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1.
Invest Ophthalmol Vis Sci ; 54(3): 1603-12, 2013 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-23361506

RESUMEN

PURPOSE: To investigate the relationship between photoreceptor layers overlying and adjacent to large drusen in intermediate nonneovascular AMD. METHODS: Patients with AMD (n = 41; aged 53-83 years) and elderly control subjects without eye disease (n = 10; aged 51-79 years) were studied with spectral-domain optical coherence tomography. Characteristics of large drusen (≥125 µm) were measured and the thickness of photoreceptor laminae overlying drusen and in retinal regions neighboring the drusen were quantified. RESULTS: There were 750 large drusen in 63 intermediate AMD eyes studied. The width of the drusen sampled averaged 352 µm (SD = 153) and the height averaged 78 µm (SD = 31). There was significant reduction of the photoreceptor outer nuclear layer (ONL) thickness overlying 92% of the drusen. The thickness of the layer corresponding to photoreceptor inner and outer segments above drusen was also reduced, and the reduction was proportional to ONL thickness. In a substantial fraction (~20%) of normally laminated paradrusen locations sampled within ~300 µm of peak drusen height, ONL thickness was significantly increased compared with age and retinal location-matched normal values. Topographical analyses of the macula showed ONL thickening occurring in paradrusen regions as well as retinal locations distant from drusen. CONCLUSIONS: Reductions in the photoreceptor laminae overlying drusen were detectable and this is consistent with histological studies revealing neuronal degeneration in AMD. ONL thickening in some macular areas of AMD eyes has not been previously reported and may be an early phenotypic marker for photoreceptor stress, as it has been speculated to be in hereditary retinal degenerations.


Asunto(s)
Degeneración Macular/patología , Células Fotorreceptoras de Vertebrados/patología , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Humanos , Mácula Lútea/patología , Persona de Mediana Edad , Drusas Retinianas/patología , Segmento Externo de las Células Fotorreceptoras Retinianas/patología , Tomografía de Coherencia Óptica
2.
Invest Ophthalmol Vis Sci ; 53(2): 841-52, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22247458

RESUMEN

PURPOSE: To measure macular visual function in patients with unstable fixation, to define the photoreceptor source of this function, and to estimate its test-retest repeatability as a prerequisite to clinical trials. METHODS: Patients (n = 38) with ABCA4-associated retinal degeneration (RD) or with retinitis pigmentosa (RP) were studied with retina-tracking microperimetry along the foveo-papillary profile between the fovea and the optic nerve head, and point-by-point test-retest repeatability was estimated. A subset with foveal fixation was also studied with dark-adapted projection perimetry using monochromatic blue and red stimuli along the horizontal meridian. RESULTS: Macular function in ABCA4-RD patients transitioned from lower sensitivity at the parafovea to higher sensitivity in the perifovea. RP patients had the inverse pattern. Red-on-red microperimetric sensitivities successfully avoided ceiling effects and were highly correlated with absolute sensitivities. Point-by-point test-retest limits (95% confidence intervals) were ±4.2 dB; repeatability was not related to mean sensitivity, eccentricity from the fovea, age, fixation location, or instability. Repeatability was also not related to the local slope of sensitivity and was unchanged in the parapapillary retina. CONCLUSIONS: Microperimetry allows reliable testing of macular function in RD patients without foveal fixation in longitudinal studies evaluating natural disease progression or efficacy of therapeutic trials. A single estimate of test-retest repeatability can be used to determine significant changes in visual function at individual retinal loci within diseased regions that are homogeneous and those that are heterogeneous and also in transition zones at high risk for disease progression.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , ADN/genética , Degeneración Macular/diagnóstico , Mutación , Degeneración Retiniana/diagnóstico , Campos Visuales/fisiología , Transportadoras de Casetes de Unión a ATP/metabolismo , Adolescente , Adulto , Niño , Ensayos Clínicos como Asunto , Adaptación a la Oscuridad , Femenino , Estudios de Seguimiento , Humanos , Degeneración Macular/genética , Degeneración Macular/fisiopatología , Masculino , Persona de Mediana Edad , Degeneración Retiniana/genética , Degeneración Retiniana/fisiopatología , Tomografía de Coherencia Óptica , Agudeza Visual , Pruebas del Campo Visual , Adulto Joven
3.
Invest Ophthalmol Vis Sci ; 52(11): 7924-36, 2011 Oct 07.
Artículo en Inglés | MEDLINE | ID: mdl-21873662

