highly on the examiner's skills. Therefore an automated and objective procedure was developed which is independent from the examiner. METHODS: A binocularly measuring instrument adapted for video pupillography was supplied with two arrays of light emitting diodes in front of each eye of the subject. By means of this illumination, pupillary light reflexes are elicited alternately. Pupil size is registered continuously, and after artifact elimination, the response amplitudes of the pupils are determined as a mean of right and left pupil. Responses elicited via right and left eye are compared. By varying the stimulus intensity it is possible to measure the amount of the relative afferent pupillary defect. The procedure was tested in 31 patients with optic nerve disorders. RESULTS: The measurements were easily feasible, stable and reliable. Correlation between the relative afferent pupillary defect detected manually by grey filter compensating and with the automated procedure proved to be high. Both variables correlated highly significant with a Spearman rank coefficient of 0.65. If the clinical test is regarded as the golden standard, the automated swinging flashlight test is able to detect 85% of the relative afferent pupillary defects > or = 0.3 logE and 94% of the defects > or = 0.6 logE. CONCLUSION: The automated swinging flashlight test can be recommended to exclude influences by the examiner or if the exact amount of the relative afferent pupillary defect is desired, e.g. when monitoring therapeutic effects in optic nerve diseases. Furthermore, an automated swinging flashlight test could serve as a screening test.

Adult↗
PubMed2001

Case populations must match the respective disease model: Genotype diversity causes linkage disequilibrium mapping failure in monogenic disorders.

Traditional linkage analysis in large families is the most promising approach for mapping disease genes of monogenic heritable disorders when the number of informative meioses is sufficient. With rare diseases, however, the low availability of informative pedigrees poses a significant limitation. As an adjunct to family linkage methods, association studies based on the investigation of individual haplotypes from a number of unrelated patients (i.e. linkage disequilibrium analysis) have recently been employed in mapping hereditary disease loci. However, such haplotype analysis is hampered by a number of effects that influence statistical evaluation, e.g. i) population history and size, ii) allele and haplotype frequencies in the respective population(s), iii) heterogeneous mutation and natural selection processes, and iv) small sample sizes of patient groups. The purpose of the present study was to determine the utility and limitations of haplotype-based genetic mapping in estimating the location of the NYX gene, which has recently been identified as the causative gene for a rare inherited retinal disorder known as the complete type of X-linked congenital stationary night blindness (CSNB1). For this purpose we recapitulated haplotypes and tested for linkage disequilibrium in 20 unrelated male CSNB1 patients from three European populations and 44 healthy individuals. All subjects were genotyped for 17 polymorphic microsatellite loci covering the Xp11.4 region with an average marker density of approximately 0.29 cM. We found that a precise model to describe mutations at loci that erroneously break up linkage is highly required, and that the case population must match the respective disease model.

Adolescent↗
PubMed2001

Evaluation of the rhodopsin knockout mouse as a model of pure cone function.

PURPOSE: To determine a time window in the rhodopsin knockout (Rho(-/-)) mouse during which retinal function is already sufficiently developed but cone degeneration is not yet substantial, thus representing an all-cone retina. METHODS: Electroretinograms (ERGs) were obtained from 14 homozygous Rho(-/-) mice and eight C57Bl/6 control mice. The same individuals were tested every 7 days, beginning as early as postnatal day (P)14. The ERG protocols included flash and flicker stimuli, both under photopic and scotopic conditions. Retinal and choroidal morphology was observed in animals of comparable age. RESULTS: Functionally, the developmental phase lasted until postnatal week (PW)3 in both the Rho(-/-) mice and the control animals. During PW4 to 6, the Rho(-/-) mice showed a plateau in ERG parameters with normal or even supernormal cone responses and complete absence of rod contributions. At PW7, there was a marked onset of degeneration, which progressed so that no ERG signals were left at PW13, when the control eyes still had normal ERG responses. Microscopically, cone degeneration paralleled the functional changes, beginning at approximately PW6 and almost complete at PW13, whereas retinal pigment epithelium (RPE) and choroid did not show any abnormalities. CONCLUSIONS: From PW4 to 6, Rho(-/-) mice appear to have normal cone and no rod function. Despite the missing rod outer segment (OS), the structure of retina, RPE, and choroid remained unchanged. Therefore, the Rho(-/-) mice can serve during this age period as a model for pure cone function. Such a model is particularly useful to evaluate rod-cone interaction and to dissect rod- from cone-mediated signaling pathways in vivo.

