RESUMEN
Corneal dystrophies are phenotypically and genetically heterogeneous, often resulting in visual impairment caused by corneal opacification. We investigated the genetic cause of an autosomal dominant corneal stromal dystrophy in a pedigree with eight affected individuals in three generations. Affected individuals had diffuse central stromal opacity, with reduced visual acuity in older family members. Histopathology of affected cornea tissue removed during surgery revealed mild stromal textural alterations with alcianophilic deposits. Whole genome sequence data were generated for four affected individuals. No rare variants (MAF < 0.001) were identified in established corneal dystrophy genes. However, a novel heterozygous missense variant in exon 4 of SPARCL1, NM_004684: c.334G > A; p.(Glu112Lys), which is predicted to be damaging, segregated with disease. SPARC-like protein 1 (SPARCL1) is a secreted matricellular protein involved in cell migration, cell adhesion, tissue repair, and remodelling. Interestingly, SPARCL1 has been shown to regulate decorin. Heterozygous variants in DCN, encoding decorin, cause autosomal dominant congenital stromal corneal dystrophy, suggesting a common pathogenic pathway. Therefore, we performed immunohistochemistry to compare SPARCL1 and decorin localisation in corneal tissue from an affected family member and an unaffected control. Strikingly, the level of decorin was significantly decreased in the corneal stroma of the affected tissue, and SPARCL1 appeared to be retained in the epithelium. In summary, we describe a novel autosomal dominant corneal stromal dystrophy associated with a missense variant in SPARCL1, extending the phenotypic and genetic heterogeneity of inherited corneal disease.
RESUMEN
Genome analysis of individuals affected by retinitis pigmentosa (RP) identified two rare nucleotide substitutions at the same genomic location on chromosome 11 (g.61392563 [GRCh38]), 69 base pairs upstream of the start codon of the ciliopathy gene TMEM216 (c.-69G>A, c.-69G>T [GenBank: NM_001173991.3]), in individuals of South Asian and African ancestry, respectively. Genotypes included 71 homozygotes and 3 mixed heterozygotes in trans with a predicted loss-of-function allele. Haplotype analysis showed single-nucleotide variants (SNVs) common across families, suggesting ancestral alleles within the two distinct ethnic populations. Clinical phenotype analysis of 62 available individuals from 49 families indicated a similar clinical presentation with night blindness in the first decade and progressive peripheral field loss thereafter. No evident systemic ciliopathy features were noted. Functional characterization of these variants by luciferase reporter gene assay showed reduced promotor activity. Nanopore sequencing confirmed the lower transcription of the TMEM216 c.-69G>T allele in blood-derived RNA from a heterozygous carrier, and reduced expression was further recapitulated by qPCR, using both leukocytes-derived RNA of c.-69G>T homozygotes and total RNA from genome-edited hTERT-RPE1 cells carrying homozygous TMEM216 c.-69G>A. In conclusion, these variants explain a significant proportion of unsolved cases, specifically in individuals of African ancestry, suggesting that reduced TMEM216 expression might lead to abnormal ciliogenesis and photoreceptor degeneration.
