RESUMEN
PURPOSE Stiff skin syndrome (SSS; MIM#184900) is a rare autosomal dominantly inherited Mendelian disorder characterised by thickened and stone-hard indurations of the skin, mild hypertrichosis, and limitation of joint mobility with flexion contractures. It is autosomal dominant with high penetrance and results from mutations in the fibrillin 1 (FBN1; MIM*134797) gene. Here we present the associated ocular phenotype in a two generation nonconsanguineous Northern Irish family.METHODS The affected patients underwent complete ophthalmic and orthoptic assessment and genetic testing.RESULTS All three patients had ophthalmoplegia of varying degrees. Direct sequencing of the FBN1 gene detected a heterozygous pathogenic mutation (c.4710G>C; p.Trp1570Cys) in all affected patients.CONCLUSIONS This is the first report of ophthalmoplegia in association with SSS.
Asunto(s)
Contractura/genética , Proteínas de Microfilamentos/genética , Mutación , Oftalmoplejía/genética , Enfermedades Cutáneas Genéticas/genética , Contractura/diagnóstico , Análisis Mutacional de ADN , Femenino , Fibrilina-1 , Fibrilinas , Humanos , Persona de Mediana Edad , Oftalmoplejía/diagnóstico , Linaje , Fenotipo , Enfermedades Cutáneas Genéticas/diagnóstico , Agudeza Visual , Adulto JovenAsunto(s)
ADN/genética , Displasia Ectodermal Anhidrótica Tipo 1/genética , Ectodisplasinas/genética , Familia , Mutación INDEL/genética , Análisis Mutacional de ADN , Displasia Ectodermal Anhidrótica Tipo 1/diagnóstico , Displasia Ectodermal Anhidrótica Tipo 1/metabolismo , Ectodisplasinas/metabolismo , Exones , Femenino , Humanos , Italia , Masculino , Linaje , FenotipoRESUMEN
Ectodermal dysplasias (EDs) are a group of genetic disorders characterized by the abnormal development of the ectodermal-derived structures. X-linked hypohidrotic ectodermal dysplasia, resulting from mutations in ED1 gene, is the most common form. The main purpose of this study was to characterize the phenotype spectrum in 45 males harboring ED1 mutations. The study showed that in addition to the involvement of the major ectodermal tissues, the majority of patients also have alterations of several minor ectodermal-derived structures. Characterizing the clinical spectrum resulting from ED1 gene mutations improves diagnosis and can direct clinical care.
Asunto(s)
Displasia Ectodermal Anhidrótica Tipo 1/genética , Displasia Ectodermal Anhidrótica Tipo 1/patología , Ectodisplasinas/genética , Mutación/genética , Fenotipo , Estudios de Cohortes , Displasia Ectodermal Anhidrótica Tipo 1/clasificación , Humanos , Italia , MasculinoRESUMEN
PURPOSE: To perform mutational screening of the visual system homeobox gene 1 (VSX1; MIM#605020) in patients with sporadic and familial keratoconus (MIM#148300) in a European population and, for the first time, report the mutational analysis of the two newly identified VSX1exons. METHODS: VSX1sequence variants in patients with keratoconus were evaluated by direct sequencing of the entire coding region, including two novel exons. In familial keratoconus cases, segregation of potentially pathogenic VSX1variants was assessed to determine pathogenicity. Transcript analysis was carried out on splice site and synonymous sequence variants not detected in controls. RESULTS: A total of 66 unrelated patients with keratoconus from the European population (27 with familial keratoconus; 39 with sporadic keratoconus) were analysed for VSX1 mutations. Four sequence variants were not observed in 100 healthy control individuals: c.432C>G (p.D144E), c.479G>A (p.G160D), c.789C>T (p.S263S), and an intronic change c.844-13T>A (numbered with respect to NM_014588). Segregation was not detected for p.D144E and c.844-13T>A. The change in p.G160D was observed in two patients with sporadic keratoconus. Although predicted to alter VSX1 splicing, p.S263S had no effect on transcript processing. Four known SNPs were detected and the following polymorphic variants were observed in keratoconus patients and controls: c.711T>A (NM_199425; p.P237P), c.844-5_-6insT (NM_014588), c.*28G>T (DQ854811/DQ854812), and c.*50G>A (DQ854809/DQ854810). CONCLUSIONS: VSX1has a minor role in keratoconus pathogenesis. The pathogenicity of p.G160D remains controversial and this change may represent a rare polymorphism or genetic modifier. Further evidence is provided that the previously reported variant, p.D144E, is a polymorphism.
