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PubMed1999

Transcription map of Xq27: candidates for several X-linked diseases.

Human Xq27 contains candidate regions for several disorders, yet is predicted to be a gene-poor cytogenetic band. We have developed a transcription map for the entire cytogenetic band to facilitate the identification of the relatively small number of expected candidate genes. Two approaches were taken to identify genes: (1) a group of 64 unique STSs that were generated during the physical mapping of the region were used in RT-PCR with RNA from human adult and fetal brain and (2) ESTs that have been broadly mapped to this region of the chromosome were finely mapped using a high-resolution yeast artificial chromosome contig. This combined approach identified four distinct regions of transcriptional activity within the Xq27 band. Among them is a region at the centromeric boundary that contains candidate regions for several rare developmental disorders (X-linked recessive hypoparathyroidism, thoracoabdominal syndrome, albinism-deafness syndrome, and Borjeson-Forssman-Lehman syndrome). Two transcriptionally active regions were identified in the center of Xq27 and include candidate regions for X-linked mental retardation syndrome 6, X-linked progressive cone dystrophy, X-linked retinitis pigmentosa 24, and a prostate cancer susceptibility locus. The fourth region of transcriptional activity encompasses the FMR1 (FRAXA) and FMR2 (FRAXE) genes. The analysis thus suggests clustered transcription in Xq27 and provides candidates for several heritable disorders for which the causative genes have not yet been found.

Chromosome Mapping↗

PubMed2002

X-linked recessive atrophic macular degeneration from RPGR mutation.

We mapped a new X-linked recessive atrophic macular degeneration locus to Xp21.1-p11.4 and show allelic involvement of the gene RPGR, which normally causes severe peripheral retinal degeneration leading to global blindness. Ten affected males whom we examined had primarily macular atrophy causing progressive loss of visual acuity with minimal peripheral visual impairment. One additional male showed extensive macular degeneration plus peripheral loss of retinal pigment epithelium and choriocapillaries. Full-field electroretinograms (ERGs) showed normal cone and rod responses in some affected males despite advanced macular degeneration, emphasizing the dissociation of atrophic macular degeneration from generalized cone degenerations, including X-linked cone dystrophy (COD1). The RPGR gene nonsense mutation G-->T at open reading frame (ORF)15+1164 cosegregated with the disease and may create a donor splice site. Identification of an RPGR mutation in atrophic maculardegeneration expands the phenotypic range associated with this gene and provides a new tool for the dissection of the relationship between clinically different retinal pathologies.

Adult↗

PubMed1987

C-wave versus electrooculogram in diseases of the retinal pigment epithelium.

The c-wave and the electrooculogram (EOG) are retinal potentials predominantly generated by the pigment epithelium. In most diseases both parameters show a parallel decrease in amplitude. However, in patients with dominant drusen, and cone dystrophies, and in clinically nonaffected members of families suffering from vitelliform macula degeneration, the EOG is close to normal whereas the c-wave shows a reduced amplitude. These findings suggest a higher sensitivity of the generators of the c-wave compared with those responsible for the EOG. Thus the direct current electroretinogram provides additional diagnostic information.

Electrooculography↗

PubMed1991

Scotopization and the Nagel-II anomaloscope.

The term scotopization refers to the intrusion of rod activity in colour vision when assessed under photopic observation conditions. Scotopization is an important symptom of cone dystrophies. The detection of scotopization is not easy. With the Nagel-II anomaloscope scotopization can be detected in two ways. One method is new and this method is described in the present paper.

Color Perception Tests↗

PubMed2001

Plasmolipin: genomic structure, chromosomal localization, protein expression pattern, and putative association with Bardet-Biedl syndrome.