Asunto(s)
Linaje , Polimorfismo de Nucleótido Simple , Retinitis Pigmentosa , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Adulto Joven , Alelos , Haplotipos , Heterocigoto , Homocigoto , Proteínas de la Membrana/genética , Fenotipo , Retinitis Pigmentosa/genética , Retinitis Pigmentosa/patologíaAsunto(s)
COVID-19 , Hospitalización , SARS-CoV-2 , Apnea Obstructiva del Sueño , Veteranos , Humanos , COVID-19/epidemiología , COVID-19/complicaciones , COVID-19/terapia , Apnea Obstructiva del Sueño/terapia , Apnea Obstructiva del Sueño/epidemiología , Masculino , Persona de Mediana Edad , Femenino , Hospitalización/estadística & datos numéricos , Anciano , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: In the first months of the pandemic, prior to the introduction of proven-effective treatments, 15-37% of patients hospitalized with COVID-19 were discharged on home oxygen. After proven-effective treatments for acute COVID-19 were established by evidence-based guidelines, little remains known about home oxygen requirements following hospitalization for COVID-19. METHODS: This was a retrospective, multi-center cohort study of subjects hospitalized for COVID-19 between October 2020-September 2021 at 3 academic health centers. Information was abstracted from electronic health records at the index hospitalization and for 60 d after discharge. The World Health Organization COVID-19 Clinical Progression Scale score was used to identify patients with severe COVID-19. RESULTS: Of 517 subjects (mean age 58 y, 47% female, 42% Black, 36% Hispanic, 22% with severe COVID-19), 81% were treated with systemic corticosteroids, 61% with remdesivir, and 2.5% with tocilizumab. About one quarter of subjects were discharged on home oxygen (26% [95% CI 22-29]). Older age (adjusted odds ratio [aOR] 1.02 per 5 y [95% CI 1.02-1.02]), higher body mass index (aOR 1.02 per kg/m2 [1.00-1.04]), diabetes (yes vs no, aOR 1.73 [1.46-2.02]), severe COVID-19 (vs moderate, aOR 3.19 [2.19-4.64]), and treatment with systemic corticosteroids (yes vs no, aOR 30.63 [4.51-208.17]) were associated with an increased odds of discharge on home oxygen. Comorbid hypertension (yes vs no, aOR 0.71 [0.66-0.77) was associated with a decreased odds of home oxygen. Within 60 d of hospital discharge, 50% had documentation of pulse oximetry; in this group, home oxygen was discontinued in 46%. CONCLUSIONS: About one in 4 subjects were prescribed home oxygen after hospitalization for COVID-19, even after guidelines established proven-effective treatments for acute illness. Evidence-based strategies to reduce the requirement for home oxygen in patients hospitalized for COVID-19 are needed.
Asunto(s)
COVID-19 , Humanos , Femenino , Persona de Mediana Edad , Masculino , COVID-19/terapia , SARS-CoV-2 , Estudios Retrospectivos , Estudios de Cohortes , Hospitalización , Oxígeno , CorticoesteroidesRESUMEN
This study sought to understand whether the risk and protective factors associated with current partner violence changed in Vietnam using findings from two comparable surveys conducted in 2010 and 2019. Fifteen (2010) and 17 (2019) factors were significantly associated with violence, and the level of consistency was high-nonpartner sexual violence, respondent and partner prior abuse, men's expressions of masculinity, and indicators of low economic status continue to put women at risk. Gender-transformative approaches that address power inequalities, foster positive parenting, and promote the political and social influence of women are required and should be adapted to the Vietnam context.
RESUMEN
BACKGROUND: Assessments of changes in prevalence and patterns of violence against women are critical to inform prevention and response approaches and to monitor progress towards elimination. Most countries in the Asia Region have data on violence and several have completed second and third waves of surveys. This study sought to assess and compare the prevalence and patterns of physical and/or sexual partner violence in seven Asian countries with at least two rounds of comparable national-level data. METHODS: We conducted primary descriptive analyses using Demographic and Health data from India, Nepal, and Pakistan (South Asia), and from Cambodia, the Philippines, Timor-Leste, and extracted data from reports from Vietnam (Southeast Asia). We examined differences in partner violence by type of violence, reference periods, severity of violence, and age group. Pearson chi-square tests and Mantel-Haenszel test for trend were used to assess whether differences between time points were significant (p < 0.05). RESULTS: Prevalence and patterns of violence vary across countries and sub-regions. In Southeast Asia, women in Cambodia and Vietnam experienced increasing and relatively high levels of sexual violence alongside declining physical violence. Reported levels of violence were lowest in the Philippines and prevalence showed consistent declines. Timor-Leste stands out as having the highest prevalence of physical partner violence, and there were consistently significant increases in estimates. Women in South Asia experienced predominantly physical violence and there were consistent declines in all three countries, though physical violence increased among older women in India. CONCLUSIONS: Data from Asian countries where more than one prevalence survey had been done provided a unique opportunity to analyse differences in estimates of violence against women at two time points. Deeper analyses into types and severity of violence revealed that overall prevalence estimates hid more complex patterns. There are clear limitations in using survey data to understand the nuances which highlighted the need for depth analysis identifying contextual factors of violence to inform situation specific policies and interventions for the greatest impact. It is also clear that more than two data points are necessary to identify change over time, and interventions driving or preventing that change.
