RESUMEN
Mucopolysaccharidosis type IIIA (MPS IIIA or Sanfilippo syndrome type A) is an autosomal recessive lysosomal storage disorder caused by pathogenic variants in the SGSH gene encoding N-sulfoglucosamine sulfohydrolase, an enzyme involved in the degradation of heparan sulfate. MPS IIIA is typically characterized by neurocognitive decline and hepatosplenomegaly with childhood onset. Here, we report on a 53-year-old male subject initially diagnosed with Usher syndrome for the concurrence of retinitis pigmentosa and sensorineural hearing loss. Clinical exome sequencing identified biallelic missense variants in SGSH, and biochemical assays showed complete deficiency of sulfamidase activity and increased urinary glycosaminoglycan excretion. Reverse phenotyping revealed left ventricle pseudo-hypertrophy, hepatosplenomegaly, bilateral deep white matter hyperintensities upon brain MRI, and decreased cortical metabolic activity by PET-CT. On neuropsychological testing, the proband presented only partial and isolated verbal memory deficits. This case illustrates the power of unbiased, comprehensive genetic testing for the diagnosis of challenging mild or atypical forms of MPS IIIA.
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Mucopolisacaridosis III , Síndromes de Usher , Masculino , Humanos , Niño , Persona de Mediana Edad , Mucopolisacaridosis III/diagnóstico , Mucopolisacaridosis III/genética , Hidrolasas/genética , Tomografía Computarizada por Tomografía de Emisión de Positrones , Síndromes de Usher/diagnóstico , Síndromes de Usher/genética , Pruebas Genéticas , Hepatomegalia/genéticaRESUMEN
The consideration and implementation by companies of only those circular economy (CE) practices involving economic returns (win-win solutions) is the result of a utopian and reductionist view of the circular transition. A more realistic and holistic perspective toward circular economy (CE) should recognize and embrace the complexities it entails and not be limited to only instrumental solutions. By drawing on the paradox theory, we delve into the conflicting issues that companies encounter in adopting circular initiatives and analyze the role of organizational attributes in the recognition and navigation of CE tensions. We tested our conceptual framework by using survey data from 303 manufacturing and construction companies in Italy. This study shows that cognitive diversity of internal managerial figures and supply chain collaboration foster the recognition of CE tensions at corporate level. In addition, the results reveal that companies with flexible organizational design, which collaborate with other supply chain actors, and recognize CE tensions are more likely to navigate CE paradoxes. Finally, the study indicates that establishing an experimentation and dialogue space increases the effect of flexible organizational design on navigating CE paradoxes. The research findings are relevant not only to managers and companies, but also to policy makers who can implement industrial policies that incentivize companies' development of organizational attributes likely to stimulate a paradoxical approach toward CE.
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Comercio , Industrias , Investigación Empírica , Italia , OrganizacionesRESUMEN
We investigated the genetic origin of the phenotype displayed by three children from two unrelated Italian families, presenting with a previously unrecognized autosomal recessive disorder that included a severe form of spondylo-epiphyseal dysplasia, sensorineural hearing loss, intellectual disability and Leber congenital amaurosis (SHILCA), as well as some brain anomalies that were visible at the MRI. Autozygome-based analysis showed that these children shared a 4.76 Mb region of homozygosity on chromosome 1, with an identical haplotype. Nonetheless, whole-exome sequencing failed to identify any shared rare coding variants, in this region or elsewhere. We then determined the transcriptome of patients' fibroblasts by RNA sequencing, followed by additional whole-genome sequencing experiments. Gene expression analysis revealed a 4-fold downregulation of the gene NMNAT1, residing indeed in the shared autozygous interval. Short- and long-read whole-genome sequencing highlighted a duplication involving 2 out of the 5 exons of NMNAT1 main isoform (NM_022787.3), leading to the production of aberrant mRNAs. Pathogenic variants in NMNAT1 have been previously shown to cause non-syndromic Leber congenital amaurosis (LCA). However, no patient with null biallelic mutations has ever been described, and murine Nmnat1 knockouts show embryonic lethality, indicating that complete absence of NMNAT1 activity is probably not compatible with life. The rearrangement found in our cases, presumably causing a strong but not complete reduction of enzymatic activity, may therefore result in an intermediate syndromic phenotype with respect to LCA and lethality.