Animals↗
PubMed2001

Segregation patterns and heteroplasmy prevalence in Leber's hereditary optic neuropathy.

PURPOSE: To investigate the segregation pattern of the mitochondrial DNA mutation at nucleotide position 3460 responsible for Leber's hereditary optic neuropathy (LHON) and to determine the prevalence of heteroplasmy for the three primary LHON mutations at positions 11778, 3460, and 14484. METHODS: Segregation analysis was performed in a cross-sectional study by determining the level of heteroplasmy in blood leukocytes of 23 LHON patients and unaffected carriers from four unrelated families. One family comprising two affected and three unaffected carriers was followed over 5.5 years for a longitudinal segregation analysis of heteroplasmy. The percentage of mutant mtDNA was determined using a novel procedure of fluorescence-based primer extension and restriction fragment length polymorphism analysis. The prevalence of heteroplasmy was assessed by determining the number of genealogically unrelated LHON pedigrees with heteroplasmic maternal family members from the LHON patient records of the Department of Ophthalmology, University of Tübingen, Germany. RESULTS: The authors observed a marked variability in the degree of heteroplasmy levels within each pedigree and a tendency toward a higher mutant allele frequency in offspring generations. Disease expression was correlated with higher levels of mutant mtDNA molecules. Longitudinal analysis revealed no statistically significant decrease in the heteroplasmy level in the family studied but a reduction of 11% and 12% in one affected and one unaffected individual, respectively. In 167 genealogically unrelated LHON families the prevalence of heteroplasmy was 5.6%, 40%, and 36.4% for the 11778, 3460, and 14484 LHON mutations, respectively. CONCLUSIONS: Cross-sectional studies of heteroplasmy for the 3460 LHON mutation suggest that the genotype shifts toward a higher mutational load in offspring generations. Long-term decrease in the blood mutant load in single cases indicates negative selection of the mutant allele in the hematopoietic cell system. The prevalence of heteroplasmy varies significantly between the different primary LHON mutations, suggesting genotypical differences in disease expression.

Chromosome Segregation↗
PubMed2001

Prevention of photoreceptor apoptosis by activation of the glucocorticoid receptor.

PURPOSE: Evidence has accumulated that excessive light exposure may promote age-related and inherited retinal degeneration, in which photoreceptor death by apoptosis leads to loss of vision. In the current study, the effect of elevated corticosteroid levels on light-induced apoptosis of photoreceptors was determined. METHODS: Photoreceptor apoptosis was induced in retinas of BALB/c mice by exposure to diffuse white light. High levels of corticosteroids were induced, either endogenously (fasting-mediated stress) or by a single intraperitoneal injection of dexamethasone (DEX). Photoreceptor damage was assessed morphologically and by electroretinography. Glucocorticoid receptor (GR) and activator protein (AP)-1 activities were shown by Western blot analysis and electrophoretic mobility shift assay (EMSA) of retinal nuclear extracts. RESULTS: Fasting and injection of DEX led to an activation of GR in the retina, as judged by its translocation to the nucleus of retinal cells. On induction of GR activity before light exposure, AP-1 activity, normally induced by damaging doses of light, remained at basal levels. Both treatments completely prevented photoreceptor apoptosis and preserved retinal function. CONCLUSIONS: Activity of the transcription factor AP-1 is associated with light-induced apoptosis. In the current study, pharmacologic suppression of AP-1 activity protected against light damage. Inhibition of AP-1 activity may have occurred by the protein-protein interaction of GR and AP-1.

Animals↗
PubMed2001

Slow and fast rod ERG pathways in patients with X-linked complete stationary night blindness carrying mutations in the NYX gene.

