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PubMed1998

GCAP1 (Y99C) mutant is constitutively active in autosomal dominant cone dystrophy.

GCAP1 stimulates photoreceptor guanylate cyclase (GC) in bleached vertebrate photoreceptors when [Ca2+]free decreases but is inactivated when cytoplasmic [Ca2+]free increase after dark adaptation. A Y99C mutation in GCAP1 has recently been found to be associated with autosomal dominant cone dystrophy. We show that the GCAP1(Y99C) mutant and native GCAP1 are highly effective in stimulation of photoreceptor GC1. The Ca2+ sensitivity of the mutant GCAP1, however, is markedly altered, causing reduced but persistent stimulation of GC1 under physiological dark conditions. These results are consistent with a model in which enhanced GC activity in dark-adapted cones leads to elevated levels of cytoplasmic cGMP. Alterations in physiological cGMP levels are also associated with other retinal degenerations, including Leber's congenital amaurosis.

Adaptation, Physiological↗
PubMed2002

Newfoundland rod-cone dystrophy, an early-onset retinal dystrophy, is caused by splice-junction mutations in RLBP1.

Some isolated populations exhibit an increased prevalence of rare recessive diseases. The island of Newfoundland is a characteristic geographic isolate, settled by a small number of families primarily during the late 1700s and early 1800s. During our studies of this population, we identified a group of families exhibiting a retinal dystrophy reminiscent of retinitis punctata albescens but with a substantially lower age at onset and more-rapid and distinctive progression, a disorder that we termed "Newfoundland rod-cone dystrophy" (NFRCD). The size of one of these families was sufficient to allow us to perform a genomewide screen to map the NFRCD locus. We detected significant linkage to markers on the long arm of chromosome 15, in a region encompassing RLBP1, the gene encoding the cellular retinaldehyde-binding protein. Previously, mutations in RLBP1 have been associated with other retinal dystrophies, leading us to hypothesize that RLBP1 mutations might also cause NFRCD. To test this hypothesis, we sequenced all coding exons and splice junctions of RLBP1. We detected two sequence alterations, each of which is likely to be pathogenic, since each segregates with the disease and is predicted to interfere with mRNA splicing. In contrast to some previously reported RLBP1 mutations, which yield a protein that may retain some residual activity, each NFRCD mutation is likely to give rise to a null allele. This difference may account for the severe phenotype in these families and exemplifies the molecular continuum that underlies clinically distinct but genetically related entities.

Adolescent↗
PubMed1999

Familial macular cone dystrophy: diagnostic value of multifocal ERG and two-color threshold perimetry.

BACKGROUND: It is difficult to detect receptor dysfunction in patients with marked bilateral visual loss but only mild morphological alterations of the fundus. METHODS: Two patients, father and son, with visual acuity loss to 20/100 were examined. Using the multifocal ERG, 61 local cone ERGs from each eye were derived from the central visual field. The dark-adapted two-color threshold perimetry using stimuli of 500 nm and 656 nm for rod and cone function was investigated along the horizontal meridian of the visual field. RESULTS: In the multifocal ERG of both patients a macular response was absent. From eccentricity at and anterior to 5 degrees, good multifocal cone activity was recorded. Cone thresholds were markedly diminished in the macula. The rod thresholds were borderline in the father and normal in the son. CONCLUSIONS: Multifocal ERG is a novel technique, very well suited to reveal the topography of cone function. Using two-color threshold perimetry affords an opportunity to differentiate between rod and cone functional defects. Both together helped to establish the diagnosis of macular cone dystrophy in the present family.

Adult↗
PubMed2004

MERTK arginine-844-cysteine in a patient with severe rod-cone dystrophy: loss of mutant protein function in transfected cells.