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Pérdida Auditiva Sensorineural/genética , Amaurosis Congénita de Leber/genética , Nicotinamida-Nucleótido Adenililtransferasa/genética , Osteocondrodisplasias/genética , Adolescente , Animales , Niño , Preescolar , Modelos Animales de Enfermedad , Exones/genética , Predisposición Genética a la Enfermedad , Pérdida Auditiva Sensorineural/complicaciones , Pérdida Auditiva Sensorineural/patología , Humanos , Lactante , Discapacidad Intelectual , Amaurosis Congénita de Leber/complicaciones , Amaurosis Congénita de Leber/patología , Masculino , Ratones , Mutación/genética , NAD/metabolismo , Osteocondrodisplasias/complicaciones , Osteocondrodisplasias/patología , Linaje , Degeneración Retiniana/genética , Degeneración Retiniana/patologíaRESUMEN
We here report on the existence of Leber's hereditary optic neuropathy (LHON) associated with peculiar combinations of individually non-pathogenic missense mitochondrial DNA (mtDNA) variants, affecting the MT-ND4, MT-ND4L and MT-ND6 subunit genes of Complex I. The pathogenic potential of these mtDNA haplotypes is supported by multiple evidences: first, the LHON phenotype is strictly inherited along the maternal line in one very large family; second, the combinations of mtDNA variants are unique to the two maternal lineages that are characterized by recurrence of LHON; third, the Complex I-dependent respiratory and oxidative phosphorylation defect is co-transferred from the proband's fibroblasts into the cybrid cell model. Finally, all but one of these missense mtDNA variants cluster along the same predicted fourth E-channel deputed to proton translocation within the transmembrane domain of Complex I, involving the ND1, ND4L and ND6 subunits. Hence, the definition of the pathogenic role of a specific mtDNA mutation becomes blurrier than ever and only an accurate evaluation of mitogenome sequence variation data from the general population, combined with functional analyses using the cybrid cell model, may lead to final validation. Our study conclusively shows that even in the absence of a clearly established LHON primary mutation, unprecedented combinations of missense mtDNA variants, individually known as polymorphisms, may lead to reduced OXPHOS efficiency sufficient to trigger LHON. In this context, we introduce a new diagnostic perspective that implies the complete sequence analysis of mitogenomes in LHON as mandatory gold standard diagnostic approach.
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ADN Mitocondrial/genética , Herencia Multifactorial , Mutación Missense , Atrofia Óptica Hereditaria de Leber/genética , Penetrancia , Adulto , Secuencia de Aminoácidos , Complejo I de Transporte de Electrón/química , Complejo I de Transporte de Electrón/genética , Epistasis Genética , Familia , Femenino , Genes Mitocondriales , Humanos , Masculino , Modelos Moleculares , NADH Deshidrogenasa/química , NADH Deshidrogenasa/genética , Linaje , Adulto JovenRESUMEN
Achromatopsia (ACHM) is a rare genetic disorder of infantile onset affecting cone photoreceptors. To determine the extent of progressive retinal changes in achromatopsia, we performed a detailed longitudinal phenotyping and genetic characterization of an Italian cohort comprising 21 ACHM patients (17 unrelated families). Molecular genetic testing identified biallelic pathogenic mutations in known ACHM genes, including four novel variants. At baseline, the patients presented a reduced best corrected visual acuity (BCVA), reduced macular sensitivity (MS), normal dark-adapted electroretinogram (ERG) responses and undetectable or severely reduced light-adapted ERG. The longitudinal analysis of 16 patients (mean follow-up: 5.4 ± 1.0 years) showed a significant decline of BCVA (0.012 logMAR/year) and MS (-0.16 dB/year). Light-adapted and flicker ERG responses decreased below noise level in three and two patients, respectively. Only two patients (12.5%) progressed to a worst OCT grading during the follow-up. Our findings corroborate the notion that ACHM is a progressive disease in terms of BCVA, MS and ERG responses, and affects slowly the structural integrity of the retina. These observations can serve towards the development of guidelines for patient selection and intervention timing in forthcoming gene replacement therapies.
