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2.
Proc Natl Acad Sci U S A ; 105(39): 15112-7, 2008 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-18809924

RESUMEN

The RPE65 gene encodes the isomerase of the retinoid cycle, the enzymatic pathway that underlies mammalian vision. Mutations in RPE65 disrupt the retinoid cycle and cause a congenital human blindness known as Leber congenital amaurosis (LCA). We used adeno-associated virus-2-based RPE65 gene replacement therapy to treat three young adults with RPE65-LCA and measured their vision before and up to 90 days after the intervention. All three patients showed a statistically significant increase in visual sensitivity at 30 days after treatment localized to retinal areas that had received the vector. There were no changes in the effect between 30 and 90 days. Both cone- and rod-photoreceptor-based vision could be demonstrated in treated areas. For cones, there were increases of up to 1.7 log units (i.e., 50 fold); and for rods, there were gains of up to 4.8 log units (i.e., 63,000 fold). To assess what fraction of full vision potential was restored by gene therapy, we related the degree of light sensitivity to the level of remaining photoreceptors within the treatment area. We found that the intervention could overcome nearly all of the loss of light sensitivity resulting from the biochemical blockade. However, this reconstituted retinoid cycle was not completely normal. Resensitization kinetics of the newly treated rods were remarkably slow and required 8 h or more for the attainment of full sensitivity, compared with <1 h in normal eyes. Cone-sensitivity recovery time was rapid. These results demonstrate dramatic, albeit imperfect, recovery of rod- and cone-photoreceptor-based vision after RPE65 gene therapy.


Asunto(s)
Ceguera/terapia , Proteínas Portadoras/genética , Proteínas del Ojo/genética , Terapia Genética , Isomerasas/genética , Células Fotorreceptoras Retinianas Bastones/fisiopatología , Retinoides/metabolismo , Ceguera/patología , Ceguera/fisiopatología , Dependovirus/genética , Humanos , Células Fotorreceptoras Retinianas Conos/enzimología , Células Fotorreceptoras Retinianas Conos/patología , Células Fotorreceptoras Retinianas Conos/fisiopatología , Células Fotorreceptoras Retinianas Bastones/enzimología , Células Fotorreceptoras Retinianas Bastones/patología , Visión Ocular/fisiología , cis-trans-Isomerasas
3.
Br J Ophthalmol ; 92(8): 1086-91, 2008 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-18653602

RESUMEN

AIM: To describe the detailed phenotypes of a multi-generation family affected by autosomal dominant cone-rod dystrophy (adCRD) and characterised by marked intrafamilial heterogeneity, due to a novel frameshift mutation in the CRX gene. METHODS: Six affected and two unaffected family members underwent detailed ophthalmological examination as well as psychophysical and electrophysiological testing. Mutation screening of the CRX gene and segregation analysis were performed in 14 family members from three generations. RESULTS: Clinical examination of six available mutation carriers showed marked phenotypic heterogeneity, presenting with a reduced cone electroretinogram (ERG) and normal rod ERG in one family branch and a negative ERG in the other as the most striking feature. Genetic screening identified a novel mutation in the CRX gene, c.636delC, that independently segregates with the disease in both branches of the family. CONCLUSION: The authors identified a novel disease causing mutation in the CRX gene associated with adCRD. Furthermore, we show here for the first time the coexistence of a reduced cone and a negative ERG component in different individuals of the same family, all affected by the same mutation.


Asunto(s)
Mutación del Sistema de Lectura , Proteínas de Homeodominio/genética , Retinitis Pigmentosa/genética , Transactivadores/genética , Análisis Mutacional de ADN/métodos , Electrorretinografía , Proteínas del Ojo/genética , Femenino , Humanos , Masculino , Linaje , Fenotipo , Células Fotorreceptoras Retinianas Conos/fisiopatología , Células Fotorreceptoras Retinianas Bastones/fisiopatología , Retinitis Pigmentosa/fisiopatología , Agudeza Visual
4.
Vis Neurosci ; 25(3): 507-16, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18598426

RESUMEN

Rayleigh match data were modeled with the aim of explaining the locations of match midpoints and matching ranges, both in normal trichromats and in subjects with congenital color deficiency. Model parameters included the wavelength of peak sensitivity of cone photopigments, the effective photopigment optical density, and the noise amplitude in the red-green color channel. In order to avoid the suprathreshold, perceptual effects of extreme L:M cone ratios on color vision, selective post-receptoral amplification of cone signals is needed. The associated noise is also amplified and this causes corresponding changes in red-green threshold sensitivity. We propose that the noise amplitude and hence the size of the matching range in normal trichromats relates to the known inter-subject variation in the relative numbers of L and M cones. If this hypothesis can be shown to account for the extremes of the red-green matching range measured in normal trichromats, it is of interest to establish the extent to which it also predicts the unexpected, small matching ranges that are observed in some subjects with red-green color deficiency. A subset of subjects with deutan deficiency that exhibited less common Nagel matches were selected for genetic analysis of their cone pigment genes in order to confirm the type of deficiency, and to predict the corresponding peak wavelength separation (delta lambda(max)) of their two, long-wavelength cone pigments. The Rayleigh match model predicted accurately the midpoint and the range for the spectral differences specified by the genes. The prediction also required plausible selection of effective optical density of the cone pigments and noise. The noise needed varied, but the estimates were confined to lie within the limits established from the matching ranges measured in normal trichromats. The model predicts correctly the small matching ranges measured in some deuteranomalous subjects, principally accounted for by a low estimate of noise level in the red-green channel. The model also predicts the "normal" matches made by some subjects that rely on two hybrid genes and therefore exhibit red-green thresholds outside the normal range, typical of mild deuteranomaly.