PURPOSE: To study the slow and fast rod signals of the scotopic 15-Hz flicker ERG in patients carrying mutations in the NYX gene, which has been recently identified as the cause of the complete form of congenital stationary night blindness, CSNB1. METHODS: Twenty eyes of 11 patients with CSNB1 who had nondetectable standard ERG rod b-waves were involved in the study. Scotopic ERG response amplitudes and phases to flicker intensities ranging from -3.37 to -0.57 log scotopic trolands. sec (scot td. sec) were measured at a flicker frequency of 15 Hz. ERG signals to flicker intensities between -3.37 and -1.97 and between -1.17 and -0.57 log scot td. sec were considered to represent primarily the slow and fast rod ERG pathway, respectively. Additionally, standard ERGs were performed. Twenty-two normal volunteers served as control subjects. RESULTS: For the slow rod ERG pathway, all patients exhibited ERG signals that were indistinguishable from noise. Accordingly, there was no systematic phase behavior for the slow rod signals. For the fast rod ERG pathway, the signals were significantly above noise, but they were significantly reduced in amplitude and advanced in phase. CONCLUSIONS: There is evidence that the slow and the fast rod ERG signals can be attributed to the rod bipolar-AII cell pathway and the rod-cone-coupling pathway, respectively. The current study provides evidence to suggest that a defective NYX gene product (nyctalopin) prevents detectable signal transmission through ON rod bipolar cells, but there is a residual transmission through rod-cone gap junctions in CSNB1, possibly through the OFF cone pathway.

Adolescent↗
PubMed2001

Identification of Usher syndrome subtypes by ERG implicit time.

PURPOSE: Usher syndrome (US) is a recessively inherited disorder combining retinitis pigmentosa (RP) and a sensorineural hearing loss. The classification in subtypes is based mainly on auditory tests. The purpose of this study was to analyze implicit time (IT) differences in the electroretinogram (ERG) between RP alone, US I, and US II. METHODS: The data of 15 control subjects and of 15 patients with US I, 15 with US II, and 15 with RP with nonzero 33-Hz flicker ERG responses were analyzed. The ITs of three signal peaks (P1-P3) were evaluated. Sensitivity and specificity of a test to distinguish between US I and II based on timing differences were determined. Multifocal (mf)ERGs were used to assess differences in disease topography. RESULTS: Despite the similar amplitude loss with retinal eccentricity in the mfERG in all three groups, the peak delay in US I was negligible compared with that in US II and RP. In the flicker ERG data, US I and control subjects had almost identical peak times, and the same was true for subjects with US II and RP. Because of the slight overlap between US I and II, the diagnostic test achieved a sensitivity of 100% and a specificity of 93.3%. CONCLUSIONS: Substantial timing differences between US I and II and their usefulness for a diagnostic test were demonstrated. This finding may also be the basis for further investigations regarding the structural differences of retinal impairment between US I and II on a cellular level.

Adolescent↗
PubMed2000

Mutations in the CNGB3 gene encoding the beta-subunit of the cone photoreceptor cGMP-gated channel are responsible for achromatopsia (ACHM3) linked to chromosome 8q21.

Achromatopsia is an autosomal recessive disorder featuring total colour blindness, photophobia, reduced visual acuity and nystagmus. While mutations in the CNGA3 gene on chromosome 2q11 are responsible for achromatopsia in a subset of patients, previous linkage studies have localized another achromatopsia locus, ACHM3, on chromosome 8q21. Using achromatopsia families in which CNGA3 mutations have been excluded, we refined the ACHM3 locus to a 3.7 cM region enclosed by markers D8S1838 and D8S273. Two yeast artificial chromosome (YAC) contigs covering nearly the entire ACHM3 interval were constructed. Database searches with YAC content sequences identified two overlapping high throughput genomic sequencing phase (HTGS) entries which contained sequences homologous to the murine cng6 gene encoding the putative beta-subunit of the cone photoreceptor cGMP-gated channel. Using RT-PCR and RACE, we identified and cloned the human cDNA homologue, designated CNGB3, which encodes an 809 amino acid polypeptide. Northern blot analysis revealed a major transcript of approximately 4.4 kb specifically expressed in the retina. The human CNGB3 gene consists of 18 exons distributed over approximately 200 kb of genomic sequence. Analysis of the CNGB3 gene in achromats revealed six different mutations including a missense mutation (S435F), two stop codon mutations (R203X and E336X), a 1 bp and an 8 bp deletion (1148delC and 819-826del) and a putative splice site mutation of intron 13. The 1148delC mutation was identified recurrently in several families, and in total was present on 11 of 22 disease chromosomes segregating in our families.

Amino Acid Sequence↗
PubMed2000

[A case of Leber optic neuropathy with a new point mutation in the cytochrome b gene].

