[Hereditary association of tapeto-retinal dystrophy, retinitis punctata albescens, with spinal-cerebellar Friedreich's ataxia].
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Adult↗
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Results for “Retinal Dystrophies”
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Molecular genetics of human retinal dystrophies.
Retinal dystrophies are a heterogeneous group of diseases in which the retina degenerates, leading to either partial or complete blindness. The severe and clearly hereditary forms, retinitis pigmentosa (RP) and various macular degenerations, affect approximately 1 in 3000 people, but many more suffer from aging macular dystrophy in later life. Patients with RP present with narrowing visual fields and night blindness, while those with diseases of the macula lose central vision first. Even before the advent of molecular genetics it was evident that these were heterogeneous disorders, with wide variation in severity, mode of inheritance and phenotype. However, with the widespread application of linkage analysis and mutation detection techniques, a complex underlying pathology has now been revealed. In total, 66 distinct non-overlapping genes or gene loci have been implicated in the various forms of retinal dystrophy, with more being reported regularly in the literature. Within the category of non-syndromic RP alone there are at least 22 genes (and probably many more) involved, with further allelic heterogeneity arising from different mutations in the same gene. This complexity presents a problem for those involved in counselling patients, and also compounds the search for therapies. Nevertheless, several lines of research raise the hope of generic treatments applicable to all such patients, while the greater understanding of normal visual function that arises from genetic studies may open up new avenues for therapy.
Genes, Dominant↗
Symptomatic abnormalities of dark adaptation in patients with EFEMP1 retinal dystrophy (Malattia Leventinese/Doyne honeycomb retinal dystrophy).
PURPOSE: To investigate the nature of symptomatic visual disturbance in patients with EFEMP1 retinal dystrophy in the absence of geographic atrophy or choroidal neovascularization. METHODS: Patients presenting to a tertiary referral centre underwent clinical evaluation, fluorescein angiography, colour contrast sensitivity, focal, pattern, and standard electroretinography, electrooculography, scotopic threshold perimetry and dark adaptometry. RESULTS: Clinical features included reduced central vision, difficulty passing from light to dark, and diffuse submacular and peripapillary deposits, which were hyperfluorescent by fluorescein angiography. Colour contrast thresholds were abnormal in all six patients studied and both pattern and focal electroretinograms were abnormal in five of six patients. The scotopic and mixed rod-cone single flash ERG was normal but two patients demonstrated reduced oscillatory potentials and one had borderline delayed 30 Hz responses. Scotopic thresholds were elevated and rod-mediated dark adaptation kinetics were markedly prolonged in all six patients when measured over the central visible confluent deposits. CONCLUSIONS: In patients with EFEMP1 retinal dystrophy with confluent macular deposits, scotopic sensitivity is reduced and dark adaptation kinetics are prolonged over the macular deposits but are normal elsewhere. These results emphasize the localised nature of functional deficits in some patients with EFEMP1 retinal dystrophy and correlate well with the patient's visual symptoms. Symptomatic visual dysfunction may precede the development of clinically evident geographic atrophy or choroidal neovascularization in this disorder.
Color Vision Defects↗
[Genetic study of retinal pigmentary dystrophy (retinitis pigmentosa) in Japan].
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Adolescent↗
Inner retinal function in hereditary retinal dystrophies.
Hereditary retinal dystrophies are most often disorders of photoreceptors and/or the retinal pigment epithelium. Structures secondary to the photoreceptor layer such as bipolar, horizontal, amacrine and ganglion cells are secondarily involved. In later stages of the disease a mild to moderate loss of inner retina occurs, but the second and third neurons remain surprisingly viable even in late and severe stages of retinal dystrophies. The function of the inner retina in patients suffering from hereditary retinal dystrophies is not easy to determine because it depends on the input of photoreceptors. The electroretinogram (ERG) offers several possibilities in this respect: b-wave, off-response (off-ERG), oscillatory potentials, scotopic threshold response of the flash ERG and the pattern ERG (PERG). We looked at two ERG tests: the PERG and the off-ERG. The PERG is an indicator of ganglion cell function. Its amplitude is related to the photoreceptor input determined by the flash ERG and visual field testing. But in cases of an undetectable flash ERG response the PERG can be recorded in some patients, but not in others. This may be an indication of a different effect on inner retinal function in different groups of patients. On- and off-responses are related to the function of depolarizing and hyperpolarizing bipolar cells. Evaluation of 301 patients with various retinal dystrophies revealed that most hereditary disorders primarily affect the photoreceptors or the pigment epithelium. In some patients, alterations of the on- and off-response amplitudes or implicit times were indicative of inner retinal disorders and different pathophysiologic mechanisms. However, interpretation has to be made carefully, as on- and off-responses may be influenced by dysfunction of photoreceptor synapses to bipolar cells, bipolar cells, Müller cells and intercellular matrix.