Plasmolipin is a membrane protein and belongs to the tetraspan molecule (4TM) family, an expanding group of myelin proteins many of which could be linked to human hereditary demyelinating neuropathies. We have cloned and sequenced the mouse plasmolipin gene, revealing the common organization of the 4TM gene group with four exons and a large first intron. Western blot analysis with an antibody raised against the C-terminal intracellular part of the protein showed that plasmolipin is expressed not only in the nervous system and kidney, but also in a number of other tissues such as thymus, testis, lung, and thyroid gland. By means of radiation hybrid mapping and FISH analysis, we could localize the human plasmolipin gene to Chromosome 16q13 within the putative region of the Bardet-Biedl syndrome type 2 (BBS2) gene locus. BBS2 is a clinically and genetically heterogeneous group of disorders resulting in rod-cone dystrophy, obesity, postaxial polydactyly, renal dysfunction, and mental retardation, which were very recently associated with a novel gene designated BBS2. With respect to intrafamiliar variations in the manifestation of BBS, we suggest that plasmolipin might be either another candidate gene or a modifier of the BBS2 phenotype.

Animals↗

PubMed2005

Fundus autofluorescence in children and teenagers with hereditary retinal diseases.

INTRODUCTION: In adults, evaluation of fundus autofluorescence (AF) plays an important role in the differential diagnosis of retinal diseases. The aim of this study was to evaluate the feasibility of recording AF in children and teenagers and to define typical AF findings of various hereditary retinal diseases during childhood. METHODS: Fifty patients aged 2 to 16 years with hereditary retinal diseases were analysed using the HRA (Heidelberg Retina Angiograph). To enhance the AF signal, a mean of up to 16 single images was calculated. Twenty healthy children (aged 4-16 years) served as controls. RESULTS: In many children as young as 5 years of age and even in one 2-year-old child good AF images could be obtained. To achieve high quality images, larger image series (about 50 single images) were taken and appropriate single images were chosen manually to calculate the mean. Characteristically, Stargardt disease shows a central oval area of reduced AF, often surrounded by more irregular AF. In patients with Best disease, a central round structure with regular or irregular intense AF is visualised. Some patients with X-linked retinoschisis show central radial structures. In many patients with rod-cone dystrophies, a central oval ring-shaped area of increased AF is present. In early-onset severe retinal dystrophy (EOSRD) with RPE65 mutations AF is completely absent, whereas in other forms of Leber congenital amaurosis, AF is normal. DISCUSSION: Fundus autofluorescence may visualise disease-specific distributions of lipofuscin in the retinal pigment epithelium, often not (yet) visible on ophthalmoscopy. AF images can be used in children to differentiate hereditary retinal diseases and to facilitate follow-up controls. In many cases, four single images are sufficient to analyse the AF pattern.

Adolescent↗

PubMed2006

Phenotype of three consanguineous Tunisian families with early-onset retinal degeneration caused by an R91W homozygous mutation in the RPE65 gene.

PURPOSE: To identify the genetic defect, and to phenotype, three consanguineous Tunisian families presenting with early-onset retinal degeneration (EORD). METHODS: All accessible family members were included. They underwent blood sampling and ophthalmological examination including, when possible, full-field ERG and pupillometry. A genome-wide linkage analysis was initiated. Mutation analysis of the RPE65 gene within the linked interval was performed by bi-directional sequencing. RESULTS: Eleven out of 53 examined members were clinically affected with an EORD. Linkage analysis revealed a maximal lod score of 4.02 (theta=0.1) for the marker D1S207 on 1p31. Mutational screening of the RPE65 gene identified a homozygous R91W mutation co-segregating with the disease in all affected individuals. Eleven homozygotes had nystagmus and acuities ranging from CF to NLP. Two retinal patterns were identified: pattern 1 presented mid-peripheral deep white dot deposits and virtually no clumped pigmentation, whereas pattern 2 showed mid-peripheral pigmented clumps without any white deposits. Homozygotes had no detectable full-field ERG and an abnormal pupillary light reflex. Eleven heterozygotes had normal visual function. CONCLUSION: We identified and characterised an endemic form of early onset rod-cone dystrophy in a consanguineous population from northeastern Tunisia, due to the prevalence of a single RPE65 mutation. Two funduscopic patterns were identified: white dot deposits in earlier stages and clumped pigment in later stages.

Adult↗

PubMed2000

Confocal laser scanning fluorescence topography: a new method for three-dimensional functional imaging of vascular structures.