Asunto(s)
Violencia de Pareja , Humanos , Femenino , Anciano , Prevalencia , Violencia , Encuestas y Cuestionarios , Pakistán , Factores de RiesgoRESUMEN
Blue cone monochromacy (BCM) is an X-linked retinal disorder characterized by low vision, photoaversion, and poor color discrimination. BCM is due to the lack of long-wavelength-sensitive and middle-wavelength-sensitive cone photoreceptor function and caused by mutations in the OPN1LW/OPN1MW gene cluster on Xq28. Here, we investigated the prevalence and the landscape of submicroscopic structural variants (SVs) at single-base resolution in BCM patients. We found that about one-third (n = 73) of the 213 molecularly confirmed BCM families carry an SV, most commonly deletions restricted to the OPN1LW/OPN1MW gene cluster. The structure and precise breakpoints of the SVs were resolved in all but one of the 73 families. Twenty-two families-all from the United States-showed the same SV, and we confirmed a common ancestry of this mutation. In total, 42 distinct SVs were identified, including 40 previously unreported SVs, thereby quadrupling the number of precisely mapped SVs underlying BCM. Notably, there was no "region of overlap" among these SVs. However, 90% of SVs encompass the upstream locus control region, an essential enhancer element. Its minimal functional extent based on deletion mapping in patients was refined to 358 bp. Breakpoint analyses suggest diverse mechanisms underlying SV formation as well as in one case the gene conversion-based exchange of a 142-bp deletion between opsin genes. Using parsimonious assumptions, we reconstructed the composition and copy number of the OPN1LW/OPN1MW gene cluster prior to the mutation event and found evidence that large gene arrays may be predisposed to the occurrence of SVs at this locus.
Asunto(s)
Defectos de la Visión Cromática , Opsinas de Bastones , Defectos de la Visión Cromática/genética , Eliminación de Gen , Humanos , Familia de Multigenes/genética , Células Fotorreceptoras Retinianas Conos , Opsinas de Bastones/genéticaRESUMEN
BACKGROUND: While several safe and effective COVID-19 vaccines have been available since December 2020, many eligible individuals choose to remain unvaccinated. This vaccine hesitancy is an important factor affecting our ability to combat the COVID-19 pandemic. METHODS: The objective of the study was to examine the attitudes and willingness among US Veterans toward receiving COVID-19 vaccination. The study used a quantitative qualitative mixed methods design with a telephone survey and then in-depth interviews in a subset of those surveyed. Participants were unvaccinated Veterans (N = 184) selected randomly from a registry of patients who had received VA healthcare during the pandemic and had a diagnostic test for COVID-19. The primary outcome was willingness to accept COVID-19 vaccination. Survey data collection and in-depth interviews were conducted by telephone. Analyses of the survey data compared the primary outcome with demographics, clinical data, and survey responses using bivariate and multiple regression analyses. A subset (N = 10) of those surveyed, participated in an in-depth interview. Interview transcripts were analyzed to derive themes using qualitative content analysis. RESULTS: Almost 40% of participants disagreed they would receive a COVID-19 vaccine. Participants who were younger, female, and had fewer comorbid conditions were more likely (P < 0.05) to disagree with COVID-19 vaccination. In multiple regression analysis, willingness to accept vaccination was associated with reliance on a doctor or family member's recommendation and with a belief that vaccines are effective. In-depth interviews revealed several barriers to COVID-19 vaccination, including lack of trust in the government and vaccine manufacturers, concerns about the speed of vaccine development, fear of side effects, and fear the vaccine was a tool of racism. CONCLUSIONS: This study illustrates the complexity of patients' deliberation about COVID-19 vaccination and may help physicians and other health care providers understand patients' perspectives about COVID-19 vaccination. The results highlight the importance of patients' trust in physicians, healthcare organizations, pharmaceutical manufacturers and the government when making health decisions.