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Defectos de la Visión Cromática/genética , Defectos de la Visión Cromática/patología , Mutación , Adolescente , Adulto , Biomarcadores , Preescolar , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 6/genética , Canales Catiónicos Regulados por Nucleótidos Cíclicos/genética , Análisis Mutacional de ADN , Proteínas del Ojo/genética , Femenino , Proteínas de Unión al GTP Heterotriméricas/genética , Humanos , Estudios Longitudinales , Masculino , Linaje , Fenotipo , Pronóstico , Estudios Retrospectivos , Tomografía de Coherencia Óptica , Adulto JovenRESUMEN
In contrast to USH2A, variants in ADGRV1 are a minor cause of Usher syndrome type 2, and the associated phenotype is less known. The purpose of the study was to characterize the retinal phenotype of 18 ADGRV1 patients (9 male, 9 female; median age 52 years) and compare it with that of 204 USH2A patients (111 male, 93 female; median age 43 years) in terms of nyctalopia onset, best corrected visual acuity (BCVA), fundus autofluorescence (FAF), and optical coherence tomography (OCT) features. There was no statistical difference in the median age at onset (30 and 18 years; Mann-Whitney U test, p = 0.13); the mean age when 50% of the patients reached legal blindness (≥1.0 log MAR) based on visual acuity (64 years for both groups; log-rank, p = 0.3); the risk of developing advanced retinal degeneration (patch or atrophy) with age (multiple logistic regression, p = 0.8); or the frequency of cystoid macular edema (31% vs. 26%, Fisher's exact test, p = 0.4). ADGRV1 and USH2A retinopathy were indistinguishable in all major functional and structural characteristics, suggesting that the loss of function of the corresponding proteins produces similar effects in the retina. The results are important for counseling ADGRV1 patients, who represent the minor patient subgroup.
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Proteínas de la Matriz Extracelular/genética , Mutación con Pérdida de Función , Receptores Acoplados a Proteínas G/genética , Retinitis Pigmentosa/genética , Síndromes de Usher/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Retinitis Pigmentosa/diagnóstico por imagen , Retinitis Pigmentosa/epidemiología , Tomografía de Coherencia Óptica , Síndromes de Usher/diagnóstico por imagen , Síndromes de Usher/epidemiologíaRESUMEN
PURPOSE: RAX2 encodes a homeobox-containing transcription factor, in which four monoallelic pathogenic variants have been described in autosomal dominant cone-dominated retinal disease. METHODS: Exome sequencing in a European cohort with inherited retinal disease (IRD) (n = 2086) was combined with protein structure modeling of RAX2 missense variants, bioinformatics analysis of deletion breakpoints, haplotyping of RAX2 variant c.335dup, and clinical assessment of biallelic RAX2-positive cases and carrier family members. RESULTS: Biallelic RAX2 sequence and structural variants were found in five unrelated European index cases, displaying nonsyndromic autosomal recessive retinitis pigmentosa (ARRP) with an age of onset ranging from childhood to the mid-40s (average mid-30s). Protein structure modeling points to loss of function of the novel recessive missense variants and to a dominant-negative effect of the reported dominant RAX2 alleles. Structural variants were fine-mapped to disentangle their underlying mechanisms. Haplotyping of c.335dup in two cases suggests a common ancestry. CONCLUSION: This study supports a role for RAX2 as a novel disease gene for recessive IRD, broadening the mutation spectrum from sequence to structural variants and revealing a founder effect. The identification of biallelic RAX2 pathogenic variants in five unrelated families shows that RAX2 loss of function may be a nonnegligible cause of IRD in unsolved ARRP cases.