Three-dimensional topography of perfused vascular structures is possible via confocal laser scanning of intravascular fluorescence. The lateral resolution is given by the spot size of the scanning laser beam (optimally 10 microm at the retina). The axial resolution, however, depends on the accuracy of detection of the surface of the fluorescent structure, which is typically one order of magnitude higher (30 microm at the retina) than the confocal resolution. The vascular structure is stained with an appropriate fluorescent dye prior to the investigation using standard systemic dye injection. Confocal scanning of the fluorescence in planes of different depths within the vascular structure under investigation leads to a three-dimensional data set. Signal processing includes passive eye tracking, lateral averaging and axial determination of the surface of the fluorescent structure. The potential of this new technique is demonstrated by showing the topography of physiological vessel structures as well as of selected vascular diseases such as cone dystrophy, RPE detachment, choroidal haemangioma and retinal laser coagulation. Confocal laser angioscopic fluorescence topography (CLAFT) measures the three-dimensional surface structure of functional (perfused) vasculature and surrounding leakage. CLAFT may help to diagnose and quantify status and time course of vascular diseases.

Contrast Media↗

PubMed1986

Foveal densitometry as a diagnostic technique in Stargardt's disease.

Foveal densitometry was performed in eight patients with Stargardt's disease. Their visual acuities were between 20/200 and 20/16. All eight had low two-way densities, ranging from 0.07 to less than or equal to 0.01 (mean value for a control group, 0.32 +/- 0.03). Two patients had poor visual acuities combined with ophthalmoscopically normal maculas. Because two-way densities were very low in these patients, ranging between 0.04 and less than or equal to 0.01, foveal densitometry may be a useful diagnostic technique in the diagnosis of Stargardt's disease. Foveal densitometry was also performed in two patients with fundus flavimaculatus and good visual acuities for the sake of comparison. Two-way densities were between 0.09 and 0.24. One patient with cone dystrophy and poor visual acuity had low two-way densities (0.02 bilaterally). Three patients with vitelliform dystrophy and vitelliform cysts on ophthalmoscopy had two-way densities between 0.07 and 0.14 and increased half-times of regeneration (between 90 and 126 seconds). One patient with a vitelliform cyst in one eye showed only fine pigmentations in the other eye, which had a normal two-way density (0.32).

Adolescent↗

PubMed2004

Electroretinographic assessment of retinal function in microphthalmia mutant mice.

The purpose of this study was to examine the effects of mutations in the mouse (Mus musculus) multi-allelic microphthalmia transcription factor (Mitf) gene on retinal function. Mitf mice provide a rare opportunity to assess retinal degeneration caused by defective retinal pigment epithelium (RPE). Electroretinography (ERG) was used to evaluate the functional state of the retina and to determine the role of the Mitf gene in visual function. Corneal ERGs were recorded with a steel wire in response to white flashes of light. Homozygous Mitf(Mi-wh)/Mitf(Mi-wh), Mitf(mi-sp)/Mitf(mi-sp) Mitf(mi-bws)/Mitf(mi-bws) and wild type mice in addition to Mitf(Mi-wh)/Mitf(mi-sp) compound heterozygous mutants were studied at 16 weeks of age. Although each animal was only tested once, multiple animals of each genotype were tested. The ERGs of Mitf(mi-sp)/Mitf(mi-sp) were found to be normal. All components of the ERGs of Mitf(mi-bws)/Mitf(mi-bws) mice were normal except the photopic b-wave and the scotopic c-wave, which were reduced in amplitude. The ERGs of Mitf(Mi-wh)/Mitf(Mi-wh) mice suggest they are probably blind. On the other hand, ERGs from Mitf(Mi-wh)/Mitf(mi-sp) mice were reduced in amplitude and delayed, indicating an RPE/photoreceptor defect. At 16 weeks post partum, Mitf(Mi-wh)/Mitf(mi-sp) mutants show evidence of rod-cone dystrophy. Surprisingly, Mitf(mi-bws)/Mitf(mi-bws) mice, which have a similar phenotype as Mitf(mi-vit) mice with respect to coat color and eye development, show mostly normal ERGs. The reduced scotopic c-wave in Mitf(mi-bws)/Mitf(mi-bws) mice, without reduction in the scotopic a-wave indicates an RPE defect without photoreceptor involvement in these mice.