Asunto(s)
COVID-19 , Veteranos , COVID-19/epidemiología , COVID-19/prevención & control , Vacunas contra la COVID-19 , Femenino , Humanos , Masculino , Pandemias , Aceptación de la Atención de Salud , Encuestas y CuestionariosRESUMEN
Background: A knowledge gap exists in understanding the beneficial use and duration of domiciliary supplemental oxygen (DSO) therapy among survivors of coronavirus disease 2019 (COVID-19) hospitalisations with persistent hypoxaemia upon discharge. The purpose of this single centre study was to begin to address this issue. Methods: In this retrospective study we report features of US military veterans residing in metropolitan Chicago with no prior DSO therapy who survived COVID-19 hospitalisation, were discharged on DSO and were followed for 6â months. Results: We found that the majority of the 65 elderly patients (median age, 70â years), predominantly obese Black males, who survived COVID-19 hospitalisations at the Jesse Brown VA Medical Center and were discharged on DSO did not undergo a formal 6-min walk test (6MWT) to re-assess ongoing ambulatory supplemental oxygen requirements (46 patients or 71%). Nonetheless, DSO therapy was discontinued in most patients predominantly within 8â weeks of hospital discharge (34 patients, 52%). In addition, a large proportion of patients, obese Black people in particular, who survived COVID-19 hospitalisations and were treated with DSO for at least 8â weeks thereafter developed post-acute sequelae of COVID-19 infection (PASC) (30 patients, 46%). Conclusions: Given these findings, we recommend that healthcare providers be appraised about proper monitoring and evaluation, including timely performance of 6MWT, of patients who survived COVID-19 hospitalisations and were treated with DSO for persistent hypoxaemia upon discharge. Whether obese Black males who survived COVID-19 hospitalisations and are treated with DSO thereafter have an elevated risk in developing PASC remains to be determined in larger, prospective studies.
RESUMEN
PURPOSE OF REVIEW: To provide a comprehensive review of usability testing of eHealth interventions for HIV. RECENT FINDINGS: We identified 28 articles that assessed the usability of eHealth interventions for HIV, most of which were published within the past 3 years. The majority of the eHealth interventions for HIV was developed on a mobile platform and focused on HIV prevention as the intended health outcome. Usability evaluation methods included eye-tracking, questionnaires, semi-structured interviews, contextual interviews, think-aloud protocols, cognitive walkthroughs, heuristic evaluations and expert reviews, focus groups, and scenarios. A wide variety of methods is available to evaluate the usability of eHealth interventions. Employing multiple methods may provide a more comprehensive assessment of the usability of eHealth interventions as compared with inclusion of only a single evaluation method.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/prevención & control , Telemedicina/métodos , Teléfono Celular , Computadoras de Mano , HumanosRESUMEN
Purpose: To assess residual cone structure in subjects with mutations in exon 2, 3, and 4 of the OPN1LW or OPN1MW opsin. Methods: Thirteen males had their OPN1LW/OPN1MW opsin genes characterized. The cone mosaic was imaged using both confocal and nonconfocal split-detection adaptive optics scanning light ophthalmoscopy (AOSLO), and retinal thickness was evaluated using optical coherence tomography (OCT). Six subjects completed serial imaging over a maximum period of 18 months and cone density was measured across imaging sessions. Results: Ten subjects had an OPN1LW/OPN1MW "interchange" opsin mutation designated as LIAVA or LVAVA, which both introduce exon 3 splicing defects leading to a lack of functional photopigment in cones expressing LIAVA and greatly reduced functional photopigment in cones expressing LVAVA. Despite disrupted cone reflectivity and reduced numerosity, residual inner segments could be visualized. Similar patterns were observed in individuals with an exon 2 insertion, or an exon 4 splice defect, both of which are also expected to produce cones that are devoid of functional opsin protein. OCT revealed variably reduced retinal thickness. A significant inverse relationship was found between the proportion of waveguiding cones and axial length. Conclusions: Split-detection imaging revealed that the altered appearance of the cone mosaic in confocal images for subjects with exon 2, 3, and 4 mutations was generally due to disrupted waveguiding, rather than structural loss, making them possible candidates for gene therapy to restore cone function. The relative fraction of waveguiding cones was highly variable across subjects, which appears to influence emmetropization in these subjects.
