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OBJECTIVE: To detect peripheral artery disease in diabetic and non-diabetic individuals. METHODS: The case-control study was conducted from October 2018 to September 2019 at Ruth K.M. Pfau Civil Hospital, Karachi, and comprised diagnosed diabetic patients with random blood sugar ≥200mg/dl in group A, and healthy non-diabetic subjects in group B. Ankle brachial pressure index was measured and mean luminal diameters of lower limb arteries were compared using colour Doppler ultrasonography. Data was analysed using SPSS 21. RESULTS: Of the 82 subjects, 41(50%) were in each of the 2 groups. The sample had 42(51.2%) males and 30(48.8%) females with overall mean age of 53.9±5.07 years (range 44-60 years). There was significant difference in the ankle brachial pressure index values between the groups (p=0.004). There was also a significant difference in the mean luminal diameters of distal arteries (p=0.001), while there was no significant difference in proximal arteries (p>0.05). CONCLUSIONS: The diabetics were more prone to developing peripheral arterial disease than nondiabetics.
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Diabetes Mellitus , Enfermedad Arterial Periférica , Masculino , Femenino , Humanos , Adulto , Persona de Mediana Edad , Estudios de Casos y Controles , Enfermedad Arterial Periférica/diagnóstico por imagen , Enfermedad Arterial Periférica/epidemiología , Arterias , Extremidad Inferior/diagnóstico por imagenRESUMEN
The use of AAV-RPE65 vectors for gene supplementation has achieved spectacular success as a treatment for individuals with autosomal recessive retinal disease caused by biallelic mutations in the visual cycle gene RPE65. However, the efficacy of this approach in treating autosomal dominant retinitis pigmentosa (adRP) associated with a monoallelic mutation encoding a rare D477G RPE65 variant has not been studied. Although lacking a severe phenotype, we now find that knock-in mice heterozygous for D477G RPE65 (D477G KI mice) can be used to evaluate outcomes of AAV-RPE65 gene supplementation. Total RPE65 protein levels, which are decreased in heterozygous D477G KI mice, were doubled following subretinal delivery of rAAV2/5.hRPE65p.hRPE65. In addition, rates of recovery of the chromophore 11-cis retinal after bleaching were significantly increased in eyes that received AAV-RPE65, consistent with increased RPE65 isomerase activity. While dark-adapted chromophore levels and a-wave amplitudes were not affected, b-wave recovery rates were modestly improved. The present findings establish that gene supplementation enhances 11-cis retinal synthesis in heterozygous D477G KI mice and complement previous studies showing that chromophore therapy results in improved vision in individuals with adRP associated with D477G RPE65.
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Retina , Retinitis Pigmentosa , Animales , Ratones , cis-trans-Isomerasas/genética , cis-trans-Isomerasas/metabolismo , Proteínas del Ojo/genética , Proteínas del Ojo/metabolismo , Mutación , Retina/metabolismo , Retinitis Pigmentosa/genética , Retinitis Pigmentosa/terapia , Retinitis Pigmentosa/metabolismoRESUMEN
SUMMARY: In elasmobranch fishes, variations in gross structural organization of cerebellum has been extensively explored. The basic histological features of cerebellum although conserved in the group but the comparative account on subtle cellular variations is largely underestimated. The present study aims to explore the histological and cellular variations in different layers of cerebellar cortex of the representative elasmobranchs' species belonging to different habitat. Our findings showed that the histological architecture of cerebellar granular layer between the examined species varies noticeably. By and large increase cellular density were observed in all the layers of cerebellum in the representative species of shark compared to ray. The findings were then compared and discussed with reference to their habitat and behavior.
En los peces elasmobranquios, las variaciones en la organización estructural general del cerebelo se han explorado ampliamente. Las características histológicas básicas del cerebelo, aunque se conservan en el grupo, pero la descripción comparativa de las variaciones celulares sutiles es limitada. El presente estudio tiene como objetivo explorar las variaciones histológicas y celulares en diferentes capas de la corteza cerebelosa de las especies representativas de elasmobranquios pertenecientes a diferentes hábitats. Nuestros hallazgos mostraron que la arquitectura histológica de la capa granular del cerebelo entre las especies examinadas varía notablemente. Se observó un gran aumento de la densidad celular en todas las capas del cerebelo en las especies representativas de tiburón en comparación con la raya. Luego, los hallazgos se compararon y discutieron con referencia a su hábitat y comportamiento.