Animals↗

PubMed2025

Bi-allelic loss-of-function variants in POC5 cause a syndromic retinal, endocrine, and neuromuscular ciliopathy.

PURPOSE: A homozygous loss-of-function (LoF) variant in POC5 was previously described in an individual with retinitis pigmentosa. We identified POC5 variants in 12 probands with a syndromic phenotype. We aim to define the phenotype spectrum and molecular mechanism associated with biallelic POC5 LoF variants. METHODS: We studied a cohort of 12 families with bi-allelic LoF POC5 variants and performed detailed phenotype analysis. POC5 localization studies were performed in 3 proband-derived fibroblast cell lines. RESULTS: Detailed phenotyping of probands with POC5 variants expands the phenotype spectrum beyond ocular manifestations. This syndrome causes not only rod-cone dystrophy but also diabetes mellitus with severe insulin resistance and partial lipodystrophy, kidney disease, and muscle cramps. The POC5 protein plays an essential role during cell cycle and cilium formation. Interestingly, POC5 localization studies in 3 proband-derived fibroblast cell lines show aberrant localization suggesting a ciliary defect. The phenotypes of the 12 families in this study fit well within the ciliopathy phenotype spectrum, except for lipodystrophy, which is not common in ciliopathies. CONCLUSION: We describe a multiorgan syndrome caused by bi-allelic LoF variants in POC5. This underscores the pleiotropic effects of POC5 variants and highlights the significance of adipose tissue and metabolic dysfunction in ciliopathies.

Humans↗

PubMed2006

Choroideremia: variability of clinical and electrophysiological characteristics and first report of a negative electroretinogram.

PURPOSE: To analyze the variability of clinical and electrophysiological characteristics in X-linked choroideremia and provide the first report of a negative electroretinogram in choroideremia. DESIGN: Retrospective study. PARTICIPANTS: The records of 18 male patients with choroideremia and 8 female carriers were evaluated. METHODS: The data were reviewed regarding visual acuity (VA), color vision, perimetry, fundus autofluorescence, and full-field electroretinography (according to standards of the International Society for Clinical Electrophysiology of Vision). MAIN OUTCOME MEASURES: Morphological and functional phenotype characteristics, fundus autofluorescence, electroretinography, and Rab escort protein 1 (REP-1) mutations. RESULTS: Four unrelated families with choroideremia (9 affected males, 7 carriers) and 10 unrelated individuals (9 affected males, 1 carrier) were included. Mutational analysis, performed in 2 families and 3 individual males, revealed REP-1 mutations in all except 1 male. The age of the males ranged from 5.9 to 63.0 years (mean, 33.9), and VA ranged from hand movements to 1.0 (median, 0.7). Fundus autofluorescence (n = 7) showed defects in the retinal pigment epithelium in all males. Electroretinography (n = 13) was almost undetectable in 6 males and reduced in 6, indicating a rod-cone dystrophy. A further male showed a negative electroretinogram, with a b:a wave ratio of 0.5. Visual acuity of the 8 carriers (age, 4.8-56.8 years [mean, 24.0]) ranged from light perception to 1.2 (median, 1.0). Light perception was present in 1 carrier manifesting choroideremia with distinct chorioretinal atrophy. Pigmentary stippling, seen in the other carriers, was seen in fundus autofluorescence (n = 1) with a distinct speckled pattern. Electroretinograms were normal in 6 of 7 and reduced in the manifesting carrier. Defects in color vision and visual field were found in affected males and in the female carriers. CONCLUSIONS: The phenotype of choroideremia presents with high variability. In addition to the previously reported findings, we observed a negative electroretinogram, indicating a postreceptoral retinal dysfunction, in 1 affected male; severe course of choroideremia with early blindness in 1 manifesting carrier; color vision deficits in the majority of affected males and carriers; and characteristic alterations in fundus autofluorescence.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Atypical multifocal ERG responses in patients with diseases affecting the photoreceptors.