PURPOSE: Mutations in the MERTK gene are responsible for retinal degeneration in the Royal College of Surgeons (RCS) rat and are a cause of human autosomal recessive retinitis pigmentosa (RP). This study reports the identification and functional analysis of novel MERTK mutations to provide information regarding whether they are causative of severe rod-cone degeneration in a young patient. METHODS: MERTK missense variants identified by single-strand conformational polymorphism (SSCP) and sequence analysis were introduced into expression constructs and used to transfect HEK293T cells. Recombinant protein expression was assayed with anti-MERTK and anti-phosphotyrosine antibodies. Protein turnover was assayed in pulse-chase studies of 35S-methionine incorporation. Transcript levels were determined by quantitative RT-PCR. RESULTS: Three MERTK sequence variants were identified in a patient with rod-cone dystrophy: R722X in exon 16 and R865W in exon 19 on the paternal allele and R844C in exon 19 on the maternal allele. The R844C sequence change affects an evolutionarily conserved amino acid residue and was not detected in unaffected individuals. In transfected HEK293Tcells, wild-type (wt) and W865 MERTK were expressed at equivalent levels and present in the plasma membrane, stimulated tyrosine phosphorylation, and induced significant rounding of the cell bodies. In contrast, C844 MERTK was expressed at low levels and did not stimulate tyrosine phosphorylation. In addition, the relative stability of C844 MERTK was significantly less than wt in assays of protein turnover. At age 13, the patient had 20/60 and 20/200 acuities, tunnel vision of 5 degrees centrally, and a far temporal peripheral crescent bilaterally, and ERGs were nondetectable. The fundi showed bull's-eye macular atrophy and widespread RPE thinning. CONCLUSIONS: The present study reports the identification of R844C, the first putative pathogenic MERTK missense mutation that results in severe retinal degeneration with childhood onset when in compound heterozygous form with a R722X allele. The loss of function of C844 MERTK is probably due to decreased protein stability.

Adolescent↗
PubMed2002

[Foveal cone dystrophy: diagnostic ranking of the multifocal electroretinogram].

BACKGROUND: In case of visual loss without morphologic pathology differentiation between a functional visual loss and a retinal disorder may be difficult. PATIENTS AND METHODS: We report on two women, aged 33 and 44, who were complaining of a progressive visual loss occurring over the past several weeks to months. They were referred to our department with the presumed diagnosis of functional visual loss. Biomicroscopy of the anterior and posterior segments, perimetry (Goldmann), colour (FM-100-Hue-Test) and stereopsis testing (Lang-Stereotest), fluorescein angiography (FLAG) and electrophysiological testing (P-ERG, VECP, EOG, multifocal electroretinography [mfERG]) were performed. RESULTS: Visual acuity was 0.16 OU and 0.25 OU respectively. A small relative central scotoma (I/1) was detected by dynamic perimetry. Colour vision, random-dot stereopsis and the results of electrophysiological testing except multifocal electroretinography (mfERG) were normal. The mfERG was able to detect a cone dysfunction which was related to the fovea. CONCLUSION: In case of visual loss of unknown etiology electrophysiological testing is indicated. The mfERG as an objective diagnostic method is able to detect a foveal cone dystrophy.

Adult↗
PubMed2005

Glare sensitivity and professional drivers' safety: a case of rod-cone dystrophy with negative electroretinogram.

BACKGROUND: To obtain a driver's licence certain requirements for visual acuity and visual field have to be fulfilled. Mesopic contrast and glare sensitivity are not regularly tested and are not crucial to passing the driving test. CASE REPORT: We report a case of a 39-year-old professional bus driver whose only complaint was increased glare sensitivity. After he had been involved in four traffic accidents, ophthalmological investigations revealed binocular annular scotomata and night blindness, leading to the diagnosis of rod-cone dystrophy. DISCUSSION: Enhanced glare sensitivity is a common complaint in elderly people or people with the beginnings of cataract but may also represent an initial symptom of a retinal disorder. It is therefore advisable for traffic safety if drivers with such complaints undergo a complete ophthalmological investigation including visual field testing.

Accidents, Traffic↗
PubMed2006

Evidence of genetic heterogeneity in MRCS (microcornea, rod-cone dystrophy, cataract, and posterior staphyloma) syndrome.

PURPOSE: To present the detailed phenotype of a subject with MRCS (microcornea, retinal dystrophy, cataract, and posterior staphyloma) syndrome and to investigate the underlying molecular genetic basis. DESIGN: Interventional case report. METHODS: Clinical examination, electrophysiologic assessment, B-scan ultrasonography, and mutation screening of the gene VMD2. The protocol of the study was approved by the local ethics committee and informed consent was obtained. RESULTS: A 12-year-old boy was identified with bilateral microcornea, rod-cone dystrophy, congenital cataracts, and posterior staphylomata associated with high myopia (MRCS). Mutation screening failed to identify disease-causing sequence variants in VMD2, the gene associated with MRCS syndrome. All previous subjects have had pathogenic VMD2 sequence alterations. CONCLUSIONS: We present a further report of the MRCS syndrome and provide evidence in support of genetic heterogeneity in this phenotype.

Bestrophins↗
PubMed2000

Early-onset severe rod-cone dystrophy in young children with RPE65 mutations.