BACKGROUND: Leber's hereditary optic neuropathy (LHON) is associated with mutations in the mitochondrial DNA (mtDNA). We report the clinical and molecular genetic findings of a patient who does not carry any of the common LHON mutations. METHODS: Clinical data were collected for the affected patient and two unaffected maternal family members. Complete sequence analysis of the mtDNA protein coding region was performed in the affected patient. RESULTS: Clinical examination of the affected patient showed typical features of LHON. A nucleotide exchange was detected at np14894 replacing an evolutionarily conserved phenylalanine by a leucine in the cytochrome b gene. The mutation was also present in two unaffected maternal family members, but absent in 60 other LHON lineages and 175 unrelated controls. CONCLUSIONS: Cytochrome b plays an important role in the electron transport chain of mitochondrial oxidative phosphorylation, and some mutations in the gene encoding cytochrome b have been associated with LHON. Our results may imply that the novel mutation at np14894 is responsible for LHON in this family.

Adult↗
PubMed2000

[Evaluating the Pro Ton applanation tonometer in rabbits].

PURPOSE: To assess use of the tonometer ProTon for measuring intraocular pressure in rabbits. MATERIALS AND METHODS: Eleven chinchilla-bastard rabbits were measured under standardized conditions with the applanation tonometer ProTon for 62 +/- 15 days. One rabbit was excluded because of intensively defensive reactions. RESULTS: Intraocular pressure in the ten rabbits was 12.15 +/- 3.63 mmHg in the right eye and 12.11 +/- 3.52 mmHg in the left eye. CONCLUSION: Intraocular pressure can be measured reliably over a long period with the applanation tonometer ProTon. It is therefore suitable for determining intraocular pressure in experimentally induced glaucoma in rabbits.

Animals↗
PubMed2000

Physical mapping and exclusion of GPR34 as the causative gene for congenital stationary night blindness type 1.

X-linked congenital stationary night blindness (CSNB) is a nonprogressive retinal disorder characterized by impaired night vision, variably involving high myopia, nystagmus, decreased visual acuity, and strabismus. Linkage studies have identified two distinct loci for X-linked CSNB1 and CSNB2 on the short arm of chromosome X. The gene mutated in families displaying the "incomplete phenotype" of CSNB (i.e., CSNB2) has recently been identified. To identify novel candidate genes for the "complete form" of CSNB (i.e., CSNB1) we screened the physically vast region Xp11.3-Xp11.4 for cDNA sequences. This led us to identify and map the G protein coupled receptor (GPCR) gene GPR34 to Xp11.4 within 650 kb of the marker DXS993. Deletion screening via Southern blotting and direct sequencing of GPR34 revealed no mutations in 19 unrelated men with CSNB1, excluding a causal role in the disease. However, because of its expression in retinal and neural tissue and the involvement of GPCRs in transmembrane signal transduction, GPR34 remains a putative candidate gene for a number of ocular diseases which also map to the Xp11.4 region.

Blotting, Southern↗
PubMed2000

Electrical multisite stimulation of the isolated chicken retina.

Visual prostheses such as subretinal implants are intended for electrical multisite excitation of the retinal network. To investigate relevant issues like spatial resolution and operational range, we have developed an in vitro method using microelectrode arrays to stimulate isolated retinae. Ganglion cell activity in the chicken retina evoked by distally applied spatial voltage patterns consisted of fast bursts, transient inhibition and delayed discharges, and depended on the amount, location and spatial pattern of the injected charge. The response was altered or disappeared when synaptic transmission was blocked. Our results indicate that shape perception and object location can be partially achieved with subretinal electrical multisite stimulation.

Animals↗
PubMed2000

Asymmetries in the time-course of chromatic adaptation and the significance of contrast.

The time-course of chromatic adaptation was determined as a function of the spectral content of the adaptation-light and of image-contrast. The adaptation-lights varied along the chromatic cardinal axes or one of their intermediate axes in an equiluminant plane in colour-space. We found an asymmetry in the initial time-course of adaptation (0.2-10 s) in that adaptation to middle-wavelength light was significantly faster than adaptation to short- and long-wavelength light. The asymmetry was only observed in the presence of a spatially complex pattern. It was fully supported by luminance and chromatic contrast and present under haploscopic stimulus conditions.

Adaptation, Physiological↗