The purpose of this study was to investigate atypical multifocal ERG (mfERG) responses for patients with diseases that can affect the photoreceptors. MfERGS were obtained from seven patients with retinitis pigmentosa (RP), three with progressive cone dystrophy (CD) and eight with diabetic retinopathy (DR). Both first- and second-order kernel responses were analyzed. The amplitudes and implicit times of the first-order responses were compared to those obtained from age-similar controls. For the first slice of the second-order response, the root-mean-square (RMS) and the signal-to-noise ratio (SNR) of each response were calculated. Achromatic visual fields were also obtained from each subject. For the three groups of patients, first-order responses with relatively large amplitudes, broad-shaped waveforms and markedly increased implicit times had non-measurable second-order responses. These responses were associated with areas of decreased visual field sensitivity. As RP, CD and DR affect the outer retina, the results are consistent with damage to the outer plexiform layer rather than damage to the inner retina.

Adult↗

PubMed1998

Ishihara color plates as a test for simultanagnosia.

PURPOSE: To alert ophthalmologists to the use of Ishihara color plates in the detection of simultanagnosia. METHODS: We examined seven patients referred for impaired vision. Evaluation included color plate testing with Ishihara color plates. RESULTS: All seven patients had simultanagnosia, with marked difficulty in identifying the numbers in Ishihara color plates despite adequate visual acuity and the ability to name all of the colors in the plates correctly. One of these patients was referred with the diagnosis of a cone dystrophy because of her poor performance on the Ishihara test. All of the patients had bilateral occipitoparietal damage or atrophy on magnetic resonance imaging. CONCLUSIONS: Ophthalmologists must be aware that a poor performance with Ishihara plates may not be attributable to an impairment of color vision but rather to occipitoparietal brain damage associated with simultanagnosia.

Agnosia↗

PubMed2001

Onset of oscillopsia after visual maturation in patients with congenital nystagmus.

PURPOSE: To describe the clinical and oculographic characteristics of a cohort of five patients with congenital nystagmus (CN) and late-onset oscillopsia caused by a coincidental decline in other visual and/or ocular motor functions. DESIGN: Retrospective, observational, case series. PARTICIPANTS: Five visually mature patients with CN and recent-onset oscillopsia were evaluated clinically and with motility recordings. INTERVENTION: Eye movement analysis was performed off-line by computer analysis of digitized data. Nystagmus was analyzed for null-zone characteristics, waveforms, frequency, amplitudes, and slow-phase drift velocity during foveation. Surgical and medical treatment of associated ocular conditions in four of five patients. MAIN OUTCOME MEASURES: Presence of symptomatic oscillopsia and average time during foveation periods of slow-phase drift velocity less than 10 degrees /second. RESULTS: One of the five patients had associated rod-cone dystrophy, and another had recurrence of childhood head posturing with return of an eccentric null zone. The remaining three patients had decompensated strabismus associated with their oscillopsia. All five patients complained of oscillopsia in primary position that was relieved in the four who received treatment. Treatment included prismatic correction in one patient and surgery in three. Recordings in primary position after treatment showed increased duration during foveation periods of slow-phase drift velocity less than 10 degrees /second and an overall decreased intensity (amplitude/frequency) of the nystagmus. CONCLUSIONS: Symptomatic oscillopsia in patients with CN is unusual. This visually disturbing symptom can be precipitated by new or changing associated visual sensory conditions (e.g., decompensating strabismus, retinal degeneration). If the associated conditions can be treated, then accompanying oscillopsia may be relieved.

Adolescent↗

PubMedDate not supplied

Push-pull model of the primate photopic electroretinogram: a role for hyperpolarizing neurons in shaping the b-wave.