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Animales , Cerebelo/anatomía & histología , Elasmobranquios/anatomía & histología , Evolución BiológicaRESUMEN
Purpose: Mutations in USH2A gene are responsible for the greatest proportion of the Usher Syndrome (USH) population, among which more than 30% are frameshift mutations on exon 13. A clinically relevant animal model has been absent for USH2A-related vision loss. Here we sought to establish a rabbit model carrying USH2A frameshift mutation on exon 12 (human exon 13 equivalent). Methods: CRISPR/Cas9 reagents targeting the rabbit USH2A exon 12 were delivered into rabbit embryos to produce an USH2A mutant rabbit line. The USH2A knockout animals were subjected to a series of functional and morphological analyses, including acoustic auditory brainstem responses, electroretinography, optical coherence tomography, fundus photography, fundus autofluorescence, histology, and immunohistochemistry. Results: The USH2A mutant rabbits exhibit hyper-autofluorescent signals on fundus autofluorescence and hyper-reflective signals on optical coherence tomography images as early as 4 months of age, which indicate retinal pigment epithelium damage. Auditory brainstem response measurement in these rabbits showed moderate to severe hearing loss. Electroretinography signals of both rod and cone function were decreased in the USH2A mutant rabbits starting from 7 months of age and further decreased at 15 to 22 months of age, indicating progressive photoreceptor degeneration, which is confirmed by histopathological examination. Conclusions: Disruption of USH2A gene in rabbits is sufficient to induce hearing loss and progressive photoreceptor degeneration, mimicking the USH2A clinical disease. Translational Relevance: To our knowledge, this study presents the first mammalian model of USH2 showing the phenotype of retinitis pigmentosa. This study supports the use of rabbits as a clinically relevant large animal model to understand the pathogenesis and to develop novel therapeutics for Usher syndrome.
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Degeneración Retiniana , Retinitis Pigmentosa , Síndromes de Usher , Humanos , Animales , Conejos , Síndromes de Usher/genética , Síndromes de Usher/patología , Degeneración Retiniana/genética , Mutación , Mamíferos , Proteínas de la Matriz Extracelular/genéticaRESUMEN
We previously identified a homozygous G178R mutation in human ASRGL1 (hASRGL1) through whole-exome analysis responsible for early onset retinal degeneration (RD) in patients with cone-rod dystrophy. The mutant G178R ASRGL1 expressed in Cos-7 cells showed altered localization, while the mutant ASRGL1 in E. coli lacked the autocatalytic activity needed to generate the active protein. To evaluate the effect of impaired ASRGL1 function on the retina in vivo, we generated a mouse model with c.578_579insAGAAA (NM_001083926.2) mutation (Asrgl1mut/mut) through the CRISPR/Cas9 methodology. The expression of ASGRL1 and its asparaginase activity were undetectable in the retina of Asrgl1mut/mut mice. The ophthalmic evaluation of Asrgl1mut/mut mice showed a significant and progressive decrease in scotopic electroretinographic (ERG) response observed at an early age of 3 months followed by a decrease in photopic response around 5 months compared with age-matched wildtype mice. Immunostaining and RT-PCR analyses with rod and cone cell markers revealed a loss of cone outer segments and a significant decrease in the expression of Rhodopsin, Opn1sw, and Opn1mw at 3 months in Asrgl1mut/mut mice compared with age-matched wildtype mice. Importantly, the retinal phenotype of Asrgl1mut/mut mice is consistent with the phenotype observed in patients harboring the G178R mutation in ASRGL1 confirming a critical role of ASRGL1 in the retina and the contribution of ASRGL1 mutations in retinal degeneration.