Asunto(s)
Percepción de Color/fisiología , Defectos de la Visión Cromática/fisiopatología , Umbral Sensorial/fisiología , Pruebas de Percepción de Colores , Defectos de la Visión Cromática/genética , Sensibilidad de Contraste/fisiología , Humanos , Valores de Referencia , Células Fotorreceptoras Retinianas Conos/fisiología , Células Fotorreceptoras Retinianas Conos/fisiopatología , Sensibilidad y Especificidad
5.
Arch Ophthalmol ; 126(7): 907-13, 2008 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-18625935

RESUMEN

OBJECTIVES: To elucidate the visual significance of the foveal pit by measuring foveal architecture and function and to reassess use of the term foveal hypoplasia (as visual acuity can vary among patients who lack a pit). METHODS: We describe 4 patients who lack a foveal pit. Visual acuities ranged from 20/20 to 20/50. Stratus and Cirrus (Carl Zeiss Meditec, Dublin, California) optical coherence tomographs (OCTs) and multifocal electroretinograms were obtained. High-resolution retinal imaging on 2 of the participants was obtained by using a high-resolution Fourier-domain OCT and an adaptive optics flood-illuminated fundus camera. RESULTS: No participants had a visible foveal pit with conventional OCT. Central widening of the outer nuclear layer and lengthening of cone outer segments were seen with high-resolution Fourier-domain OCT. Adaptive optics imaging showed normal cone diameters in the central 1 degrees to 2 degrees. Central multifocal electroretinogram responses were normal. CONCLUSIONS: We show that a foveal pit is not required for foveal cone specialization, anatomically or functionally. This helps to explain the potential for good acuity in the absence of a pit and raises questions about the visual role of the foveal pit. Because the term foveal hypoplasia commonly carries a negative functional implication, it may be more proper to call the anatomic lack of a pit fovea plana.


Asunto(s)
Anomalías del Ojo/fisiopatología , Fóvea Central/anomalías , Células Fotorreceptoras Retinianas Conos/fisiopatología , Agudeza Visual/fisiología , Adulto , Albinismo Oculocutáneo/fisiopatología , Niño , Electrorretinografía , Anomalías del Ojo/diagnóstico , Femenino , Fijación Ocular/fisiología , Angiografía con Fluoresceína , Análisis de Fourier , Humanos , Masculino , Fotograbar , Tomografía de Coherencia Óptica
6.
J Neuroophthalmol ; 28(2): 120-5, 2008 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-18562844

RESUMEN

BACKGROUND: New technology allows more precise definition of structural alterations of all retinal layers although it has not been used previously in cases of optic disc drusen. METHODS: Using Stratus and Fourier domain (FD) optical coherence tomography (OCT) and adaptive optics (AO) through a flood-illuminated fundus camera, we studied the retinas of a patient with long-standing optic disc drusen and acute visual loss at high altitude attributed to ischemic optic neuropathy. RESULTS: Stratus OCT and FD-OCT confirmed severe thinning of the retinal nerve fiber layer (RNFL). FD-OCT revealed disturbances in the photoreceptor layer heretofore not described in optic disc drusen patients. AO confirmed the FD-OCT findings in the photoreceptor layer and also showed reduced cone density at retinal locations associated with reduced visual sensitivity. CONCLUSIONS: Based on this study, changes occur not only in the RNFL but also in the photoreceptor layer in optic nerve drusen complicated by ischemic optic neuropathy. This is the first reported application of FD-OCT and the AO to this condition. Such new imaging technology may in the future allow monitoring of disease progression more precisely and accurately.


Asunto(s)
Drusas del Disco Óptico/patología , Drusas del Disco Óptico/fisiopatología , Neuropatía Óptica Isquémica/patología , Neuropatía Óptica Isquémica/fisiopatología , Células Fotorreceptoras/patología , Células Ganglionares de la Retina/patología , Adulto , Mal de Altura/complicaciones , Circulación Cerebrovascular/fisiología , Análisis de Fourier , Humanos , Hipoxia/complicaciones , Masculino , Atrofia Óptica/etiología , Atrofia Óptica/patología , Atrofia Óptica/fisiopatología , Drusas del Disco Óptico/complicaciones , Neuropatía Óptica Isquémica/etiología , Óptica y Fotónica/instrumentación , Arteria Retiniana/fisiopatología , Células Fotorreceptoras Retinianas Conos/patología , Células Fotorreceptoras Retinianas Conos/fisiopatología , Tomografía de Coherencia Óptica/instrumentación , Tomografía de Coherencia Óptica/métodos , Baja Visión/etiología , Baja Visión/patología , Baja Visión/fisiopatología , Campos Visuales/fisiología
7.
Am J Ophthalmol ; 145(6): 1099-106, 2008 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-18400204