RESUMEN

PURPOSE. To determine the disease course in Usher syndrome type IB (USH1B) caused by myosin 7A (MYO7A) gene mutations. METHODS. USH1B patients (n = 33, ages 2-61) representing 25 different families were studied by ocular examination, kinetic and chromatic static perimetry, dark adaptometry, and optical coherence tomography (OCT). Consequences of the mutant alleles were predicted. RESULTS. All MYO7A patients had severely abnormal ERGs, but kinetic fields revealed regional patterns of visual loss that suggested a disease sequence. Rod-mediated vision could be lost to different degrees in the first decades of life. Cone vision followed a more predictable and slower decline. Central vision ranged from normal to reduced in the first four decades of life and thereafter was severely abnormal. Dark adaptation kinetics was normal. Photoreceptor layer thickness in a wide region of central retina could differ dramatically between patients of comparable ages; and there were examples of severe losses in childhood as well as relative preservation in patients in the third decade of life. Comparisons were made between the mutant alleles in mild versus more severe phenotypes. CONCLUSIONS. A disease sequence in USH1B leads from generally full but impaired visual fields to residual small central islands. At most disease stages, there was preserved temporal peripheral field, a potential target for early phase clinical trials of gene therapy. From data comparing patients' rod disease in this cohort, the authors speculate that null MYO7A alleles could be associated with milder dysfunction and fewer photoreceptor structural losses at ages when other genotypes show more severe phenotypes.


Asunto(s)
Mutación , Miosinas/genética , Degeneración Retiniana/fisiopatología , Síndromes de Usher/fisiopatología , Trastornos de la Visión/fisiopatología , Campos Visuales/fisiología , Adolescente , Adulto , Niño , Preescolar , Adaptación a la Oscuridad , Electrorretinografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Miosina VIIa , Fenotipo , Células Fotorreceptoras de Vertebrados/patología , Degeneración Retiniana/genética , Tomografía de Coherencia Óptica , Síndromes de Usher/genética , Trastornos de la Visión/genética , Pruebas del Campo Visual , Adulto Joven
4.
Invest Ophthalmol Vis Sci ; 51(2): 1079-85, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19797198

RESUMEN

PURPOSE: To determine whether normal function and structure, as recently found in forms of Usher syndrome, also occur in a population of patients with nonsyndromic retinitis pigmentosa (RP). METHODS: Patients with simplex, multiplex, or autosomal recessive RP (n = 238; ages 9-82 years) were studied with static chromatic perimetry. A subset was evaluated with optical coherence tomography (OCT). Co-localized visual sensitivity and photoreceptor nuclear layer thickness were measured across the central retina to establish the relationship of function and structure. Comparisons were made to patients with Usher syndrome (n = 83, ages 10-69 years). RESULTS: Cross-sectional psychophysical data identified patients with RP who had normal rod- and cone-mediated function in the central retina. There were two other patterns with greater dysfunction, and longitudinal data confirmed that progression can occur from normal rod and cone function to cone-only central islands. The retinal extent of normal laminar architecture by OCT corresponded to the extent of normal visual function in patients with RP. Central retinal preservation of normal function and structure did not show a relationship with age or retained peripheral function. Usher syndrome results were like those in nonsyndromic RP. CONCLUSIONS: Regional disease variation is a well-known finding in RP. Unexpected was the observation that patients with presumed recessive RP can have regions with functionally and structurally normal retina. Such patients will require special consideration in future clinical trials of either focal or systemic treatment. Whether there is a common molecular mechanism shared by forms of RP with normal regions of retina warrants further study.