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Autoantígenos , Degeneración Retiniana , Animales , Humanos , Lactante , Ratones , Asparaginasa/genética , Autoantígenos/metabolismo , Modelos Animales de Enfermedad , Escherichia coli , Ratones Endogámicos C57BL , Péptido Hidrolasas/genética , Fenotipo , Degeneración Retiniana/metabolismoRESUMEN
OBJECTIVE: To compare the sphenoid volume between the genders and to analyse variations in septal insertions on bony wall of optic nerve and internal carotid artery. METHODS: The prospective study was conducted from October 2020 to February 2021 at the Radiology Department of Dow University of Health Sciences, Karachi, and comprised paranasal sinus patients of either gender aged 20-60 without any bony deformity of sphenoid sinus who were analysed for sphenoid volume, number of septa and variable septal insertions using computed tomography of paranasal sinus. On the basis of septal insertions, the scans were categorised into Group 1 with no risky septal insertion, Group 2 with septal insertion on bony wall of optic nerve, Group 3 with septal insertion of internal carotid artery, and Group 4 with septal insertion on both optic nerve and internal carotid artery. Differences in sphenoid volume were analysed between males and females and among the four groups. Data was analysed using Graph Pad Prism 9. RESULTS: Of the 300 patients, 171(57%) were males and 129(43%) were females. The overall mean age was 39.28±10.9 years. Multiple septa were found in 208(69.3%) of the sinuses. There were 129(43.7%) patients in Group 1, 34(11.3%) in Group 2, 119(39%) in Group 3 and 18(6%) in Group 4. Significant difference was found between volume and gender as well as among the four groups (p<0.001). CONCLUSIONS: The sphenoid volume between the genders and the variations in septal insertions on bony wall of optic nerve and internal carotid artery were significantly different.
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Hueso Esfenoides , Seno Esfenoidal , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pakistán , Estudios Prospectivos , Hueso Esfenoides/diagnóstico por imagen , Seno Esfenoidal/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodosRESUMEN
Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by expansion of a polyglutamine (polyQ)-encoding CAG repeat in the ATXN3 gene. Because the ATXN3 protein regulates photoreceptor ciliogenesis and phagocytosis, we aimed to explore whether expanded polyQ ATXN3 impacts retinal function and integrity in SCA3 patients and transgenic mice. We evaluated the retinal structure and function in five patients with SCA3 and in a transgenic mouse model of this disease (YACMJD84.2, Q84) using optical coherence tomography (OCT) and electroretinogram (ERG). In the transgenic mice, we further: a) determined the retinal expression pattern of ATXN3 and the distribution of cones and rods using immunofluorescence (IF); and b) assessed the retinal ultrastructure using transmission electron microscopy (TEM). Some patients with SCA3 in our cohort revealed: i) reduced central macular thickness indirectly correlated with disease duration; ii) decreased thickness of the macula and the ganglion cell layer, and reduced macula volume inversely correlated with disease severity (SARA score); and iii) electrophysiological dysfunction of cones, rods, and inner retinal cells. Transgenic mice replicated the human OCT and ERG findings with aged homozygous Q84/Q84 mice showing a stronger phenotype accompanied by further thinning of the outer nuclear layer and photoreceptor layer and highly reduced cone and rod activities, thus supporting severe retinal dysfunction in these mice. In addition, Q84 mice showed progressive accumulation of ATXN3-positive aggregates throughout several retinal layers and depletion of cones alongside the disease course. TEM analysis of aged Q84/Q84 mouse retinas supported the ATXN3 aggregation findings by revealing the presence of high number of negative electron dense puncta in ganglion cells, inner plexiform and inner nuclear layers, and showed further thinning of the outer plexiform layer, thickening of the retinal pigment epithelium and elongation of apical microvilli. Our results indicate that retinal alterations detected by non-invasive eye examination using OCT and ERG could represent a biological marker of disease progression and severity in patients with SCA3.