RESUMEN

PURPOSE: To describe patients with cone dystrophy and supernormal rod electroretinogram (ERG) and search for mutations in the recently described KCNV2 gene. DESIGN: Clinical and molecular study. METHODS: Patients from three families originating from France, Morocco, and Algeria had standard ophthalmologic examination and color vision analysis, Goldmann perimetry, International Society for Clinical Electrophysiology of Vision (ISCEV) protocol in accordance with ERG testing, autofluorescence evaluation, and optical coherence tomography 3 scanning. The two coding exons of KCNV2 were polymerase chain reaction amplified and sequenced. RESULTS: All patients had the characteristic features of supernormal, delayed rod ERG responses at the highest levels of stimulation and markedly reduced cone responses. In the French family, two affected sisters were compound heterozygotes for the recurrent c.1381G>A (Gly461Arg) mutation and for a novel c.442G>T (Glu148Stop) mutation. In the Moroccan family, affected members were homozygotes for the novel c.1404delC mutation (His468fsX503) and in the Algerian family, the proband was homozygote for the novel c.1001delC mutation (Ala334fsX453). In the three families, parents were unaffected heterozygote carriers. None of the mutations were present in 50 control chromosomes. CONCLUSIONS: The three novel truncative mutations are likely to be null mutations leading to loss of function, with no difference in the phenotype presentation. Amino acid changes are found exclusively in the N-terminal fragment of the protein and in the P-loop, indicating the importance of those regions for the function of the KCNV2 protein.


Asunto(s)
Defectos de la Visión Cromática/genética , Mutación , Canales de Potasio con Entrada de Voltaje/genética , Células Fotorreceptoras Retinianas Conos/fisiopatología , Degeneración Retiniana/genética , Células Fotorreceptoras Retinianas Bastones/fisiología , Adolescente , Adulto , Niño , Defectos de la Visión Cromática/diagnóstico , Defectos de la Visión Cromática/fisiopatología , Consanguinidad , Adaptación a la Oscuridad , Electrorretinografía , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Linaje , Estimulación Luminosa , Reacción en Cadena de la Polimerasa , Degeneración Retiniana/diagnóstico , Degeneración Retiniana/fisiopatología , Tomografía de Coherencia Óptica
8.
J Neurosci ; 28(15): 4008-14, 2008 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-18400900

RESUMEN

Lecithin retinol acyl transferase (LRAT) and retinal pigment epithelium protein 65 (RPE65) are key enzymes of the retinoid cycle. In Lrat(-/-) and Rpe65(-/-) mice, models of human Leber congenital amaurosis, the retinoid cycle is disrupted and 11-cis-retinal, the chromophore of visual pigments, is not produced. The Lrat(-/-) and Rpe65(-/-) retina phenotype presents with rapid sectorial cone degeneration, and the visual pigments, S-opsin and M/L-opsin, fail to traffic to cone outer segments appropriately. In contrast, rod opsin traffics normally in mutant rods. Concomitantly, guanylate cyclase 1, cone T alpha-subunit, cone phosphodiesterase 6alpha' (PDE6alpha'), and GRK1 (G-protein-coupled receptor kinase 1; opsin kinase) are not transported to Lrat(-/-) and Rpe65(-/-) cone outer segments. Aberrant localization of these membrane-associated proteins was evident at postnatal day 15, before the onset of ventral and central cone degeneration. Protein levels of cone T alpha and cone PDE6alpha' were reduced, whereas their transcript levels were unchanged, suggesting posttranslational degradation. In an Rpe65(-/-)Rho(-/-) double knock-out model, trafficking of cone pigments and membrane-associated cone phototransduction polypeptides to the outer segments proceeded normally after 11-cis-retinal administration. These results suggest that ventral and central cone opsins must be regenerated with 11-cis-retinal to permit transport to the outer segments. Furthermore, the presence of 11-cis-retinal is essential for proper transport of several membrane-associated cone phototransduction polypeptides in these cones.


Asunto(s)
Proteínas de la Membrana/metabolismo , Células Fotorreceptoras Retinianas Conos/metabolismo , Retinaldehído/metabolismo , Aciltransferasas/deficiencia , Aciltransferasas/metabolismo , Animales , Ceguera/congénito , Ceguera/genética , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Modelos Animales de Enfermedad , Proteínas del Ojo/genética , Proteínas del Ojo/metabolismo , Guanilato Ciclasa/metabolismo , Ratones , Ratones Noqueados , Degeneración Nerviosa/etiología , Degeneración Nerviosa/fisiopatología , Isoformas de Proteínas/metabolismo , Transporte de Proteínas/efectos de los fármacos , Receptores de Superficie Celular/metabolismo , Células Fotorreceptoras Retinianas Conos/fisiopatología , Pigmentos Retinianos/metabolismo , Retinaldehído/deficiencia , Retinaldehído/farmacología , Opsinas de Bastones/metabolismo , Factores de Tiempo , Visión Ocular , cis-trans-Isomerasas
9.
Exp Eye Res ; 86(6): 914-28, 2008 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-18440505