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Proteínas del Ojo/genética , Proteínas de Homeodominio/genética , Retinitis Pigmentosa/genética , Factores de Transcripción/genética , Adulto , Análisis Mutacional de ADN/métodos , Proteínas del Ojo/metabolismo , Proteínas del Ojo/fisiología , Femenino , Genes Recesivos/genética , Estudios de Asociación Genética/métodos , Genotipo , Haplotipos/genética , Proteínas de Homeodominio/metabolismo , Proteínas de Homeodominio/fisiología , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Mutación Missense/genética , Linaje , Fenotipo , Retina/metabolismo , Retina/patología , Enfermedades de la Retina/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/fisiología , Población Blanca/genéticaRESUMEN
The original version of this Article contained an incorrect version of Fig. 3, which included two variants initially shown in black text in Fig. 3a that the authors removed from the final manuscript. The correct version of Fig. 3 without the two variants now appears in the PDF and HTML versions of the Article.
RESUMEN
PURPOSE: Usher syndrome (USH) is a multisensory deficiency involving vision, hearing and the vestibular system. The purpose of this study is to report on the functional data (i.e. electroretinography, visual fields, visual acuity) of patients with retinitis pigmentosa (RP) due to Usher syndrome that were collected in a multicentre European study (TREATRUSH). METHODS: A total of 268 genetically confirmed USH patients underwent electrophysiological examinations in the context of multimodal ophthalmological examination in the study (75 USH1, 189 USH2 and four USH3). Full-field electroretinography (ERG) was performed according to ISCEV standards, visual field determination was carried out with either the Octopus or Goldmann perimeters and visual acuity was examined with either ETDRS or Snellen charts. The data were compared between USH subtypes (USH1/USH2/USH3) and correlated with age. RESULTS: Visual acuity decreases significantly with age for both USH1 and USH2 (p < 0.001), without a difference between the two cohorts. When corrected for age, the preserved kinetic visual field was significantly larger in USH2 than in USH1 (p = 0.04). Furthermore, the preserved kinetic visual field area showed a significant decrease with age (based on an exponential fit) in both USH1 and USH2 (p < 0.001). In USH1 patients, however, the visual field was already vastly reduced at an early age. The ERG results were abnormal in all patients. Detectable data for scotopic ERG were obtained from nine patients, and data of photopic ERG were obtained from 24 patients, without a difference between USH1 and USH2 subtypes. CONCLUSIONS: There are differences in the phenotypes of RP in USH subtypes, most visible in the progression of visual fields between USH1 and USH2. The perimetric reduction occurs earlier in USH1 than in USH2. In both subtypes, visual acuity decreases significantly with age and the ERG is not detectable already at early ages.
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Electrorretinografía , Retinitis Pigmentosa/fisiopatología , Síndromes de Usher/fisiopatología , Agudeza Visual/fisiología , Campos Visuales/fisiología , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Retina/fisiopatología , Retinitis Pigmentosa/etnología , Síndromes de Usher/etnología , Pruebas del Campo Visual , Población Blanca , Adulto JovenRESUMEN
PURPOSE: To investigate the natural history of Stargardt disease over a multiyear follow-up. METHODS: We reviewed medical records of Stargardt disease patients, with clinical diagnosis of Stargardt disease at a single institution, which was also supported by molecular diagnosis. All patients underwent best-corrected visual acuity, fundus photography, optical coherence tomography, and full-field electroretinography. RESULTS: The study cohort consisted of 157 Stargardt disease patients aged 30.4 ± 1.1 years. Longitudinal analysis (mean follow-up: 3 years) showed a significant worsening of best-corrected visual acuity at an average rate of 1.5 Early Treatment Diabetic Retinopathy Study letters/year (P < 0.001), an enlargement of retinal pigment epithelium lesion area by optical coherence tomography at an average linear rate of 0.10 mm/year (P < 0.001), and a thinning of central macular thickness at a mean rate of -1.42 µm/year (P < 0.001). Survival analysis showed that patients with 2 alleles harboring likely-null variants, on average, reached most severe disease stage, i.e., legal blindness, alteration in both dark-adapted and light-adapted electroretinographic responses, and retinal pigment epithelium lesion area larger than 2.5 mm significantly earlier than patients with at least one allele harboring a missense variant. CONCLUSION: The current longitudinal study showed a significant genotype-phenotype correlation characterization, because patients harboring 2 likely-null alleles reach a severe disease stage about 10 years earlier than patients with at least one missense allele.