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Enfermedad de Machado-Joseph , Anciano , Animales , Ataxina-3/genética , Ataxina-3/metabolismo , Modelos Animales de Enfermedad , Humanos , Enfermedad de Machado-Joseph/genética , Enfermedad de Machado-Joseph/metabolismo , Ratones , Ratones Transgénicos , Retina/metabolismoRESUMEN
BACKGROUND: Self-determination theory (SDT) of human motivation was used to examine associations between different forms of motivation in Argus II retinal prosthesis users and their engagement and satisfaction with the Argus device. MATERIALS AND METHODS: Nine subjects were administered: 1) a Situational Motivation Scale (SIMS) questionnaire to measure intrinsic motivation, identified regulation, external regulation, and amotivation, and 2) the Argus questionnaire (AQ) which was organized into 5 categories to measure 'Decision to get an Argus implant,' 'Self-perception as an Argus user', 'Utility of Argus,' 'Perceived competence,' and 'Family support.' Spearman correlations (rs) were used to find associations between measures from SIMS and AQ. RESULTS: Nine subjects completed both questionnaires. Statistically significant associations were observed between identified regulation and AQ items from categories: Decision to get Argus, Self-perception, Utility of Argus, and Perceived competence; and between intrinsic motivation and AQ items from Self-perception and Utility. External regulation was negatively associated with Family support, and amotivation was associated with one item from Self-perception. Engagement with the device and satisfaction were associated to both identified regulation and intrinsic motivation. There was no significant relationship between external regulation and adherence to the device. CONCLUSIONS: The SDT model can be used to investigate the types of motivation that influence uptake and engagement of the Argus device. Clinicians can use this knowledge to improve outcomes by supporting confidence in users and by encouraging them to maintain internalization and continued commitment to adherence.
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Autonomía Personal , Prótesis Visuales , Humanos , Motivación , Satisfacción Personal , Encuestas y CuestionariosRESUMEN
Purpose: Photoacoustic tomography (PAT) has demonstrated the ability to characterize molecular components and architectural heterogeneities of intraocular tumors in enucleated human globes and in animals in vivo. Although laser safety levels have been established for illumination through the cornea, the safety limit for PAT illumination through the sclera has not been investigated. The purpose of this study is to examine if the energy level used in intraocular PAT results in ocular damage. Methods: Rabbit eyes were exposed to pulsed laser illumination at 20 mJ/cm2 at the scleral surface. Eyes were examined at 1, 7, and 28 days after the laser exposure. Examination procedures included white light and fluorescence fundus imaging, optical coherence tomography (OCT), electroretinography (ERG), and histology with hematoxylin and eosin (H&E) staining as well as terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL staining). Results: Fundus imaging and OCT of rabbit eyes at 1, 7, and 28 days following exposure of the laser illumination of the PAT system did not reveal any damage to the retinal structures. ERG showed no significant difference between the experimental and control eyes. Similarly, H&E histology did not show abnormalities in either the scleral tissue where the laser illumination was delivered or in the retinal layers. No sign of apoptosis in the layers of the retina, choroid, or optic nerve was found on TUNEL staining. Conclusions: Similar to the application of PAT to other organs, the proposed laser illumination energy level at 20 mJ/cm2 does not impose detectable harm to the ocular tissue. Translational Relevance: This study addresses illumination safety issues for PAT.
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Coroides , Neoplasias , Animales , Coroides/patología , Electrorretinografía , Neoplasias/patología , Conejos , Retina/diagnóstico por imagen , Tomografía de Coherencia Óptica/métodosRESUMEN
PURPOSE: To investigate real-world safety and efficacy of voretigene neparvovec gene therapy administration in pediatric patients with biallelic RPE65 disease-causing variants. METHODS: A retrospective study of 27 eyes of 14 patients with RPE65-associated Leber congenital amaurosis examined postoperative complications and longitudinal changes in photoreceptor function following treatment with subretinal injection of voretigene neparvovec. Full-field stimulus threshold testing (FST), Goldmann visual fields (GVF), best-corrected visual acuity (BCVA), and central subfield thickness (CST) on optical coherence tomography (OCT) scans were collected preoperatively and up to 12 months posttreatment. RESULTS: Baseline through 6-12 month follow-up FST and GVF data were obtained for 13 eyes of 7 patients. FST improved for each eye after treatment with a mean improvement of 2.1 log-units (P < 0.001) and GVF improved for each eye with a mean improvement of 221 sum degrees (P < 0.001). BCVA improved from logMAR 0.98 at baseline to logMAR 0.83 at last follow-up (P < 0.001). Across 19 eyes of 10 patients included in CST analysis, there was a small but statistically significant 9-µ decrease in mean CST from baseline to last follow-up (P < 0.001). The most common postoperative issues included elevation in intraocular pressure (59%), persistent intraocular inflammation (15%), and vitreous opacities (26%) that resolved over a period of months. CONCLUSIONS: This report provides some of the earliest longitudinal real-world evidence of the pediatric safety and efficacy of voretigene neparvovec using multiple functional and structural measures of the retina. Outcomes demonstrate significant improvements in visual function consistent with clinical trial results.