RESUMEN

The purpose of this study was to determine the contributions of postreceptoral neurons to the light-adapted ERG of the Nob mouse, a model for complete-type congenital stationary night blindness (CSNB1) that lacks a b-wave from depolarizing bipolar cells. Ganzfeld ERGs were recorded from anesthetized adult control mice, control mice injected intravitreally with L-2-amino-4-phosphonobutyric acid (Control APB mice) to remove On pathway activity, and Nob mice. ERGs also were recorded after PDA (cis-2,3-piperidine-dicarboxylic acid, 3-5mM) was injected to block transmission to hyperpolarizing (Off) bipolar and horizontal cells, and all third-order neurons. Stimuli were brief (<4ms, 0.4-2.5log sc td s) and long (200ms, 2.5-4.6log sc td) LED flashes (lambda(max)=513nm, on a rod suppressing background (2.6log sc td). Sinusoidal modulation of the LEDs (mean, 2.6log sc td; contrast, 100%; 3-36Hz) was used to study flicker ERGs. Brief-flash ERGs of Nob mice presented as long-lasting negative waves with a positive-going intrusion that started about 50ms after the flash and peaked around 120ms. Control APB mice had similar responses, and in both cases, PDA removed the positive-going intrusion. For long flashes, PDA removed a small, slow "d-wave" after light offset. With sinusoidal stimulation, the fundamental (F1) amplitude of control mice ERG peaked at 8Hz ( approximately 70microV). For Nob mice the peak was approximately 20microV at 6Hz before PDA and approximately 10muV at 3Hz or lower after PDA. F1 responses were present up to 21Hz in control and Nob eyes and 15Hz in Nob eyes after PDA. Between 3 and 6Hz, F1 phase was 170-210 degrees more delayed in Nob than control mice; phase was hardly altered by PDA. With vector analysis, a substantial postreceptoral input to the Nob flicker ERG was revealed. In control mice, the second harmonic (F2) response showed peaks of approximately 10mocrpV at 3Hz and 13Hz. Nob mice showed almost no F2. In summary, in this study it was found that in Nob mice, postreceptoral neurons from the Off pathway make a positive-going contribution to the light-adapted flash ERG, and contribute substantially to sinusoidal flicker ERG.


Asunto(s)
Ceguera Nocturna/fisiopatología , Retina/fisiopatología , Adaptación Ocular , Envejecimiento/fisiología , Aminobutiratos , Animales , Modelos Animales de Enfermedad , Electrorretinografía , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Ceguera Nocturna/congénito , Ceguera Nocturna/genética , Estimulación Luminosa/métodos , Ácidos Pipecólicos , Células Fotorreceptoras Retinianas Conos/fisiopatología , Transmisión Sináptica
10.
Invest Ophthalmol Vis Sci ; 49(5): 2201-7, 2008 May.
Artículo en Inglés | MEDLINE | ID: mdl-18436853

RESUMEN

PURPOSE: To investigate whether there is a significant correlation between the photopic negative response (PhNR) of the electroretinogram (ERG) and retinal nerve fiber layer thickness and optic disc topography in glaucomatous eyes. METHODS: Ninety-nine eyes of 53 patients with open-angle glaucoma (OAG) and 30 eyes of 28 normal volunteers were studied. Photopic ERGs were elicited by red stimuli (644 nm, 1600 cd/m(2)) on a blue background (470 nm, 40 cd/m(2)). The mean deviation (MD) of the visual field was obtained by static visual field analyses. The topography of the optic nerve head was determined by confocal scanning laser ophthalmoscopy. The retinal nerve fiber layer thickness (RNFLT) around the optic nerve head was measured with a scanning laser polarimeter. RESULTS: The amplitude of the PhNR and the PhNR/b-wave ratio decreased with an increase in visual field defects. The logarithmic values of the PhNR amplitude and PhNR/b-wave amplitude ratio were significantly correlated with the MD better than the linear values. The PhNR amplitude and PhNR/b-wave amplitude ratio were significantly correlated with the RNFLT and the rim area of the optic disc and with the cup/disc area ratio. These correlations were higher when expressed linearly than when stated logarithmically. The sensitivity and specificity were 77% and 90% for the PhNR amplitude and 70% and 87% for the PhNR/b-wave amplitude ratio when the optimal cutoff values were used. Although the a-wave amplitude correlated with the MD, the a-wave amplitudes of most of the patients fell within the normal range. The correlation between the b-wave amplitude and MD was not significant. CONCLUSIONS: The PhNR amplitudes correlate with the decrease in function and morphology of retinal neurons in eyes with OAG. The linear relationship between the PhNR and the structural parameters indicates that inner retinal function declines proportionately with neural loss in eyes with glaucoma.