Adolescent↗
The role of molecular genetics in the prenatal diagnosis of retinal dystrophies.
Inherited retinal dystrophies are important causes of incurable blindness in developed countries. Advances in molecular genetics promise significant improvements in their management. Immediate benefits of present knowledge are presymptomatic and prenatal diagnosis in selected cases. To study the predictive power of these techniques a simulated genetic risk estimation was undertaken in a cone-rod retinal dystrophy pedigree known to be linked to chromosome 19. Using data on five fully informative, flanking DNA markers, phenotype was correctly assigned with only a 2% probability of error. If the two most closely linked markers were found to be uninformative, this error probability remained unchanged. Using genetic risk calculations and direct mutation detection many retinal dystrophies could now be identified by prenatal diagnosis.
Blindness↗
Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa.
Mutation of a receptor tyrosine kinase gene, Mertk, in the Royal College of Surgeons (RCS) rat results in defective phagocytosis of photoreceptor outer segments by the retinal pigment epithelium (RPE) and retinal degeneration. We screened the human orthologue, MERTK, located at 2q14.1 (ref. 10), in 328 DNA samples from individuals with various retinal dystrophies and found three mutations in three individuals with retinitis pigmentosa (RP). Our findings are the first conclusive evidence implicating the RPE phagocytosis pathway in human retinal disease.
Adult↗
Membrane voltage and whole-cell currents in cultured pericytes of control rats and rats with retinal dystrophy.
PURPOSE: Retinal vascular changes are associated with retinitis pigmentosa in man and the retinal dystrophy of the Royal College of Surgeons (RCS) rat. Recently we demonstrated that retinal capillary pericytes possess electrical membrane characteristics typical for smooth muscle cells and may thus regulate retinal blood flow in vivo. METHODS: In the present study we compared cultured pericytes of 5-7 day old RCS and control rats by measurement of membrane voltage (Vmem) with microelectrodes and currents with the whole-cell configuration of the patch-clamp technique. RESULTS: Resting membrane voltage (-37.6 mV +/- 1.0 mV, n = 106 and -36.6 mV +/- 0.7 mV, n = 102, respectively) and whole-cell currents, which are mainly determined by a potassium conductance, were comparable in pericytes of control and RCS rats. The electrogenic component of the Na(+)-K(+)-ATPase in RCS rat pericytes was reduced, because depolarization of their membrane voltage by Na(+)-K(+)-ATPase inhibitor ouabain (10(-4) mol.1-1 or K+ free solution was significantly decreased compared to control pericytes. Norepinephrine (10(-5) mol.1-1) depolarized Vmem of control rat pericytes by delta 7.0 mV +/- 1.3 mV (n = 7), whereas it hyperpolarized Vmem of RCS rat pericytes by delta 2.0 mV +/- 0.8 mV (n = 11). The depolarization of Vmem by histamine (10(-5) mol.1-1) was significantly reduced in pericytes of RCS rats (delta 2.6 mV +/- 0.4 mV, n = 7) compared to control pericytes (delta 4.3 mV +/- 0.5 mV, n = 6). In pericytes of RCS rats ATP-induced activation of inward and outward currents and depolarization of membrane voltage were also significantly reduced. CONCLUSIONS: The data indicate that there are differences in the electrophysiological properties of retinal capillary pericytes of 5-7 days old RCS and control rats. Whereas resting membrane voltage and K+ conductance are comparable in both groups, there are significant differences in the electrical activity of Na(+)-K(+)-ATPase and in the effects of vasoactive substances on the membrane voltage and currents. These differences might contribute to the vascular changes observed in RP, and possibly accelerate the progress of retinal dystrophy.