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Amaurosis Congénita de Leber , Niño , Humanos , Amaurosis Congénita de Leber/diagnóstico , Amaurosis Congénita de Leber/genética , Amaurosis Congénita de Leber/terapia , Mutación , Retina , Estudios Retrospectivos , Tomografía de Coherencia Óptica , Agudeza Visual , cis-trans-Isomerasas/genéticaRESUMEN
Patients with inherited retinal dystrophies (IRDs) were recruited from two understudied populations: Mexico and Pakistan as well as a third well-studied population of European Americans to define the genetic architecture of IRD by performing whole-genome sequencing (WGS). Whole-genome analysis was performed on 409 individuals from 108 unrelated pedigrees with IRDs. All patients underwent an ophthalmic evaluation to establish the retinal phenotype. Although the 108 pedigrees in this study had previously been examined for mutations in known IRD genes using a wide range of methodologies including targeted gene(s) or mutation(s) screening, linkage analysis and exome sequencing, the gene mutations responsible for IRD in these 108 pedigrees were not determined. WGS was performed on these pedigrees using Illumina X10 at a minimum of 30X depth. The sequence reads were mapped against hg19 followed by variant calling using GATK. The genome variants were annotated using SnpEff, PolyPhen2, and CADD score; the structural variants (SVs) were called using GenomeSTRiP and LUMPY. We identified potential causative sequence alterations in 61 pedigrees (57%), including 39 novel and 54 reported variants in IRD genes. For 57 of these pedigrees the observed genotype was consistent with the initial clinical diagnosis, the remaining 4 had the clinical diagnosis reclassified based on our findings. In seven pedigrees (12%) we observed atypical causal variants, i.e. unexpected genotype(s), including 4 pedigrees with causal variants in more than one IRD gene within all affected family members, one pedigree with intrafamilial genetic heterogeneity (different affected family members carrying causal variants in different IRD genes), one pedigree carrying a dominant causative variant present in pseudo-recessive form due to consanguinity and one pedigree with a de-novo variant in the affected family member. Combined atypical and large structural variants contributed to about 20% of cases. Among the novel mutations, 75% were detected in Mexican and 50% found in European American pedigrees and have not been reported in any other population while only 20% were detected in Pakistani pedigrees and were not previously reported. The remaining novel IRD causative variants were listed in gnomAD but were found to be very rare and population specific. Mutations in known IRD associated genes contributed to pathology in 63% Mexican, 60% Pakistani and 45% European American pedigrees analyzed. Overall, contribution of known IRD gene variants to disease pathology in these three populations was similar to that observed in other populations worldwide. This study revealed a spectrum of mutations contributing to IRD in three populations, identified a large proportion of novel potentially causative variants that are specific to the corresponding population or not reported in gnomAD and shed light on the genetic architecture of IRD in these diverse global populations.