Asunto(s)
Sensibilidad de Contraste/fisiología , Células Fotorreceptoras de Vertebrados/fisiología , Retinitis Pigmentosa/fisiopatología , Campos Visuales/fisiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Visión de Colores/fisiología , Adaptación a la Oscuridad/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Células Fotorreceptoras de Vertebrados/patología , Retinitis Pigmentosa/diagnóstico , Estudios Retrospectivos , Tomografía de Coherencia Óptica , Síndromes de Usher/diagnóstico , Síndromes de Usher/fisiopatología , Pruebas del Campo Visual
5.
Hum Mol Genet ; 18(5): 931-41, 2009 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-19074458

RESUMEN

Autosomal recessive retinal diseases caused by mutations in the ABCA4 gene are being considered for gene replacement therapy. All individuals with ABCA4-disease show macular degeneration, but only some are thought to progress to retina-wide blindness. It is currently not predictable if or when specific ABCA4 genotypes will show extramacular disease, and how fast it will progress thereafter. Early clinical trials of focal subretinal gene therapy will aim to arrest disease progression in the extramacular retina. In 66 individuals with known disease-causing ABCA4 alleles, we defined retina-wide disease expression by measuring rod- and cone-photoreceptor-mediated vision. Serial measurements over a mean period of 8.7 years were consistent with a model wherein a normal plateau phase of variable length was followed by initiation of retina-wide disease that progressed exponentially. Once initiated, the mean rate of disease progression was 1.1 log/decade for rods and 0.45 log/decade for cones. Spatio-temporal progression of disease could be described as the sum of two components, one with a central-to-peripheral gradient and the other with a uniform retina-wide pattern. Estimates of the age of disease initiation were used as a severity metric and contributions made by each ABCA4 allele were predicted. One-third of the non-truncating alleles were found to cause more severe disease than premature truncations supporting the existence of a pathogenic component beyond simple loss of function. Genotype-based inclusion/exclusion criteria and prediction of the age of retina-wide disease initiation will be invaluable for selecting appropriate candidates for clinical trials in ABCA4 disease.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Progresión de la Enfermedad , Terapia Genética/tendencias , Enfermedades de la Retina/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Niño , Estudios de Cohortes , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Mutación , Linaje , Enfermedades de la Retina/patología , Enfermedades de la Retina/fisiopatología , Enfermedades de la Retina/terapia , Adulto Joven
6.
Invest Ophthalmol Vis Sci ; 48(10): 4759-65, 2007 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-17898302

RESUMEN

PURPOSE: To investigate in vivo the retinal microstructure in X-linked retinitis pigmentosa (XLRP) caused by RPGR mutations as a prelude to treatment initiatives for this common form of RP. METHODS: Patients with RPGR-XLRP (n = 12; age range, 10-56 years) were studied by optical coherence tomography (OCT) in a wide region of central retina. Overall retinal thickness and outer nuclear layer (ONL) and inner retinal parameters across horizontal and vertical meridians were analyzed and compared. RESULTS: Retinal architecture of all patients with RPGR mutations was abnormal. At the fovea in younger patients, the ONL could be normal; but, at increasing eccentricities, there was a loss of photoreceptor laminar structure, even at the youngest ages studied. At later ages and advanced disease stages, the ONL was thin and reduced in extent. Inner retinal thickness, in contrast, was normal or hyperthick. Inner retinal thickening was detectable at all ages studied and was strongly associated with ONL loss. CONCLUSIONS: Inner retinal laminar abnormalities in RPGR-XLRP are likely to reflect a neuronal-glial retinal remodeling response to photoreceptor loss and are detectable relatively early in the disease course. These results should be factored into emerging therapeutic strategies for this form of RP.