PURPOSE: To describe the ocular phenotype of patients with RPE65 mutations in infancy and young childhood. METHODS: Four children from three families with severe early-onset visual impairment related to electrophysiologically detectable retinal dystrophy were screened for mutations in the RPE65 gene. Visual function from infancy to the age of 10 years was assessed with age-adapted methods. Clinical examinations and electroretinograms (ERGs) were also performed on the six parents. RESULTS: In all three families, patients were compound heterozygous for mutations of the RPE65 gene (ins144T/IVS1+5G-->A, R91W/Y368H, 1114delA+T457N/IVS1+5G-->A). Visual acuity was measurable in all patients at the age of 6 to 10 years, despite severe visual impairment noted during infancy and congenital nystagmus in three of the four patients. Photophobia was not a feature. Funduscopic changes were discrete, the most prominent finding being increased granularity in the macula and the periphery. Peripheral vision was well preserved, measured by Goldmann perimetry. Rod ERGs were not recordable, whereas cone ERGs were detectable in early childhood. All features taken together suggest a specific form of Leber congenital amaurosis (LCA) distinguishable on clinical grounds. ERGs were normal in five of the six parents. One father had an ERG compatible with congenital stationary night blindness unrelated to his heterozygous state for the RPE65 mutation. CONCLUSIONS: RPE65 mutations on both alleles may be associated with early-onset severe rod-cone dystrophy. Visual functions of the four patients were better than is usually seen in LCA, in particular in cases associated with retGC1 mutations. RPE65 mutations should be suspected in infants who appear to be blind in dim surroundings but react to objects in bright illumination and have nonrecordable rod ERGs and residual cone ERGs.

Age of Onset↗
PubMed1991

Ultrastructural and ERG findings in progressive rod-cone dystrophy in a litter of Labrador retrievers.

Early ultrastructural findings of a progressive photoreceptor dystrophy and corresponding ERG findings are reported in 3 Labrador Retrievers from a litter of 7 pups bred from 2 dogs clinically and electroretinographically affected with generalized progressive retinal dystrophy. The pups were euthanized at 5, 11 and 15 months post partum. The most prominent ultrastructural finding was photoreceptor dystrophy. At 5 months the outer nuclear layer (ONL) consisted of 8-10 layers and seemed reduced in thickness, pyknotic nuclei were seen in this layer. The receptor outer segments (OS) were short and swollen. Some disorientation of OS discs occurred. In the 11-months specimen 7-8 ONL layers were identified. Overall thinning of the neuro-retina had occurred and fewer receptors compared to the 5-months specimen were present. By 15 months the ONL was further reduced to about 4 layers. Enlarged internuclear spaces were present in the ONL as well as around inner segments (IS). Phagocytic cells were frequent among remains of OS. The pigment epithelium appeared normal. The dark adapted ERG b-wave amplitudes and photopic 30 Hz flicker responses were low in comparison to controls of the same breed, and decreased with age. The condition represents a progressive rod-cone dystrophy which shares similarities with primary receptor dystrophy in man such as retinitis pigmentosa.

Animals↗
PubMed1992

Cone dystrophies: clinical and electrophysiological findings.

We analyzed the clinical and electrophysiological findings of 77 patients suffering from progressive cone or cone-rod dystrophies. The onset of symptoms was at the average age of 19.7 +/- 19.4 years. In some patients, the disease started within the 5th decade. The mean visual acuity was 0.19 +/- 0.2, while in 38%, the visual acuity was lower than 0.1. Color vision defects and visual field defects were found in most patients. The electrooculogram was recorded in 59 patients and was normal in only 19. On the electroretinogram (ERG), 60 patients had a reduction of the 30-Hz flicker amplitude and of the responses at maximum stimulus intensity when dark and light adapted. The ERG alterations showed a correlation to the visual field defects and to the reduction of the light rise on the electrooculogram. No correlation existed between the ERG amplitudes and visual acuity or color vision. Ophthalmoscopically, the posterior pole was normal in 25 patients. In the remaining patients, fundus changes ranged from mild pigment irregularities to severe pigment clumping. No correlation between fundus changes and functional findings existed.

Adolescent↗
PubMed2004

Auto-immune-like cone dystrophy.

PURPOSE: To describe rapid loss of cone vision in an adult due to putative auto-immune rejection. METHODS: Clinical and electrophysiological examination, including full-field and multi-focal electroretinograms (ERGs), were used to assess retinal function. Serum was analyzed for antibodies to retinal antigens. RESULTS: The patient lost cone vision in the course of several months while rod vision remained unaffected. Initially short wavelength (S) cone function appeared more resistant to the degeneration. Cancer associated retinal antibodies were present in the sera of the patient but no cancer has been found. CONCLUSION: Rapid loss of cone function can occur in an adult without a concomitant neoplasm although serum antibodies to retinal antigens suggest an autoimmune cause.