Adrenergic alpha-Agonists↗
Familial internal limiting membrane dystrophy. A new sheen retinal dystrophy.
OBJECTIVE: To describe the clinicopathologic features of a previously unreported retinal dystrophy. METHODS: Fourteen members of a single family were examined. The medical records of 2 additional family members were reviewed. Pathologic examination was performed on 2 eyes of 1 affected patient. RESULTS: Five individuals were identified with a retinal dystrophy characterized by a glistening inner retinal surface throughout the posterior pole. Visual loss occurred in 3 affected patients in later life owing to superficial polycystic retinal edema and retinal folds. Electroretinographic testing revealed a selective diminution of the b wave. Pathologic examination revealed an abnormal internal limiting membrane with schisis cavities in the inner retina. Endothelial cell swelling, pericyte degeneration, and basement membrane thickening were present in retinal capillaries. CONCLUSIONS: A previously unreported sheen retinal dystrophy is described. Pedigree analysis suggests an autosomal dominant mode of inheritance. A primary defect in Müller cells is the suspected, but unproved, cause. No effective treatment for the associated visual loss is known. The term familial internal limiting membrane dystrophy is proposed to describe this condition.
Adult↗
Genetic blindness: current concepts in the pathogenesis of human outer retinal dystrophies.
Outer retinal dystrophies are the major causes of incurable blindness in the Western world. Understanding the etiology of retinal dystrophies has improved remarkably over the past decade. A number of genes, such as RHO, PDE-beta, RDS, TIMP3, MYO7A, RETGC1, RPGR, CRX and ABCR, are now known to be particularly important. Characterization of the genetic basis for disease is leading to new concepts of pathogenesis at the molecular and cellular levels. Such detailed understanding of disease processes is also stimulating a renewed interest in therapeutic strategies.
Apoptosis↗
Animal models of human retinal dystrophies.
Naturally occurring retinal dystrophies in laboratory and companion animals represent a wealth of different conditions, some of which are important from a comparative point of view, and all of which offer opportunities to further the understanding of retinal function and reaction in health and disease. The study of animal models of retinal dystrophies has provided candidate genes for investigation in conditions of man such as retinitis pigmentosa and has also led to the identification of new genes and even new families of genes. Mutations in the gene for the beta subunit of cyclic GMP phosphodiesterase cause retinal dystrophies in man, mice and dog, and mutations in the gene for the structural protein peripherin/RDS result in a retinal dystrophy in the mouse and a spectrum of differing retinal dystrophies in man. Animals with homologous retinal dystrophies to man may make useful models for investigation of treatment either by drugs or by gene therapy. Furthermore the use of transgenics and gene targeting in laboratory mice offers the opportunity to create new models of human retinal dystrophies and also to investigate the effect of gene dysfunction.
3',5'-Cyclic-GMP Phosphodiesterases↗
Carrier detection in X-pigmentary retinal dystrophy (X-linked retinitis pigmentosa) by DNA restriction fragment length polymorphism studies.
As part of a patient care and DNA research programme commenced in 1985, a number of DNA markers on the short arm of the X chromosome have been used to demonstrate restriction fragment length polymorphisms (RFLPs) segregating with the X-pigmentary retinal dystrophy (X-linked retinitis pigmentosa) gene. The analysis of the segregation of the RFLPs in 3 kindreds enables carrier detection, to a high degree of probability, in females at risk who are not manifesting symptoms and signs.
Adult↗
Retinal dystrophy combined with alopecia.
Retinitis pigmentosa or pigmentary retinal dystrophy is the most important group among the tapeto-retinal dystrophies. The degenerative process found in the retina has, in many cases, a corresponding counterpart in other parts of the body, most commonly in the CNS. Combinations of retinal dystrophy, and for instance, deafness or mental retardation are well known. Also combinations of retinal dystrophy and metabolic dyscrasia have been reported. Only few reports on the combination of retinal dystrophy and dermatological affections have been found. We have found two cases of almost total alopecia combined with retinal dystrophy. Since we have succeeded in finding a few similar cases in the literature we consider this apparently rare combination worth a somewhat closer analysis as it might constitute a specific entity.
Adult↗
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↗
Reduced rhodopsin phosphorylation during retinal dystrophy.