Asunto(s)
Proteínas del Ojo/genética , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Mutación , Retina/patología , Retinitis Pigmentosa/diagnóstico , Adolescente , Adulto , Niño , Preescolar , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Humanos , Persona de Mediana Edad , Neuroglía/patología , Neuronas/patología , Retinitis Pigmentosa/genética , Tomografía de Coherencia Óptica
7.
Invest Ophthalmol Vis Sci ; 48(3): 1319-29, 2007 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-17325179

RESUMEN

PURPOSE: To determine macular pigment (MP) optical density (OD) in patients with ABCA4-associated retinal degenerations (ABCA4-RD) and the response of MP and vision to supplementation with lutein. METHODS: Patients with Stargardt disease or cone-rod dystrophy and known or suspected disease-causing mutations in the ABCA4 gene were included. All patients had foveal fixation. MPOD profiles were measured with heterochromatic flicker photometry. Serum carotenoids, visual acuity, foveal sensitivity, and retinal thickness were quantified. Changes in MPOD and central vision were determined in a subset of patients receiving oral supplementation with lutein for 6 months. RESULTS: MPOD in patients ranged from normal to markedly abnormal. As a group, patients with ABCA4-RD had reduced foveal MPOD, and there was a strong correlation with retinal thickness. Average foveal tissue concentration of MP, estimated by dividing MPOD by retinal thickness, was normal in patients, whereas serum concentration of lutein and zeaxanthin was significantly lower than normal. After oral lutein supplementation for 6 months, 91% of the patients showed significant increases in serum lutein, and 63% of the patients' eyes showed a significant augmentation in MPOD. The retinal responders tended to be female and to have lower serum lutein and zeaxanthin, lower MPOD, and greater retinal thickness at baseline. Responding eyes had significantly lower baseline MP concentration than did nonresponding eyes. Central vision was unchanged after the period of supplementation. CONCLUSIONS: MP is strongly affected by the stage of ABCA4 disease leading to abnormal foveal architecture. MP could be augmented by supplemental lutein in some patients. There was no change in central vision after 6 months of lutein supplementation. Long-term influences of this supplement on the natural history of these macular degenerations require further study.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Luteína/administración & dosificación , Luteína/metabolismo , Retina/metabolismo , Degeneración Retiniana/metabolismo , Pigmentos Retinianos/metabolismo , Xantófilas/metabolismo , Administración Oral , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fotometría , Proyectos Piloto , Retina/patología , Degeneración Retiniana/genética , Tomografía de Coherencia Óptica , Agudeza Visual/efectos de los fármacos , Zeaxantinas , beta Caroteno/sangre
8.
Invest Ophthalmol Vis Sci ; 47(11): 5004-10, 2006 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17065520

RESUMEN

PURPOSE: To define the retinal phenotype in patients with the Bardet-Biedl syndrome and mutations in the BBS1 gene. METHODS: Ten patients (age range, 16-48 years), representing eight pedigrees, with BBS1 gene mutations were studied clinically and with kinetic perimetry, chromatic static perimetry, electroretinography (ERG), and optical coherence tomography. RESULTS: Of the 10 patients, 8 were M390R homozygotes and 2 were compound heterozygotes with one allele also M390R. A spectrum of retinal disease expression was present. The mildest disease was a subtle maculopathy with relatively limited peripheral retinal dysfunction. Moderate disease showed retina-wide rod > cone dysfunction, and often there was a negative ERG waveform. More severe disease expression had different patterns: either loss of central function but retained abnormal peripheral function or a retained small central island of impaired function only. Moderate and severe disease showed loss of retinal and photoreceptor layer thickness across wide expanses of retina. Severity differed in family members and was independent of age. In addition, severity was not explained by genotype at a recently reported BBS epistatic gene, MGC1203. CONCLUSIONS: The cardinal feature of retinal degeneration in BBS1 can show a wide spectrum of disease expression.