Existing models of the primate photopic electroretinogram (ERG) attribute the light-adapted b-wave to activity of depolarizing bipolar cells (DBCs), mediated through a release of potassium that is monitored by Müller cells. However, possible ERG contributions from OFF-bipolar cells (HBCs) and horizontal cells (HzCs) have not been explored. We examined the contribution of these hyperpolarizing second-order retinal cells to the photopic ERG of monkey by applying glutamate analogs to suppress photoreceptor transmission selectively to HBC/HzCs vs. DBCs. ERGs of Macaca monkeys were recorded at the cornea before and after intravitreal injection of drugs. Photopic responses were elicited by bright 200-220 ms flashes on a steady background of 3.3 log scotopic troland to suppress rod ERG components. 2-amino-4-phosphonobutyric acid (APB), which blocks DBC light responses, abolished the photopic b-wave and indicated that DBC activity is requisite for photopic b-wave production. However, applying cis-2,3-piperidine dicarboxylic acid (PDA) and kynurenic acid (KYN), to suppress HBCs/HzCs and third-order neurons, revealed a novel ERG response that was entirely positive and was sustained for the duration of the flash. The normally phasic b-wave was subsumed into this new response. Applying n-methyl-dl-aspartate (NMA) did not replicate the PDA+KYN effect, indicating that third-order retinal cells are not involved. This suggests that HBC/HzC activity is critical for shaping the phasic b-wave. Components attributable to depolarizing vs. hyperpolarizing cells were separated by subtracting waveforms after each drug from responses immediately before. This analysis indicated that DBCs and HBC/HzCs each can produce large but opposing field potentials that nearly cancel and that normally leave only the residual phasic b-wave response in the photopic ERG. Latency of the DBC component was 5-9 ms slower than the HBC/HzC component. However, once activated, the DBC component had a steeper slope. This resembles properties known for the two types of cone synapses in lower species, in which the sign-preserving HBC/HzC synapse has faster kinetics but probably lower gain than the slower sign-inverting G-protein coupled DBC synapse. A human patient with "unilateral cone dystrophy" was found to have a positive and sustained ERG that mimicked the monkey ERG after PDA+KYN, indicating that these novel positive photopic responses can occur naturally even without drug application. These results demonstrate that hyperpolarizing second-order neurons are important for the primate photopic ERG.(ABSTRACT TRUNCATED AT 400 WORDS)

Aminobutyrates↗

PubMed1993

Childhood blindness in the West Bank and Gaza Strip: prevalence, aetiology and hereditary factors.

A study of all the schools for the blind in the West Bank and Gaza Strip was undertaken during 1991-2. Two hundred and five children had a complete ophthalmic examination. This represented 94% of all children aged 5-15 years attending schools for the blind. According to WHO categories of visual loss, 63% were blind and 21% had severe visual impairment. The main causes of blindness and severe visual loss were retinal (52%), optic atrophy (12%), glaucoma (9%) and cataract (7%). Common retinal diseases included degenerative myopia, Leber's congenital amaurosis, cone dystrophy and retinitis pigmentosa. Depending on the locality, 44-85% of these children were the product of a consanguineous marriage and a positive family history was present in 57%. The minimum prevalence of childhood blindness was estimated to be 0.32/1000 children. A reduction in the prevalence of blindness requires a reduction in consanguineous marriages, genetic counselling for affected families and public health measures to ensure early referral for management of cataract and glaucoma.

Adolescent↗

PubMed1996

The role of ERG/VEP and eye movement recordings in children with ocular motor apraxia.

Ocular motor apraxia (OMA) is characterised by an intermittent inability to initiate voluntary saccades, and a failure to produce optokinetic and vestibular quick phases. Some patients have no other abnormalities (idiopathic OMA), whereas in others it appears associated with a variety of neurological conditions which may affect the sensory visual pathway. Electroretinograms (ERGs), flash and pattern visual evoked potentials (VEPs) and eye movements were assessed in 53 children with OMA (age range 17 days to 14 years) to determine their efficacy in helping to distinguish between idiopathic and non-idiopathic cases. Seven patients (13.2%) had idiopathic OMA and the remaining 46 (86.8%) had other associated clinical conditions. All patients had episodes of absent quick phases ('lock up') during optokinetic nystagmus (OKN) and/or vestibular testing. Flash ERGs were abnormal in only 7 patients (13.2%); 6 had syndromes involving a pigmentary retinopathy (Joubert's, Bardet-Biedl, infantile Refsum's, Kearns-Sayre's), and the seventh had a cone dystrophy with vermis hypoplasia. VEPs were normal in all 7 patients with idiopathic OMA. Thirty-three (72%) patients with OMA in association with neurological conditions had abnormal VEPs and 13 had normal VEPs (28%). There was a significant positive correlation between VEP abnormality and poor OKN gain. VEP/ERG testing and eye movement studies are useful when OMA is suspected as they help in distinguishing isolated idiopathic cases from those with more widespread neurological abnormalities.

Adolescent↗