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Angiografía con Fluoresceína/métodos , Predicción , Oftalmoscopía/métodos , Epitelio Pigmentado de la Retina/patología , Enfermedad de Stargardt/diagnóstico , Tomografía de Coherencia Óptica/métodos , Agudeza Visual , Transportadoras de Casetes de Unión a ATP/genética , Adulto , Progresión de la Enfermedad , Electrorretinografía , Femenino , Estudios de Seguimiento , Fondo de Ojo , Estudios de Asociación Genética , Humanos , Incidencia , Italia/epidemiología , Masculino , Mutación , Estudios Retrospectivos , Enfermedad de Stargardt/epidemiología , Enfermedad de Stargardt/genéticaRESUMEN
Retinitis pigmentosa (RP) is a clinically heterogenous disease that comprises a wide range of phenotypic and genetic subtypes. Pericentral RP is an atypical form of RP characterized by bone-spicule pigmentation and/or atrophy confined in the near mid-periphery of the retina. In contrast to classic RP, the far periphery is better preserved in pericentral RP. The aim of this study was to perform the first detailed clinical and genetic analysis of a cohort of European subjects with pericentral RP to determine the phenotypic features and the genetic bases of the disease. A total of 54 subjects from 48 independent families with pericentral RP, non-syndromic and syndromic, were evaluated through a full ophthalmological examination and underwent clinical exome or retinopathy gene panel sequencing. Disease-causative variants were identified in 22 of the 35 families (63%) in 10 different genes, four of which are also responsible for syndromic RP. Thirteen of the 34 likely pathogenic variants were novel. Intra-familiar variability was also observed. The current study confirms the mild phenotype of pericentral RP and extends the spectrum of genes associated with this condition.
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Retinitis Pigmentosa/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Estudios de Cohortes , Exoma , Femenino , Pruebas Genéticas , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Linaje , Retinitis Pigmentosa/epidemiología , Adulto JovenRESUMEN
Drawing on Bansal & Roth's model of ecological responsiveness, the study investigates how environmental managers' cognitive framings of sustainability issues and interpretations of field-level contextual factors affect decision-making processes with regard to environmental management system (EMS) internalization. Using data from a survey questionnaire of 457 ISO 14001-certified and EMAS-registered European companies, the research analyses the influence of managers' perceptions of contextual factors (i.e. environmental issue salience and governmental regulatory incentives) and managers' cognitive traits (i.e. managers' environmental concern and cognitive framings of environmental practices) on internalization. The results highlight that, while managers' perceived stakeholders' concern for the natural environment directly influences substantive internalization, governmental regulatory reliefs fail to influence the internalization of EMS. Similarly, managers' environmental concern emerges as an antecedent of internalization, while managers' adherence to an alignment logic between economic and environmental objectives does not contribute to internalization. Furthermore, the study contributes to the conceptualization of substantive internalization of environmental practices, by highlighting the existence of two distinct dimensions of EMS internalization, i.e. operational and strategic internalization.
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Toma de Decisiones , Ambiente , Cognición , Encuestas y CuestionariosRESUMEN
Retinal photoreceptors are particularly vulnerable to local high-glucose concentrations. Oxidative stress is a risk factor for diabetic retinopathy development. Melanocortin receptors represent a family of G-protein-coupled receptors classified in five subtypes and are expressed in retina. Our previous data indicate that subtypes 1 and 5 receptor agonists exert a protective role on experimental diabetic retinopathy. This study focuses on their role in primary retinal cell cultures in high-glucose concentrations. After eye enucleation from wild-type male C57BL/6 mice, retinal cells were isolated, plated in high-glucose concentration and treated with melanocortin receptors 1 and 5 agonists and antagonists. Immunocytochemical and biochemical analysis showed that treatment with melanocortin receptors 1 and 5 agonists reduced anti-inflammatory cytokines and chemokines and enhanced manganese superoxide dismutase and glutathione peroxidase levels, preserving photoreceptor integrity. According with these evidences, we propose a major role of melanocortin receptors 1 and 5 on primary retinal cell response against high glucose or oxidative insults.