Aged↗
PubMed1994

'Unilateral cone dystrophy': ERG changes implicate abnormal signaling by hyperpolarizing bipolar and/or horizontal cells.

The two cases described here appear to represent the infrequently reported entity of "unilateral cone (cone-rod) dystrophy." Both cases give the suggestion that daylight vision can be affected by abnormalities in visual signals in the proximal retina, after they leave the cone photoreceptors themselves. The ERG waveform changes in these two cases are consistent with a deficit in signaling by the hyperpolarizing bipolar cells, and the complaint of abnormal color perception in both cases presented here raises the possibility that the OFF-pathway through hyperpolarizing bipolar cells may be important for color processing.

Aged↗
PubMed1992

Color electroretinography. A method for separation of dysfunctions of cones.

Electroretinograms to white and color stimuli were recorded in four normal subjects and nine subjects with different cone dysfunctions, including protanopia, cone dystrophy, cone dystrophy with supernormal b-waves at dark adaptation, cone dystrophy with missing b-waves during light adaptation and rod-cone dystrophy with blue cone hypersensitivity. Color stimuli were obtained with Kodak Wratten filters in blue, blue-green, green, yellow and red. Electroretinograms to all stimuli were recorded during dark and light adaptation with different stimulus intensities and to 30-Hz flicker stimulation. In protanopia, responses to red during light adaptation and flicker stimulation were reduced. All cone dystrophies showed reduced amplitudes and prolonged implicit times to red when dark adapted. The light-adapted responses were equally reduced to all color stimuli in cone dystrophy and cone dystrophy with supernormal b-waves. Contrary to other cone dystrophies, in cone dystrophy with missing b-waves, responses to red were severely reduced and responses to green were preserved, indicating a predominantly red cone dysfunction. Blue cone hypersensitivity was clearly distinct from other dystrophies in having large response to blue and blue-green and much smaller responses to all other colors in all stimulus conditions. The electroretinogram with color stimuli allowed separation of different cone dysfunctions and identification of new retinal dysfunction syndromes.

Adaptation, Ocular↗
PubMed1978

Familial foveal retinoschisis associated with a rod-cone dystrophy.

A brother and sister born of a consanguinous marriage had bilateral foveal retinoschisis and a generalized rod-cone dysfunction. This was associated with nyctalopia, hyperopia, minimal vitreous opacities in the sister, a paramacular tapetal sheen reflex, normal retinal vessels, an abnormal electroretinogram, and a normal electro-oculogram in the less affected brother. Foveal retinoschisis is not pathognomonic for x-chromosome-linked juvenile retinoschisis. It may be seen as a manifestation of a macular dystrophy or associated with a generalized tapetoretinal dystrophy.

Adult↗
PubMed1990

[Paraneoplastic retinopathy simulating cone dystrophy with achromatopsia].

A 72-year-old woman developed recurrent blindness on exposure to bright light (sunlight). Examination revealed total achromatopsia; bilateral central scotomas, predominant suppression of the cone response by electroretinography, and narrowing of the retinal arteries on ophthalmoscopy. The general examination revealed a pelvic tumor that later proved to be a pleomorphic carcinoma of presumed uterine origin. The patient died of metastatic disease 9 months after the ocular symptoms developed. Histopathologic examination of the eyes revealed loss of the photoreceptors, most extensive in the macular regions, and selective loss of the cones from the rest of the retinas. No ocular metastases of inflammation were found. The changes described are interpreted as paraneoplastic retinopathy of autoimmune origin.

Aged↗
PubMed1983

Cone dystrophy, nyctalopia, and supernormal rod responses. A new retinal degeneration.

An unusual retinal degeneration considered to be inherited as an autosomal recessive trait occurred in two of four children in a Hispanic family. The abnormality causes a progressive and generalized loss of cone vision, including decreased acuity, decreased color vision, central scotomas to small test objects, photo-phobia, and a profound diminution of the cone-mediated electroretinographic (ERG) pattern. A loss of the foveal reflex and an increased granularity of the macula is seen funduscopically. In addition, there is a most unusual alteration of the rod system detectable in the rod-mediated ERG pattern. This rod response is supernormal in amplitude (greater than 1,000 microV, extrapolated), delayed in time course, and insensitive to dim stimuli, ie, the function relating response to light intensity has been drastically altered. The insensitivity to dim stimuli is accompanied by a mild nyctalopia. Some of these abnormalities could be caused by a defect in the retinal enzyme, cyclic nucleotide phosphodiesterase.

Adolescent↗