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Etnicidad/genética , Degeneración Retiniana/genética , Consanguinidad , Análisis Mutacional de ADN/métodos , Exoma/genética , Proteínas del Ojo/genética , Femenino , Estudios de Asociación Genética/métodos , Ligamiento Genético/genética , Genotipo , Humanos , Masculino , México , Mutación/genética , Pakistán , Linaje , Retina/patología , Secuenciación del Exoma/métodos , Secuenciación Completa del Genoma/métodosRESUMEN
Background: Several novel treatments of inherited retinal degenerations have undergone phase I/IIa clinical trials with limited sample size, yet investigators must still determine if toxicity or an efficacy signal occurred or if the change was due to test-retest variability (TRV) of the measurement tool.Materials and Methods: Synthetic datasets were used to compare three types of TRV estimators under different sample sizes, mean drift, skewness, and number of baseline measurements.Results: Mixed effects models underestimated the standard deviation of measurement error (SDEM); the unbiased change score estimator method (UBS) was more accurate. The fixed effect model had less bias and smaller standard deviation than UBS if >2 baseline measurements. The change score estimator had no bias; other estimators introduced bias for lower variability. With sample size <10, all estimators had high variance. With sample size ≥10, the differences between methods were often minimal. The pooled estimator model did not capture drift, whereas a fixed effect regression or mixed effects models accounted for drift while maintaining an accurate measure of variance. With small sample sizes, the bootstrap estimates of SDEM were severe underestimates, while the jackknife estimates were mildly low but much better. The jackknife was more accurate for the unbiased change score method than for the pooled estimator.Conclusions: The ideal phase I/IIa study has ≥20 subjects and uses UBS or its fixed effect model generalization if >2 baseline measurements. With non-ideal study parameters, investigators should at least quantify the error estimate present in their data analysis.
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Terapia Genética , Reproducibilidad de los Resultados , Degeneración Retiniana/terapia , Sesgo , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Conjuntos de Datos como Asunto , Electrorretinografía , Humanos , Método de Montecarlo , Retina/fisiopatología , Degeneración Retiniana/fisiopatología , Tamaño de la Muestra , Agudeza Visual/fisiología , Pruebas del Campo VisualRESUMEN
Photoacoustic microscopy (PAM) has significant potential as a promising diagnostic method for eye diseases and can provide anatomic and functional information of the retinal and choroidal vasculature. However, there are no FDA-approved PAM systems for ophthalmic imaging. In this study, a comprehensive safety evaluation was performed to evaluate the safety of PAM retinal imaging and whether PAM causes damage to retinal structure or function in rabbit eyes. 12 Dutch-Belted pigmented rabbits received photoacoustic imaging to 57% of the retinal surface area with a laser energy of 5% of the ANSI safety limit for five consecutive days and followed before imaging and 3 days, 1, 2, 3, and 4 weeks post imaging. Retinal morphologic analyses using slit lamp examination, fundus photography, red free, FA, FAF, ICGA, and OCT showed no retinal hemorrhage, edema, detachment, vascular abnormalities, or pigmentary abnormalities in the retina or choroid after PAM imaging. Full-field ERG analysis showed no significant difference in scotopic or photopic a- and b-wave amplitudes or implicit times between the control and experimental eyes over time (n = 6, P values > 0.05). Retinal ultrastructural evaluation using TEM showed normal structure of organelles and nuclei, and no significant loss of cells after PAM. TUNEL assay showed no evidence of cells apoptosis in retina. Retinal histopathology indicated that the architecture and thickness of the retinal layers was well preserved in all experimental eyes. A positive control at 500% of the ANSI limit demonstrated significant damage. The comprehensive retinal safety evaluation demonstrated no damage to retinal structure or function for 4 weeks after PAM imaging in rabbits.
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Microscopía Acústica/métodos , Técnicas Fotoacústicas/métodos , Retina/diagnóstico por imagen , Animales , Modelos Animales , Conejos , Reproducibilidad de los Resultados , Vasos Retinianos/diagnóstico por imagenRESUMEN
Purpose: The purpose of this study was to evaluate baseline best corrected visual acuity (BCVA), full-field electroretinography (ERG), full-field stimulus thresholds (FST), and their relationship with baseline demographic and clinical characteristics in the Rate of Progression in Usher syndrome type 2 (USH2A)-related Retinal Degeneration (RUSH2A) multicenter study. Methods: Participants had Usher syndrome type 2 (USH2, N = 80) or autosomal recessive nonsyndromic retinitis pigmentosa (ARRP, N = 47) associated with biallelic variants in the USH2A gene. Associations of demographic and clinical characteristics with BCVA, ERG, and FST were assessed with regression models. Results: In comparison to ARRP, USH2 had worse BCVA (median 79 vs. 82 letters; P < 0.001 adjusted for age), lower rod-mediated ERG b-wave amplitudes (median 0.0 vs. 6.6 µV; P < 0.001) and 30 Hz flicker cone-mediated ERG amplitudes (median 1.5 vs. 3.1 µV; P = 0.001), and higher (white, blue, and red) FST thresholds (means [-26, -31, -23 dB] vs. [-39, -45, -28 dB]; P < 0.001 for all stimuli). After adjusting for age, gender, and duration of vision loss, the difference in BCVA between diagnosis groups was attenuated (P = 0.09). Only diagnosis was associated with rod- and cone-mediated ERG parameters, whereas both genders (P = 0.04) and duration of visual loss (P < 0.001) also were associated with FST white stimulus. Conclusions: USH2 participants had worse BCVA, ERG, and FST than ARRP participants. FST was strongly associated with duration of disease; it remains to be determined whether it will be a sensitive measure of progression. Translational Relevance: Using standardized research protocols in RUSH2A, measures have been identified to monitor disease progression and treatment response and differentiate features of prognostic relevance between USH2 and ARRP participants with USH2A mutations.