Asunto(s)
Defectos de la Visión Cromática , Opsinas de los Conos/genética , Genes Ligados a X/genética , Mutación , Células Fotorreceptoras Retinianas Conos/patología , Adulto , Longitud Axial del Ojo/patología , Defectos de la Visión Cromática/genética , Defectos de la Visión Cromática/patología , Emetropía/fisiología , Exones/genética , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Retina/patología , Opsinas de Bastones/genéticaRESUMEN
Retinal dystrophies are a heterogeneous group of disorders of visual function leading to partial or complete blindness. We report the genetic basis of an unusual retinal dystrophy in five families with affected females and no affected males. Heterozygous missense variants were identified in the X-linked phosphoribosyl pyrophosphate synthetase 1 (PRPS1) gene: c.47C > T, p.(Ser16Phe); c.586C > T, p.(Arg196Trp); c.641G > C, p.(Arg214Pro); and c.640C > T, p.(Arg214Trp). Missense variants in PRPS1 are usually associated with disease in male patients, including Arts syndrome, Charcot-Marie-Tooth, and nonsyndromic sensorineural deafness. In our study families, affected females manifested a retinal dystrophy with interocular asymmetry. Three unrelated females from these families had hearing loss leading to a diagnosis of Usher syndrome. Other neurological manifestations were also observed in three individuals. Our data highlight the unexpected X-linked inheritance of retinal degeneration in females caused by variants in PRPS1 and suggest that tissue-specific skewed X-inactivation or variable levels of pyrophosphate synthetase-1 deficiency are the underlying mechanism(s). We speculate that the absence of affected males in the study families suggests that some variants may be male embryonic lethal when inherited in the hemizygous state. The unbiased nature of next-generation sequencing enables all possible modes of inheritance to be considered for association of gene variants with novel phenotypic presentation.
Asunto(s)
Genes Ligados a X , Mutación Missense , Degeneración Retiniana/diagnóstico , Degeneración Retiniana/genética , Ribosa-Fosfato Pirofosfoquinasa/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Modelos Moleculares , Linaje , Fenotipo , Conformación Proteica , Ribosa-Fosfato Pirofosfoquinasa/química , Adulto JovenRESUMEN
PURPOSE: Mutations in the coding sequence of the L and M opsin genes are often associated with X-linked cone dysfunction (such as Bornholm Eye Disease, BED), though the exact color vision phenotype associated with these disorders is variable. We examined individuals with L/M opsin gene mutations to clarify the link between color vision deficiency and cone dysfunction. METHODS: We recruited 17 males for imaging. The thickness and integrity of the photoreceptor layers were evaluated using spectral-domain optical coherence tomography. Cone density was measured using high-resolution images of the cone mosaic obtained with adaptive optics scanning light ophthalmoscopy. The L/M opsin gene array was characterized in 16 subjects, including at least one subject from each family. RESULTS: There were six subjects with the LVAVA haplotype encoded by exon 3, seven with LIAVA, two with the Cys203Arg mutation encoded by exon 4, and two with a novel insertion in exon 2. Foveal cone structure and retinal thickness was disrupted to a variable degree, even among related individuals with the same L/M array. CONCLUSIONS: Our findings provide a direct link between disruption of the cone mosaic and L/M opsin variants. We hypothesize that, in addition to large phenotypic differences between different L/M opsin variants, the ratio of expression of first versus downstream genes in the L/M array contributes to phenotypic diversity. While the L/M opsin mutations underlie the cone dysfunction in all of the subjects tested, the color vision defect can be caused either by the same mutation or a gene rearrangement at the same locus.