Asunto(s)
Electrorretinografía , Glaucoma de Ángulo Abierto/fisiopatología , Fibras Nerviosas/patología , Disco Óptico/patología , Enfermedades del Nervio Óptico/fisiopatología , Células Fotorreceptoras Retinianas Conos/fisiopatología , Células Ganglionares de la Retina/patología , Anciano , Anciano de 80 o más Años , Gonioscopía , Humanos , Luz , Persona de Mediana Edad , Oftalmoscopía , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Trastornos de la Visión/fisiopatología , Campos Visuales/fisiología
11.
Invest Ophthalmol Vis Sci ; 49(3): 1116-25, 2008 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-18326739

RESUMEN

PURPOSE: This study tests whether cones in the rhodopsin-mutant transgenic P23H-3 retina are damaged by ambient light and whether subsequent light restriction allows repair of damaged cones. METHODS: P23H-3 rats were raised in scotopic cyclic (12 hours of 5 lux, 12 hours of dark) ambient light. At postnatal day 90 to 130, some were transferred to photopic conditions (12 hours of 300 lux, 12 hours of dark) for 1 week and then returned to scotopic conditions for up to 5 weeks. Photoreceptor function was assessed by the dark-adapted flash-evoked electroretinogram, using a two-flash paradigm to isolate the cone response. Outer-segment structure was demonstrated by immunohistochemistry for cone and rod opsins and by electron microscopy. RESULTS: Exposure for 1 week to photopic ambient light reduced the cone b-wave, the rod b-wave, and the rod a-wave by 40% to 60% and caused shortening and disorganization of cone and rod outer segments. Restoration of scotopic conditions for 2 to 5 weeks allowed partial recovery of the cone b-wave and the rod a- and b-waves, and regrowth of outer segments. CONCLUSIONS: Modest increases in ambient light cause rapid and significantly reversible loss of cone and rod function in the P23H-3 retina. The reduction and recovery of cone function are associated with shortening and regrowth of outer segments. Because the P23H mutation affects a protein expressed specifically in rods, this study emphasizes the close dependence of cones on rod function. It also demonstrates the capacity of cones and rods to repair their structure and regain function.


Asunto(s)
Mutación , Traumatismos Experimentales por Radiación/fisiopatología , Células Fotorreceptoras Retinianas Conos/fisiopatología , Degeneración Retiniana/fisiopatología , Células Fotorreceptoras Retinianas Bastones/fisiopatología , Rodopsina/genética , Animales , Animales Modificados Genéticamente , Animales Recién Nacidos , Muerte Celular/fisiología , Supervivencia Celular/fisiología , Adaptación a la Oscuridad , Electrorretinografía , Técnica del Anticuerpo Fluorescente Indirecta , Luz/efectos adversos , Estimulación Luminosa , Traumatismos Experimentales por Radiación/genética , Ratas , Ratas Sprague-Dawley , Retina/efectos de la radiación , Células Fotorreceptoras Retinianas Conos/efectos de la radiación , Células Fotorreceptoras Retinianas Conos/ultraestructura , Degeneración Retiniana/genética , Células Fotorreceptoras Retinianas Bastones/efectos de la radiación , Células Fotorreceptoras Retinianas Bastones/ultraestructura , Opsinas de Bastones/metabolismo
12.
Invest Ophthalmol Vis Sci ; 49(3): 1126-35, 2008 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-18326740

RESUMEN

PURPOSE: To define rod and cone function further in terms of visual cycle mechanism, the retinal phenotype resulting from Rpe65 (retinoid isomerase I) deficiency in Nrl(-)(/)(-) mice having a single class of photoreceptors resembling wild-type cones was characterized and outcomes of retinoid supplementation evaluated. METHODS: Rpe65(-)(/)(-)/Nrl(-)(/)(-) mice were generated by breeding Rpe65(-)(/)(-) and Nrl(-)(/)(-) strains. Retinal histology, protein expression, retinoid content, and electroretinographic (ERG) responses were evaluated before and after treatment with 11-cis retinal by intraperitoneal injection. Results Retinas of young Rpe65(-)(/-)/Nrl(-)(/-) mice exhibited normal lamination, but lacked intact photoreceptor outer segments at all ages examined. Rpe65, Nrl, and rhodopsin were not detected, and S-opsin and M/L-opsin levels were reduced. Retinyl esters were the only retinoids present. In contrast, Nrl(-)(/)(-) mice exhibited decreased levels of retinaldehydes and retinyl esters, and elevated levels of retinols. ERG responses were elicited from Rpe65(-)(/-)/Nrl(-)(/-) mice only at the two highest intensities over a 4-log-unit range. Significant retinal thinning and outer nuclear layer loss occurred in Rpe65(-)(/-)/Nrl(-)(/-) mice with aging. Administration of exogenous 11-cis retinal did not rescue retinal morphology or markedly improve ERG responses. CONCLUSIONS: The findings provide clarification of reported cone loss of function in Rpe65(-)(/-)/Nrl(-)(/-) mice, now showing that chromophore absence results in destabilized cone outer segments and rapid retinal degeneration. The data support the view that rod-dominant retinas do not have a cone-specific mechanism for 11-cis retinal synthesis and have potential significance for therapeutic strategies for rescue of cone-rich retinal regions affected by disease in the aging human population.