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Retinitis Pigmentosa , Síndromes de Usher , Electrorretinografía , Femenino , Humanos , Masculino , Agudeza Visual , Campos VisualesRESUMEN
Expansion of a CAG repeat in ATXN3 causes the dominant polyglutamine disease spinocerebellar ataxia type 3 (SCA3), yet the physiological role of ATXN3 remains unclear. Here, we focus on unveiling the function of Ataxin-3 (ATXN3) in the retina, a neurological organ amenable to morphological and physiological studies. Depletion of Atxn3 in zebrafish and mice causes morphological and functional retinal alterations and, more precisely, photoreceptor cilium and outer segment elongation, cone opsin mislocalization, and cone hyperexcitation. ATXN3 localizes at the basal body and axoneme of the cilium, supporting its role in regulating ciliary length. Abrogation of Atxn3 expression causes decreased levels of the regulatory protein KEAP1 in the retina and delayed phagosome maturation in the retinal pigment epithelium. We propose that ATXN3 regulates two relevant biological processes in the retina, namely, ciliogenesis and phagocytosis, by modulating microtubule polymerization and microtubule-dependent retrograde transport, thus positing ATXN3 as a causative or modifier gene in retinal/macular dystrophies.
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Ataxina-3/metabolismo , Cilios/metabolismo , Retina/metabolismo , Animales , Cilios/genética , Modelos Animales de Enfermedad , Humanos , Ratones , Fagocitosis/fisiología , Transfección , Pez CebraRESUMEN
Major advances in the study of inherited retinal diseases (IRDs) have placed efforts to develop treatments for these blinding conditions at the forefront of the emerging field of precision medicine. As a result, the growth of clinical trials for IRDs has increased rapidly over the past decade and is expected to further accelerate as more therapeutic possibilities emerge and qualified participants are identified. Although guided by established principles, these specialized trials, requiring analysis of novel outcome measures and endpoints in small patient populations, present multiple challenges relative to study design and ethical considerations. This position paper reviews recent accomplishments and existing challenges in clinical trials for IRDs and presents a set of recommendations aimed at rapidly advancing future progress. The goal is to stimulate discussions among researchers, funding agencies, industry, and policy makers that will further the design, conduct, and analysis of clinical trials needed to accelerate the approval of effective treatments for IRDs, while promoting advocacy and ensuring patient safety.
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Enfermedades de la Retina , Humanos , Medicina de Precisión , Retina , Enfermedades de la Retina/tratamiento farmacológicoRESUMEN
PURPOSE: To report a case of pituitary adenoma in a patient with retinitis pigmentosa (RP) and consequent rapid constriction of the visual field in each eye, which is atypical for either of these pathologies. OBSERVATIONS: A 45-year old male, with a long-standing history of RP, presented with rapid vision loss over 3 months. Examination revealed a severe drop in visual acuity and significant progression of concentric visual field constriction in each eye compared to 3 months prior. MRI revealed a pituitary macroadenoma compressing the optic chiasm. The patient underwent endoscopic trans-sphenoidal resection of the tumor and experienced partial recovery of visual acuity but not visual field. CONCLUSIONS AND IMPORTANCE: The visual field deficit in this patient was atypical for pituitary adenoma or optic neuropathy. The pattern was most consistent with RP, but the rate of progression was not. In a patient with chiasmal pathology in the setting of pre-existing retinopathy, visual field progression may not be limited exclusively to the bitemporal regions. Rapid constriction of the visual field in a patient with RP should prompt a work-up for alternative etiologies which includes neuro-imaging.