Asunto(s)
Defectos de la Visión Cromática/genética , Enfermedades Genéticas Ligadas al Cromosoma X/patología , Células Fotorreceptoras Retinianas Conos/patología , Enfermedades de la Retina/patología , Opsinas de Bastones/genética , Adolescente , Adulto , Estudios de Casos y Controles , Niño , Defectos de la Visión Cromática/patología , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Genotipo , Humanos , Masculino , Mosaicismo , Mutación/genética , Fenotipo , Retina/patología , Enfermedades de la Retina/genética , Adulto JovenRESUMEN
We describe novel CHRDL1 mutations in ten families with X-linked megalocornea (MGC1). Our mutation-positive cohort enabled us to establish ultrasonography as a reliable clinical diagnostic tool to distinguish between MGC1 and primary congenital glaucoma (PCG). Megalocornea is also a feature of Neuhäuser or megalocornea-mental retardation (MMR) syndrome, a rare condition of unknown etiology. In a male patient diagnosed with MMR, we performed targeted and whole exome sequencing (WES) and identified a novel missense mutation in CHRDL1 that accounts for his MGC1 phenotype but not his non-ocular features. This finding suggests that MMR syndrome, in some cases, may be di- or multigenic. MGC1 patients have reduced central corneal thickness (CCT); however no X-linked loci have been associated with CCT, possibly because the majority of genome-wide association studies (GWAS) overlook the X-chromosome. We therefore explored whether variants on the X-chromosome are associated with CCT. We found rs149956316, in intron 6 of CHRDL1, to be the most significantly associated single nucleotide polymorphism (SNP) (pâ=â6.81×10(-6)) on the X-chromosome. However, this association was not replicated in a smaller subset of whole genome sequenced samples. This study highlights the importance of including X-chromosome SNP data in GWAS to identify potential loci associated with quantitative traits or disease risk.
Asunto(s)
Parálisis Cerebral/genética , Enfermedades de la Córnea/genética , Paquimetría Corneal , Enfermedades Hereditarias del Ojo/genética , Proteínas del Ojo/genética , Genes Ligados a X , Estudios de Asociación Genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Discapacidad Intelectual/genética , Megalencefalia/genética , Mutación/genética , Proteínas del Tejido Nervioso/genética , Adolescente , Adulto , Parálisis Cerebral/diagnóstico por imagen , Preescolar , Enfermedades de la Córnea/diagnóstico por imagen , Epilepsia/complicaciones , Epilepsia/genética , Exoma/genética , Enfermedades Hereditarias del Ojo/diagnóstico por imagen , Familia , Femenino , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico por imagen , Predisposición Genética a la Enfermedad , Glaucoma/congénito , Glaucoma/genética , Humanos , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/diagnóstico por imagen , Masculino , Megalencefalia/diagnóstico por imagen , Persona de Mediana Edad , Hipotonía Muscular/complicaciones , Hipotonía Muscular/genética , Linaje , Fenotipo , Ultrasonografía , Adulto JovenRESUMEN
Mutations in the OPN1LW (L-) and OPN1MW (M-)cone opsin genes underlie a spectrum of cone photoreceptor defects from stationary loss of color vision to progressive retinal degeneration. Genotypes of 22 families with a range of cone disorders were grouped into three classes: deletions of the locus control region (LCR); missense mutation (p.Cys203Arg) in an L-/M-hybrid gene; and exon 3 single-nucleotide polymorphism (SNP) interchange haplotypes in an otherwise normal gene array. Moderate-to-high myopia was observed in all mutation categories. Individuals with LCR deletions or p.Cys203Arg mutations were more likely to have nystagmus and poor vision, with disease progression in some p.Cys203Arg patients. Three disease-associated exon 3 SNP haplotypes encoding LIAVA, LVAVA, or MIAVA were identified in our cohort. These patients were less likely to have nystagmus but more likely to show progression, with all patients over the age of 40 years having marked macular abnormalities. Previously, the haplotype LIAVA has been shown to result in exon 3 skipping. Here, we show that haplotypes LVAVA and MIAVA also result in aberrant splicing, with a residual low level of correctly spliced cone opsin. The OPN1LW/OPN1MW:c.532A>G SNP, common to all three disease-associated haplotypes, appears to be principally responsible for this mutational mechanism.