Asunto(s)
Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/fisiología , Proteínas Portadoras/fisiología , Proteínas del Ojo/fisiología , Células Fotorreceptoras Retinianas Conos/ultraestructura , Degeneración Retiniana/metabolismo , Retinaldehído/biosíntesis , Animales , Western Blotting , Cromatografía Líquida de Alta Presión , Adaptación a la Oscuridad , Electrorretinografía , Femenino , Técnica del Anticuerpo Fluorescente Indirecta , Genotipo , Inyecciones Intraperitoneales , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Electrónica de Transmisión , Células Fotorreceptoras Retinianas Conos/metabolismo , Células Fotorreceptoras Retinianas Conos/fisiopatología , Degeneración Retiniana/tratamiento farmacológico , Degeneración Retiniana/fisiopatología , Retinaldehído/administración & dosificación , Retinoides/metabolismo , Opsinas de Bastones/metabolismo , cis-trans-Isomerasas
14.
Ophthalmology ; 115(4): 723-9, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18201765

RESUMEN

PURPOSE: To test whether choroideremia carriers have a mosaic pattern of retinal dysfunction, as noted in carriers of X-linked recessive retinitis pigmentosa and X-linked retinoschisis. DESIGN: Prospective observational case series. PARTICIPANTS: Seven obligate choroideremia carriers (age range, 18-72) with visual acuity (VA) of 20/25 or better were recruited into the study. METHODS: The carriers underwent VA testing (Snellen chart), ophthalmic examination, Humphrey visual field (VF), and multifocal electroretinographic testing. The amplitude and implicit time scales were measured by the algorithm of Hood and Li. The amplitude measures (a scales) and implicit time measures (t scales) were reported abnormal when they were >2 standard deviations above the mean of age-similar normally sighted control subjects. MAIN OUTCOME MEASURES: Mapping of local 103 electroretinographic response amplitudes and implicit times. RESULTS: Only 1 of the 7 carriers showed abnormal Humphrey VF thresholds, whereas 6 of the 7 carriers showed a mosaic pattern of retinal dysfunction measured by multifocal electroretinographic testing. All 6 carriers showed statistically significant implicit time delays, whereas 4 carriers showed statistically significant amplitude reductions and implicit time delays (P<0.05 to P<0.0006). One carrier with a normal-appearing macula and normal Humphrey VF showed a cluster of statistically significant implicit time delays within the macula (P<0.05 to P<0.0006). The overall extent of local electroretinographic abnormalities corresponded to the severity of ophthalmoscopically apparent pigmentary changes. The one carrier with mild threshold elevation on Humphrey VF testing showed the most ophthalmoscopically apparent extensive fundus pigmentary changes. CONCLUSIONS: We demonstrated a mosaic pattern of retinal cone dysfunction in carriers of choroideremia. Our findings are consistent with the Lyon hypothesis of random X-chromosome inactivation. Multifocal electroretinographic testing is potentially sensitive to detect local retinal dysfunction in choroideremia carriers even in those with a normal-appearing macula and good VA.


Asunto(s)
Coroideremia/fisiopatología , Electrorretinografía , Heterocigoto , Mosaicismo , Psicofísica , Retina/fisiopatología , Adulto , Anciano , Coroideremia/diagnóstico , Coroideremia/genética , Estudios de Cohortes , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/fisiopatología , Humanos , Persona de Mediana Edad , Estudios Prospectivos , Psicofísica/métodos , Células Fotorreceptoras Retinianas Conos/fisiopatología , Campos Visuales
15.
Invest Ophthalmol Vis Sci ; 49(1): 55-65, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18172075

RESUMEN

PURPOSE: A cathode-ray-tube (CRT) monitor-based technique was used to isolate clinically significant components of dark adaptation. The utility of the technique in identifying adaptation abnormalities in eyes with age-related maculopathy (ARM) is described. METHODS: A CRT dark adaptometer was developed to assess cone and rod recovery after photopigment bleach. The following measures were obtained: cone recovery rate (R(c); in decades per minute) and absolute threshold (Tf(c); log candelas per square meter), rod recovery rate (R(r); decades per minute), and rod-cone transition (rod-cone break [RCB], in minutes). These components were isolated by appropriately selecting stimulus size, stimulus location, pigment bleach, and test duration and by coupling the CRT with judiciously selected neutral-density (ND) filters. The protocol was developed by using 5 young observers and was tested on 27 subjects with ARM in the study eye and 22 age-matched control subjects. RESULTS: The parameters necessary for effective isolation of cone and early phase rod dark adaptation were a 2.6 ND filter (for a standard CRT monitor, 0.08-80 cd . m(-2) luminance output); a 4 degrees foveated, 200-ms, achromatic spot; approximately 30% pigment bleaching; and a 30-minute test duration. These settings returned obvious rod and cone recovery curves in control and ARM eyes that were compatible with conventional test methods and identified 93% of participants with ARM as having delayed dynamics in at least one of the parameters. Cone recovery dynamics were significantly slower in the ARM group when compared with age-matched control subjects (R(c), 0.99 +/- 0.35 vs. 2.63 +/- 0.61 decades . min(-1), P < 0.0001). Three of the 27 eyes with ARM did not achieve RCB during the allowed duration (30 minutes). The remaining eyes with ARM (n = 24) exhibited a significant delay in rod recovery (R(r)(,) ARM, 0.16 +/- 0.03 vs. controls, 0.22 +/- 0.02 decades . min(-1), P < 0.0001) and the average time to RCB (+/-SD) in the ARM group was significantly longer than in the control subjects (19.12 +/- 5.17 minutes vs. 10.40 +/- 2.49 minutes, P < 0.0001). CONCLUSIONS: The CRT dark-adaptation technique described in this article is an effective test for identifying abnormalities in cone and rod recovery. Slowed cone and rod recovery and a delayed RCB were evident in the eyes with ARM. The test method is potentially useful for clinical intervention trials in which ARM progression is monitored.