Asunto(s)
Proteínas del Ojo/genética , Proteínas de Homeodominio/genética , Queratocono/genética , Mutación , Población Blanca/genética , Análisis Mutacional de ADN , Exones/genética , Predisposición Genética a la Enfermedad , Humanos , Datos de Secuencia Molecular , Análisis de Secuencia de ADNRESUMEN
PURPOSE: To characterize the ophthalmic findings, intrafamilial variability, and molecular genetic basis of oculodentodigital dysplasia (ODDD; MIM no. 164200). METHODS: Ophthalmic examination included best-corrected visual acuity, slit-lamp biomicroscopy, direct and indirect ophthalmoscopy, Goldmann applanation tonometry and A-scan ultrasonography. Blood samples were taken for DNA extraction and mutation screening of GJA1 (connexin 43). RESULTS: All three affected individuals had characteristic features of ODDD. The ophthalmic features were epicanthus, microcornea, and the presence of glaucoma. The ocular phenotype resulted from a heterozygous T>C transition at nucleotide 338 in GJA1 (L113P) that was not detected in 120 chromosomes of unaffected individuals. The L113P mutation results in a nonconservative substitution in the cytoplasmic loop of Cx43 (GJA1) and is predicted to disrupt the high-order structure of Cx43. CONCLUSIONS: This report describes the ocular phenotype in a molecularly characterized ODDD syndrome family. The ocular features in this family highlight the key role Cx43 plays in eye development and in the development of glaucoma. L113P represents a pathogenic mutation in GJA1 (Cx43) and results in ODDD with marked intrafamilial variation in glaucoma type and severity.
Asunto(s)
Anomalías Múltiples/genética , Conexina 43/genética , Anomalías del Ojo/genética , Mutación Missense , Adulto , Análisis Mutacional de ADN/métodos , Hipoplasia del Esmalte Dental/genética , Facies , Femenino , Dedos/anomalías , Glaucoma/genética , Humanos , Masculino , Persona de Mediana Edad , Linaje , Sindactilia/genética , SíndromeRESUMEN
Evidence of Epstein-Barr virus (EBV) shedding in the saliva and tear film has been sought to explain the pathogenesis of the oral and ocular features of Sjogren's syndrome. Patients with human immunodeficiency virus (HIV) infection are purported to have a higher incidence of keratoconjunctivitis sicca. Twenty patients with definite Sjogren's syndrome (primary and secondary), 19 with HIV infection, and 15 normal controls were recruited and studied. Human herpes viruses (EBV 1 and 2, CMV, HZV, and HSV-1) in tear film were detected by polymerase chain reaction of DNA extracted from Schirmer strips. HSV-1, VZV, and CMV were not detected in any tear samples. EBV-1 DNA was found in the tear film of 4 patients with Sjogren's syndrome, which was not significantly different from the control group (P = 0.18). Twelve patients with HIV infection had evidence of EBV-1 in their tears, which was significantly different from controls (P = 0.0002) and patients with Sjogren's syndrome (P = 0.014). EBV-2 was found in 3 patients with HIV and in 1 patient with secondary Sjogren's syndrome, and was always found as a co-infection with EBV-1 (P = 0.01). This represents the first report examining EBV types 1 and 2 in the tear film and also EBV in the tear film of patients with HIV. Shedding of EBV in the tear film was not related to the presence of keratoconjunctivitis sicca in Sjogren's syndrome. EBV-2 co-infection with EBV-1 has not been previously reported in the tear film. EBV infection is abnormally regulated in Sjogren's syndrome and HIV, and it is likely that the presence of EBV in the tear film is related to the patients' altered immune status.
Asunto(s)
Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por VIH/complicaciones , Herpesvirus Humano 4/aislamiento & purificación , Síndrome de Sjögren/complicaciones , Lágrimas/virología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , ADN Viral/análisis , Femenino , Infecciones por VIH/virología , Herpesvirus Humano 4/clasificación , Humanos , Queratoconjuntivitis Seca/virología , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa/métodos , Síndrome de Sjögren/virologíaRESUMEN
Collagen corneal shields were developed as a corneal bandage lens and are currently indicated for ocular surface protection following surgery and in traumatic and nontraumatic corneal conditions. Collagen shields are manufactured from porcine or bovine collagen and three different collagen shields are currently available with dissolution times of 12, 24, and 72 hours. The theoretical, experimental, and clinical evidence supports a role for collagen corneal shields as a drug delivery device and in the promotion of epithelial and stromal healing. Presoaking the collagen shield in a pharmacological agent with adjunctive topical treatment represents the most efficacious method of utilizing collagen shields for drug delivery. In microbial keratitis collagen shields can enhance drug delivery, promote epithelial and stromal healing, neutralize collagenases, and reduce corneal inflammation. This review will examine the evidence that supports the role of collagen shields in drug delivery and corneal wound healing. Despite a large volume of experimental (animal) work, studies on human subjects, particularly randomized controlled trials, are lacking. The authors are advocating the reassessment of the application and benefits of corneal collagen shields to clinical practice.