Asunto(s)
Opsinas de los Conos/genética , Estudios de Asociación Genética , Genotipo , Mutación , Fenotipo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Sustitución de Aminoácidos , Niño , Preescolar , Orden Génico , Silenciador del Gen , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Haplotipos , Hemicigoto , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense , Oftalmoscopios , Linaje , Polimorfismo de Nucleótido Simple , Empalme del ARN , Retinitis Pigmentosa/diagnóstico , Retinitis Pigmentosa/genética , Eliminación de Secuencia , Adulto JovenRESUMEN
Human X-linked blue-cone monochromacy (BCM), a disabling congenital visual disorder of cone photoreceptors, is a candidate disease for gene augmentation therapy. BCM is caused by either mutations in the red (OPN1LW) and green (OPN1MW) cone photoreceptor opsin gene array or large deletions encompassing portions of the gene array and upstream regulatory sequences that would predict a lack of red or green opsin expression. The fate of opsin-deficient cone cells is unknown. We know that rod opsin null mutant mice show rapid postnatal death of rod photoreceptors. Using in vivo histology with high-resolution retinal imaging, we studied a cohort of 20 BCM patients (age range 5-58) with large deletions in the red/green opsin gene array. Already in the first years of life, retinal structure was not normal: there was partial loss of photoreceptors across the central retina. Remaining cone cells had detectable outer segments that were abnormally shortened. Adaptive optics imaging confirmed the existence of inner segments at a spatial density greater than that expected for the residual blue cones. The evidence indicates that human cones in patients with deletions in the red/green opsin gene array can survive in reduced numbers with limited outer segment material, suggesting potential value of gene therapy for BCM.
Asunto(s)
Defectos de la Visión Cromática/terapia , Terapia Genética , Opsinas de Bastones/genética , Adolescente , Adulto , Animales , Niño , Preescolar , Defectos de la Visión Cromática/genética , Defectos de la Visión Cromática/patología , Femenino , Eliminación de Gen , Humanos , Ratones , Persona de Mediana Edad , Mutación , Células Fotorreceptoras Retinianas Conos/metabolismo , Células Fotorreceptoras Retinianas Conos/patologíaRESUMEN
PURPOSE: 48,XXYY syndrome was first described in 1964 and approximately 100 cases have been reported in the literature. We report a case of 48,XXYY syndrome associated with high myopia and retinal dysfunction. METHODS: Case report. RESULTS: A 28-year-old man was referred with progressive deterioration of visual acuity (VA) bilaterally during the previous 4-5 years. Physical examination revealed tall stature, large feet and irregular teeth. Refraction revealed high myopia with VA 6/60 bilaterally. Fundoscopy revealed a normal vitreous, lightly pigmented retinal pigment epithelium and choroid but no bone spicules or overt signs of retinal degeneration. His visual fields were constricted. Electrodiagnostic testing revealed bilateral generalised retinal dysfunction with severe macular involvement. During follow-up, his ophthalmic examination did not exhibit significant changes while VA was gradually deteriorating. Eight years after presentation, VA was 3/60 bilaterally; electrophysiological testing showed no further change. At that stage, his parents consented for DNA analysis in order to determine the cause of retinal dysfunction. Chromosomal analysis revealed an abnormal male karyotype with two X chromosomes and two Y chromosomes consistent with 48,XXYY syndrome. CONCLUSIONS: The present report is the first to describe retinal dysfunction and high myopia with 48,XXYY syndrome. The severe macular and generalised retinal dysfunction in this case are not those associated with myopia and are in keeping with a primary retinal dysfunction. A coincidental finding cannot be excluded, but ERGs have not previously been reported in 48,XXYY syndrome, and retinal dystrophy may be a previously undiagnosed component of this syndrome.