Asunto(s)
Adaptación a la Oscuridad/fisiología , Degeneración Macular/fisiopatología , Células Fotorreceptoras Retinianas Conos/fisiopatología , Células Fotorreceptoras Retinianas Bastones/fisiopatología , Adulto , Anciano , Técnicas de Diagnóstico Oftalmológico , Humanos , Estimulación Luminosa , Recuperación de la Función , Células Fotorreceptoras Retinianas Conos/efectos de la radiación , Células Fotorreceptoras Retinianas Bastones/efectos de la radiación , Umbral Sensorial/fisiología , Visión Ocular/fisiología
16.
Doc Ophthalmol ; 116(1): 41-7, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17721714

RESUMEN

Multifocal electroretinograms were recorded in one case of incomplete form of congenital stationary night blindness. First order kernel revealed reduced cone macular P1 responses with normal implicit time (22.7 nV, 33.3 ms; normal 43.3 +/- 8.2 nV, 32.7 +/- 0.6 ms) whereas more peripheral responses exhibited low responses of extremely delayed implicit time (5.1 nV, 47.5 ms; normal 7.4 +/- 2.1 nV, 32.3 +/- 0.8 ms). Responses from the first slice of the second kernel were present in the macular area but absent from the more peripheral areas. In comparison, mfERGs in the complete form of CSNB showed normal amplitude but slightly delayed responses at all eccentricities and normal second kernel responses. Results are discussed in terms of the dichotomy in synaptic transmission between macular and peripheral cones.


Asunto(s)
Electrorretinografía/métodos , Ceguera Nocturna/fisiopatología , Células Fotorreceptoras Retinianas Conos/fisiopatología , Enfermedades de la Retina/fisiopatología , Adolescente , Adulto , Humanos , Masculino , Ceguera Nocturna/congénito , Enfermedades de la Retina/congénito
17.
Vision Res ; 48(2): 273-80, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18158169

RESUMEN

Focal macular cone electroretinograms (ERGs) and multifocal ERGs were recorded to study the macular function in patients with the complete-type of congenital stationary night blindness (cCSNB). The waveforms of the focal macular cone ERGs and the on- and off-responses of the multifocal ERGs in the cCSNB patients were similar to those recorded from monkey retinas treated with L-2 amino-4-phosphonobutyric acid (APB), suggesting that patients with cCSNB have a complete defect of the on-pathway even in the central retina. The results also demonstrated that there was a paradoxical positive response in the central retina of cCSNB patients, as compared to the negative full-field ERGs in the same subjects.


Asunto(s)
Mácula Lútea/fisiopatología , Ceguera Nocturna/fisiopatología , Células Fotorreceptoras Retinianas Conos/fisiopatología , Adolescente , Adulto , Aminobutiratos/farmacología , Animales , Electrorretinografía/métodos , Femenino , Humanos , Macaca mulatta , Masculino , Persona de Mediana Edad , Ceguera Nocturna/congénito , Retina/efectos de los fármacos , Retina/fisiología
18.
Acta Ophthalmol ; 86(3): 338-40, 2008 May.
Artículo en Inglés | MEDLINE | ID: mdl-17662094

RESUMEN

PURPOSE: To assess the impact of acute retinal pigment epithelium (RPE) loss on photopic and scotopic sensitivity. METHODS: A 68-year-old woman who had been followed for drusenoid RPE detachment in age-related macular degeneration presented with an acute spontaneous retinal pigment epithelium tear. Three months later, she was seen for routine follow-up and was examined by manual photopic and scotopic threshold perimetry (a static 0.46-degree-diameter 660 nm stimulus under photopic conditions; then, following 25 min of dark adaptation, a static 0.46-degree-diameter 532 nm stimulus under scotopic conditions). The stimuli were applied over the RPE defect and at reference points of similar eccentricity in the opposite vertical haemifield of the same eye where the RPE remained present. RESULTS: Acute RPE loss was associated with only a marginal reduction of photopic sensitivity (-1.5 dB) but a pronounced loss of scotopic sensitivity (-19.5 dB). CONCLUSION: Our observations show that RPE is essential for scotopic but not for photopic retinal function, supporting the theory that cone photopigment regeneration occurs within the human neurosensory retina independently of the RPE.