Asunto(s)
Síndrome de Bardet-Biedl/genética , Mutación , Proteínas/genética , Degeneración Retiniana/genética , Anomalías Múltiples/genética , Anomalías Múltiples/fisiopatología , Adolescente , Adulto , Síndrome de Bardet-Biedl/fisiopatología , Electrorretinografía , Femenino , Expresión Génica , Humanos , Masculino , Proteínas Asociadas a Microtúbulos , Persona de Mediana Edad , Fenotipo , Retina/fisiopatología , Degeneración Retiniana/fisiopatología , Tomografía de Coherencia Óptica , Agudeza Visual , Pruebas del Campo Visual , Campos Visuales
9.
Hum Mol Genet ; 13(5): 525-34, 2004 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-14709597

RESUMEN

Mutations in ABCA4, which encodes a photoreceptor specific ATP-binding cassette transporter (ABCR), cause autosomal recessive forms of human blindness due to retinal degeneration (RD) including Stargardt disease. The exact disease sequence leading to photoreceptor and vision loss in ABCA4-RD is not known. Extrapolation from murine and in vitro studies predicts that two of the earliest pathophysiological features resulting from disturbed ABCR function in man would be slowed kinetics of the retinoid cycle and accelerated deposition of lipofuscin in the retinal pigment epithelium (RPE). To determine the human pathogenetic sequence, we studied surrogate measures of retinoid cycle kinetics, lipofuscin accumulation, and rod and cone photoreceptor and RPE loss in ABCA4-RD patients with a wide spectrum of disease severities. There were different extents of photoreceptor/RPE loss and lipofuscin accumulation in different regions of the retina. Slowing of retinoid cycle kinetics was not present in all patients; when present, it was not homogeneous across the retina; and the extent of slowing correlated well with the degree of degeneration. The orderly relationship between these phenotypic features permitted the development of a model of disease sequence in ABCA4-RD. The model predicted lipofuscin accumulation as a key and early component of the disease expression in man, as in mice. In man, however, abnormal slowing of the rod and cone retinoid cycle occurs at later stages of the disease sequence. Knowledge of the human ABCA4 disease sequence will be critical for defining rates of progression, selecting appropriate patients and retinal locations for future therapy, and choosing appropriate treatment outcomes.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Lipofuscina/metabolismo , Modelos Biológicos , Fenotipo , Degeneración Retiniana/metabolismo , Adulto , Adaptación a la Oscuridad/fisiología , Progresión de la Enfermedad , Fluorescencia , Genes Recesivos , Humanos , Cinética , Persona de Mediana Edad , Mutación/genética , Estimulación Luminosa , Células Fotorreceptoras de Vertebrados/metabolismo , Epitelio Pigmentado Ocular/metabolismo , Degeneración Retiniana/fisiopatología
10.
Exp Eye Res ; 74(3): 371-81, 2002 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-12014918

RESUMEN

Choroideremia is an incurable X-linked retinal degeneration caused by mutations in the gene encoding Rab escort protein-1. A group of clinically defined and genotyped patients were studied to determine: (1) the degree of rod and cone dysfunction and structural abnormality in the central retina and the level of macular pigment; and (2) the response of macular pigment and foveal vision to a 6 month trial of supplementation with oral lutein (at 20 mg per day). Rod and cone-mediated function was measured with dark-adapted static perimetry; in vivo retinal structure was determined with optical coherence tomography; and macular pigment optical density was measured with heterochromatic flicker photometry. In this cohort of patients (ages 15-65 years), both rod- and cone-mediated central function declined with age as did central retinal thickness. Macular pigment levels did not differ between patients and male control subjects. Supplementation of oral lutein in a subset of patients led to an increase in serum lutein and macular pigment levels; absolute foveal sensitivity did not change. It is concluded that macular pigment density can be augmented by oral intake of lutein in patients with choroideremia. There was no short-term change in the central vision of the patients on the supplement, but long-term influences of lutein supplementation on disease natural history warrant further study.


Asunto(s)
Coroideremia/tratamiento farmacológico , Suplementos Dietéticos , Luteína/uso terapéutico , Mácula Lútea/metabolismo , Pigmentos Retinianos/metabolismo , Adolescente , Adulto , Anciano , Envejecimiento/fisiología , Coroideremia/metabolismo , Coroideremia/fisiopatología , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Células Fotorreceptoras de Vertebrados/fisiología , Agudeza Visual , Pruebas del Campo Visual
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