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BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell dyscrasia and precursor to multiple myeloma. It has known ocular manifestations, but has not previously been shown to have an association with autoimmune retinopathy. CASE PRESENTATION: A 57 year-old female presented with 1 year of progressive, bilateral, peripheral vision loss, photopsias, and nyctalopia. Her fundus examination and extensive ancillary testing were concerning for hereditary versus autoimmune retinopathy. The patient was found to have anti-retinal antibodies against carbonic anhydrase II and enolase proteins with a negative genetic retinal dystrophy panel. Malignancy work-up was negative, but the patient was diagnosed with MGUS, a premalignant condition. The patient was treated with immunosuppressive therapies, with rituximab demonstrating the most robust therapeutic response with respect to patient symptoms and ophthalmic testing. CONCLUSIONS: MGUS should be considered as a potential etiology of autoimmune retinopathy in patients without other autoimmune or malignant disease processes. Immunosuppressive therapy may be helpful in limiting disease progression, with rituximab showing efficacy in retinopathy refractory to other agents.
Asunto(s)
Enfermedades Autoinmunes/etiología , Autoinmunidad , Paraproteinemias/complicaciones , Retina/patología , Enfermedades de la Retina/etiología , Campos Visuales/fisiología , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/inmunología , Adaptación a la Oscuridad/fisiología , Progresión de la Enfermedad , Electrorretinografía , Femenino , Angiografía con Fluoresceína/métodos , Fondo de Ojo , Humanos , Persona de Mediana Edad , Paraproteinemias/inmunología , Enfermedades de la Retina/diagnóstico , Enfermedades de la Retina/inmunología , Tomografía de Coherencia Óptica/métodosRESUMEN
PURPOSE: X-linked retinitis pigmentosa can manifest in female carriers with widely variable severity, whereas others remain unaffected. The contribution of X-chromosome inactivation (XCI) to phenotypic variation has been postulated but not demonstrated. Furthermore, the impact of genotype and genetic modifiers has been demonstrated in affected males but has not been well established in female carriers. The purpose of this study was to describe the scope of clinical phenotype in female carriers with mutations in RPGR and quantify the contribution of genotype, genetic modifiers, and XCI to phenotypic severity. DESIGN: Cohort study. PARTICIPANTS: Seventy-seven female carriers with RPGR mutations from 41 pedigrees. METHODS: Coding single nucleotide polymorphisms were sequenced in candidate genetic modifier genes encoding known RPGR-interacting proteins. X-chromosome inactivation ratios were determined in genomic DNA isolated from blood (n = 42) and saliva (n = 20) using methylation status of X-linked polymorphic repeats. These genetic data were compared with disease severity based on quantitative clinical parameters. MAIN OUTCOME MEASURES: Visual acuity, Humphrey visual field (HVF) results, full-field electroretinography results, and dark adaptation. RESULTS: Most individuals at all ages were mildly affected or unaffected, whereas those who progressed to moderate or severe vision loss were older than 30 years. RPGR genotype was not associated with clinical severity. The D1264N variant in RPGRIP1L was associated with more severe disease. Skewed XCI toward inactivation of the normal RPGR allele was associated with more severe disease. The XCI ratio in both blood and saliva was a predictor of visual function as measured by HVF diameter, rod amplitude, flicker amplitude, and flicker implicit time. For carriers with extreme XCI skewing of 80:20 or more, 57% were affected severely compared with 8% for those with XCI of less than 80:20 (P = 0.002). CONCLUSIONS: Female carriers with mutations in RPGR demonstrate widely variable clinical severity. X-chromosome inactivation ratios correlate with clinical severity and may serve as a predictor of clinically significant disease. Because RPGR gene therapy trials are underway, a future imperative exists to determine which carriers require intervention and when to intervene. X-chromosome inactivation analysis may be useful for identifying candidates for early intervention.