Asunto(s)
Materiales Biocompatibles , Apósitos Biológicos , Colágeno , Lentes de Contacto , Enfermedades de la Córnea/terapia , Antibacterianos/administración & dosificación , Sistemas de Liberación de Medicamentos , HumanosRESUMEN
Cryopreservation of murine spermatozoa would provide an efficient method for preserving important genotypes. However, to date such methods have resulted in low survivals with significant variability. To address this issue, a series of five experiments was performed to determine the cryobiological characteristics of murine spermatozoa. Experiments 1 and 2 investigated the effect of Percoll separation on the hydraulic conductivity (L(p)) of murine spermatozoa. Both Percoll separation and cryoprotective agents (CPAs) decreased the L(p). However, these effects were not additive. Experiment 3 was performed to determine the effect of temperature on L(p) in the presence of cryoprotectants (L(p)(CPA)), cryoprotectant permeability (P(CPA)), and the reflection coefficient (sigma) in spermatozoa from both ICR and B6C3F1 mice. Permeability parameters decreased as temperature decreased, and permeability characteristics differed between strains. In experiments 4 and 5, theoretical simulations for CPA addition and removal were developed and empirically tested. Strain-specific methods for CPA addition and removal based upon the fundamental cryobiological characteristics of murine spermatozoa resulted in higher survivals than current methods or procedures, which were used as controls.
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Permeabilidad de la Membrana Celular/efectos de los fármacos , Criopreservación , Crioprotectores/farmacología , Povidona , Dióxido de Silicio , Espermatozoides/citología , Animales , Separación Celular/métodos , Masculino , Ratones , Modelos Biológicos , Motilidad Espermática , TemperaturaRESUMEN
Osmotic tolerance of spermatozoa is a critical determinant of functional survival after cryopreservation. This study first tested the hypothesis that mouse spermatozoa behave as linear osmometers, using an electronic particle counter to measure the change in sperm volume in response to anisosmotic solutions. The resulting Boyle-van't Hoff plot was linear (r2 = 0.99) from 75 to 1200 mOsmolal and indicates that 60.7% of the total cell volume is osmotically inactive. Next, mouse sperm tolerance to osmotic stress was determined by assessment of plasma membrane integrity, mitochondrial viability, and motility. Each functional endpoint was measured after exposure to anisosmotic solutions and again after return to isosmolality. The dual fluorescent stains-carboxyfluorescein diacetate with propidium iodide and Rhodamine 123 with propidium iodide-were used to determine membrane integrity and functional mitochondria, respectively. Motility was measured by video microscopy in the range of 1-2400 mOsmolal and was further analyzed from 140 to 600 mOsmolal using computer-assisted semen analysis. The data indicate that motility is substantially more sensitive to osmotic stress than either mitochondrial viability or membrane integrity and that mouse spermatozoa should be maintained within 76-124% of their isosmotic volume during cryopreservation in order to maintain > 80% of pretreatment motility.
Asunto(s)
Espermatozoides/fisiología , Animales , Membrana Celular/fisiología , Tamaño de la Célula/fisiología , Citometría de Flujo , Técnicas In Vitro , Masculino , Ratones , Ratones Endogámicos ICR , Ratones Endogámicos , Mitocondrias/fisiología , Fragilidad Osmótica/fisiología , Presión Osmótica , Motilidad Espermática/fisiología , Espermatozoides/ultraestructuraRESUMEN
The presence of bilateral, multiple patches of congenital hypertrophy of the retinal pigment epithelium (CHRPE) is cited as an early phenotypic marker of the familial adenomatous polyposis coli (FAPC) gene. However, the degree of concordance between CHRPE and the presence of familial adenomatous polyposis (FAP) has not been adequately assessed in individual families. We studied the eyes of 28 members of a single kindred spanning three generations with FAPC; 14 were affected and 14 unaffected but 'at risk'. Six affected and 8 unaffected at risk individuals possessed a total of 34 retinal lesions, 17 in each group. Two affected individuals and 1 at risk individual had the classical pattern of CHRPE associated with FAPC. The sensitivity of CHRPE as an ocular marker for FAPC in this kindred was 14.2%. Our findings have implications for the use of CHRPE for the presymptomatic screening of family members at risk of FAPC. Therefore, ocular examination should not replace colonoscopic screening in an individual at risk of FAPC.