Asunto(s)
Síndrome de Klinefelter/fisiopatología , Miopía Degenerativa/fisiopatología , Retina/fisiopatología , Distrofias Retinianas/fisiopatología , Adulto , Electrorretinografía , Potenciales Evocados Visuales/fisiología , Humanos , Síndrome de Klinefelter/complicaciones , Síndrome de Klinefelter/diagnóstico , Masculino , Miopía Degenerativa/complicaciones , Miopía Degenerativa/diagnóstico , Oftalmoscopía , Distrofias Retinianas/complicaciones , Distrofias Retinianas/diagnóstico , Trastornos de la Visión/etiología , Trastornos de la Visión/fisiopatología , Agudeza Visual/fisiología , Campos Visuales/fisiologíaRESUMEN
Cysteine dioxygenase (CDO) is a mononuclear nonheme iron(II)-dependent enzyme critical for maintaining appropriate cysteine (Cys) and taurine levels in eukaryotic systems. Because CDO possesses both an unusual 3-His facial ligation sphere to the iron center and a rare Cys-Tyr cross-link near the active site, the mechanism by which it converts Cys and molecular oxygen to cysteine sulfinic acid is of broad interest. However, as of yet, direct experimental support for any of the proposed mechanisms is still lacking. In this study, we have used NO as a substrate analogue for O2 to prepare a species that mimics the geometric and electronic structures of an early reaction intermediate. The resultant unusual S = (1)/2 {FeNO}(7) species was characterized by magnetic circular dichroism, electron paramagnetic resonance, and electronic absorption spectroscopies as well as computational methods including density functional theory and semiempirical calculations. The NO adducts of Cys- and selenocysteine (Sec)-bound Fe(II)CDO exhibit virtually identical electronic properties; yet, CDO is unable to oxidize Sec. To explore the differences in reactivity between Cys- and Sec-bound CDO, the geometries and energies of viable O2-bound intermediates were evaluated computationally, and it was found that a low-energy quintet-spin intermediate on the Cys reaction pathway adopts a different geometry for the Sec-bound adduct. The absence of a low-energy O2 adduct for Sec-bound CDO is consistent with our experimental data and may explain why Sec is not oxidized by CDO.
Asunto(s)
Cisteína-Dioxigenasa/química , Compuestos Ferrosos/química , Óxido Nítrico/química , Oxígeno/química , Dicroismo Circular , Cisteína-Dioxigenasa/genética , Espectroscopía de Resonancia por Spin del Electrón , Expresión Génica , Modelos MolecularesRESUMEN
PURPOSE: To evaluate retinal structure and photoreceptor mosaic integrity in subjects with OPN1LW and OPN1MW mutations. METHODS: Eleven subjects were recruited, eight of whom have been previously described. Cone and rod density was measured using images of the photoreceptor mosaic obtained from an adaptive optics scanning light ophthalmoscope (AOSLO). Total retinal thickness, inner retinal thickness, and outer nuclear layer plus Henle fiber layer (ONL+HFL) thickness were measured using cross-sectional spectral-domain optical coherence tomography (SD-OCT) images. Molecular genetic analyses were performed to characterize the OPN1LW/OPN1MW gene array. RESULTS: While disruptions in retinal lamination and cone mosaic structure were observed in all subjects, genotype-specific differences were also observed. For example, subjects with "L/M interchange" mutations resulting from intermixing of ancestral OPN1LW and OPN1MW genes had significant residual cone structure in the parafovea (â¼25% of normal), despite widespread retinal disruption that included a large foveal lesion and thinning of the parafoveal inner retina. These subjects also reported a later-onset, progressive loss of visual function. In contrast, subjects with the C203R missense mutation presented with congenital blue cone monochromacy, with retinal lamination defects being restricted to the ONL+HFL and the degree of residual cone structure (8% of normal) being consistent with that expected for the S-cone submosaic. CONCLUSIONS: The photoreceptor phenotype associated with OPN1LW and OPN1MW mutations is highly variable. These findings have implications for the potential restoration of visual function in subjects with opsin mutations. Our study highlights the importance of high-resolution phenotyping to characterize cellular structure in inherited retinal disease; such information will be critical for selecting patients most likely to respond to therapeutic intervention and for establishing a baseline for evaluating treatment efficacy.