During inherited retinal dystrophy in Irish Setter dogs, decreased activity of cGMP phosphodiesterase (PDE) results in high cGMP levels and retinal degeneration (1-3). This defect could be in PDE itself, or in its interactions with other proteins of the rod outer segment. We report herein that when retinas from 8-week-old dogs were phosphorylated with gamma-32P-ATP, and separated on SDS-PAGE, phosphorylation of rd dog rhodopsin was reduced. When rd retinas were mixed with normal dog retinas, phosphorylation of the latter was inhibited. Since rd-mediated inhibition was prevented by 1 mM NaF, the results suggest that the cause of reduced rd phosphorylation is increased phosphatase activity. Together, these results demonstrate that decreased phosphorylation of rhodopsin due to increased phosphatase activity is a fundamental biochemical change which may partially account for the degenerative process and loss of visual acuity during inherited retinal dystrophy.
Animals↗
Retinal dystrophies associated with peripheral retinal vasculopathy.
A pair of identical twins with cone-rod dystrophy and 1 patient with dominant retinitis pigmentosa are reported who had a peculiar vascular retinopathy characterised by perivenous accumulation of fluorescein in the temporal periphery. Other retinal dystrophies associated with leaking retinal vessels are discussed.
Adult↗
A novel locus for autosomal dominant cone and cone-rod dystrophies maps to the 6p gene cluster of retinal dystrophies.
PURPOSE: To characterize clinically and genetically a four-generation Italian family with autosomal dominant retinal dystrophy. METHODS: Thirty-seven family members underwent a detailed ophthalmologic investigation, comprising visual acuity determination, fundoscopy, electroretinogram, and electrooculogram. A genome-wide scan was performed, and three candidate genes mapping to the linked region were screened for mutations by direct sequencing. RESULTS: Nineteen individuals were affected by cone-rod dystrophy and four by cone dystrophy, whereas, in another subject, the diagnosis was compatible with central areolar choroidal dystrophy. The genome-wide search allowed mapping the disease locus to chromosome 6, region p12.2-p21.1, with a maximum lod score of 6.71. Analysis of key recombinants in affected individuals placed the locus to a 12-Mb region flanked by newly generated markers 6-41025 and 6-52969. Assuming complete penetrance, recombinations in two healthy individuals defined a smaller critical region of 3.7 Mb between markers 6-42153 and D6S459. Three genes mapping within the linked interval (RDS, GUCA1A, and GUCA1B) were considered excellent candidates because of their involvement in distinct forms of retinal dystrophies. However, mutation analyses of these genes failed to identify pathogenetic mutations. CONCLUSIONS: The significant lod scores obtained and the absence of mutations in RDS, GUCA1A, and GUCA1B support the existence of a novel, yet unidentified gene responsible for retinal dystrophy within the chromosome 6 cluster.
Adult↗
Inherited retinal dystrophy in the rat.
Retinal dystrophies, known in man, dog, mouse, and rat, involve progressive loss of photoreceptor cells with onset during or soon after the developmental period. Functional (electroretinogram), chemical (rhodopsin analyses) and morphological (light and electron microscopy) data obtained in the rat indicated two main processes: (a) overproduction of rhodopsin and an associated abnormal lamellar tissue component, (b) progressive loss of photoreceptor cells. The first abnormality recognized was the appearance of swirling sheets or bundles of extracellular lamellae between normally developing retinal rods and pigment epithelium; membrane thickness and spacing resembled that in normal outer segments. Rhodopsin content reached twice normal values, was present in both rods and extracellular lamellae, and was qualitatively normal, judged by absorption maximum and products of bleaching. Photoreceptors attained virtually adult form and ERG function. Then rod inner segments and nuclei began degenerating; the ERG lost sensitivity and showed selective depression of the a-wave at high luminances. Outer segments and lamellae gradually degenerated and rhodopsin content decreased. No phagocytosis was seen, though pigment cells partially dedifferentiated and many migrated through the outer segment-debris zone toward the retina. Eventually photoreceptor cells and the b-wave of the ERG entirely disappeared. Rats kept in darkness retained electrical activity, rhodopsin content, rod structure, and extracellular lamellae longer than litter mates in light.
Animals↗