Asunto(s)
Epitelio Pigmentado Ocular/patología , Células Fotorreceptoras Retinianas Conos/fisiopatología , Desprendimiento de Retina/complicaciones , Desprendimiento de Retina/patología , Perforaciones de la Retina/patología , Células Fotorreceptoras Retinianas Bastones/fisiopatología , Enfermedad Aguda , Femenino , Fondo de Ojo , Humanos , Persona de Mediana Edad , Desprendimiento de Retina/fisiopatología , Perforaciones de la Retina/etiología , Perforaciones de la Retina/fisiopatología , Tomografía de Coherencia Óptica , Pruebas del Campo Visual , Campos Visuales
19.
Vis Neurosci ; 24(6): 805-16, 2007.
Artículo en Inglés | MEDLINE | ID: mdl-18093368

RESUMEN

The number of L cones in the retina normally exceeds that of the M cones. Because normal color vision does not depend on the ratio of L- and M-photoreceptors, their signals must undergo an alteration in gain before being analyzed in the cortex. Previous studies have shown that this gain must take place before the cortex, but after the bipolar/amacrine cell layer of the retina. The aim of this study was to obtain topographical information about L- and M-cone activity at the ganglion cell layer using multifocal pattern electroretinography (mfPERG). A standard (black and white) stimulus was used, as well as stimuli modulating only the long wavelength-sensitive (L) or only the middle wavelength-sensitive (M) cones. The L:M ratio was calculated from the amplitude of the L-cone isolating mfPERG to that of the M-cone isolating mfPERG of 10 trichromats. Both the positive and negative components of the waveform were analyzed. Additional recordings of single cone modulated mfERGs were obtained from nine of the 10 subjects. We also recorded from one protanope and one deuteranope. The L:M cone amplitude ratios for both deflections of the mfPERG in the trichromats were around unity (medians 1.18 and 1.16, respectively) for the central 8 degrees of retina. In the peripheral retina between 12.8 degrees and 26 degrees , this ratio increased to 1.42 for the positive component, and 1.37 for the negative component. The median L:M cone amplitude ratios for the mfPERG were higher and ranged between 1.00-2.78 in the central 8 degrees and 1.29-2.78 in the periphery. The results indicate that a major gain adjustment of the retinal signals takes place at the ganglion cell level, and that the ratio is higher at eccentric locations than in the central retinal area.


Asunto(s)
Defectos de la Visión Cromática/fisiopatología , Electrorretinografía , Células Fotorreceptoras Retinianas Conos/fisiopatología , Adulto , Color , Percepción de Color , Pruebas de Percepción de Colores , Sensibilidad de Contraste/fisiología , Femenino , Humanos , Masculino , Estimulación Luminosa/métodos , Psicofísica , Tiempo de Reacción , Umbral Sensorial/fisiología , Campos Visuales/fisiología
20.
Eur J Neurosci ; 26(9): 2506-15, 2007 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17970721

RESUMEN

Knowledge about the plastic and regenerative capacity of the retina is of key importance for therapeutic approaches to restore vision in patients who suffer from degenerative retinal diseases. In the retinae of mice, mutant for the presynaptic scaffolding protein Bassoon, signal transfer at photoreceptor ribbon synapses is disturbed due to impaired ribbon attachment to the active zone. In a long-term study we observed, with light and electron microscopic immunocytochemistry and electroretinographic recordings, two overlapping events in the Bassoon mutant retina, i.e. loss of photoreceptor synapses in the outer plexiform layer, and structural remodeling and formation of ectopic photoreceptor synapses in the outer nuclear layer, a region usually devoid of synapses. Formation of ectopic synaptic sites starts around the time when photoreceptor synaptogenesis is completed in wild-type mice and progresses throughout life. The result is a dense plexus of ectopic photoreceptor synapses with significantly altered but considerable synaptic transmission. Ectopic synapse formation is led by the sprouting of horizontal cells followed by the extension of rod bipolar cell neurites that fasciculate with and grow along the horizontal cell processes. Although only the rod photoreceptors and their postsynaptic partners show structural and functional remodeling, our study demonstrates the potential of the retina for long-lasting plastic changes.


Asunto(s)
Regeneración Nerviosa/genética , Plasticidad Neuronal/genética , Células Fotorreceptoras Retinianas Conos/fisiopatología , Degeneración Retiniana/fisiopatología , Células Fotorreceptoras Retinianas Bastones/fisiopatología , Sinapsis/genética , Animales , Diferenciación Celular/genética , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Microscopía Inmunoelectrónica , Proteínas del Tejido Nervioso/genética , Vías Nerviosas/patología , Vías Nerviosas/fisiopatología , Recuperación de la Función/genética , Células Bipolares de la Retina/patología , Células Bipolares de la Retina/fisiología , Células Fotorreceptoras Retinianas Conos/patología , Degeneración Retiniana/genética , Degeneración Retiniana/patología , Células Horizontales de la Retina/patología , Células Horizontales de la Retina/fisiopatología , Células Fotorreceptoras Retinianas Bastones/patología , Sinapsis/ultraestructura , Transmisión Sináptica/genética , Visión Ocular/genética
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