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Antioxidantes/metabolismo , Glucosa/toxicidad , Neuroprotección/efectos de los fármacos , Células Fotorreceptoras de Vertebrados/enzimología , Células Fotorreceptoras de Vertebrados/patología , Receptores de Melanocortina/agonistas , Animales , Western Blotting , Ensayo de Inmunoadsorción Enzimática , Regulación de la Expresión Génica/efectos de los fármacos , Glutatión Peroxidasa/metabolismo , Inmunohistoquímica , Masculino , Ratones Endogámicos C57BL , Opsinas/metabolismo , Cultivo Primario de Células , Receptores de Melanocortina/metabolismo , Coloración y Etiquetado , Superóxido Dismutasa/metabolismoRESUMEN
BACKGROUND: Bardet-Biedl syndrome (BBS) is a rare genetic disorder that features retinal degeneration, obesity, polydactyly, learning disabilities and renal abnormalities. The diagnosis is often missed at birth, the median age at diagnosis being 9 years. In the attempt to shed light on BBS and improve its diagnosis and treatment, we evaluated the genotype-phenotype relationship in patients with a molecular diagnosis of BBS. METHODS: We analyzed three common BBS genes, BBS1, BBS10 and BBS2, in 25 Italian patients fulfilling the clinical criteria of BBS. In 12 patients, we identified gene-specific biallelic variants and thus correlated genotype to the ophthalmic, renal and audio-vestibular phenotypes. RESULTS: At least one sequence variant was found in 60% of patients. The most common mutated gene was BBS1 followed by BBS10. Of the 17 sequence variants we found, 11 have not previously been associated with BBS. In 12 patients, we identified biallelic pathogenic variants; they had retinitis pigmentosa with early onset of visual impairment. However, retinal dystrophy was less severe in patients with BBS1 than in those with BBS10 variants. Overall, we found a high prevalence of renal dysmorphism and dysfunction. Notably, patients with BBS10 variants had the most severe renal impairment, which resulted in a critical decline in renal function. All the patients who underwent audio-vestibular evaluation had dysfunction of the cochlear outer hair cells, thus confirming the presence of hearing defects. CONCLUSION: BBS1, BBS2 and BBS10 are major causative genes in Italian BBS patients. BBS10 was associated with the worse outcome in terms of the renal, ocular and audiovestibular phenotypes. Cochlear dysfunction should be included among the hallmarks of BBS.
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Síndrome de Bardet-Biedl/genética , Ojo/fisiopatología , Riñón/fisiopatología , Población Blanca/genética , Adolescente , Adulto , Anciano , Umbral Auditivo , Síndrome de Bardet-Biedl/patología , Chaperoninas , Niño , ADN/química , ADN/aislamiento & purificación , ADN/metabolismo , Análisis Mutacional de ADN , Ojo/diagnóstico por imagen , Femenino , Estudios de Asociación Genética , Genotipo , Chaperoninas del Grupo II/genética , Humanos , Italia , Masculino , Proteínas Asociadas a Microtúbulos/genética , Persona de Mediana Edad , Fenotipo , Polimorfismo Genético , Proteínas/genética , Tomografía de Coherencia Óptica , Adulto JovenRESUMEN
PURPOSE: To evaluate differences in the visual phenotype and natural history of Usher syndrome caused by mutations in MYO7A or USH2A, the most commonly affected genes of Usher syndrome Type I (USH1) and Type II (USH2), respectively. METHODS: Eighty-eight patients with a clinical diagnosis of USH1 (26 patients) or USH2 (62 patients) were retrospectively evaluated. Of these, 48 patients had 2 disease-causing mutations in MYO7A (10 USH1 patients), USH2A (33 USH2 patients), and other USH (5 patients) genes. Clinical investigation included best-corrected visual acuity, Goldmann visual field, fundus photography, electroretinography, and audiologic and vestibular assessments. Longitudinal analysis was performed over a median follow-up time of 3.5 years. RESULTS: Patients carrying mutations in MYO7A had a younger age of onset of hearing and visual impairments than those carrying mutations in USH2A, leading to an earlier diagnosis of the disease in the former patients. Longitudinal analysis showed that visual acuity and visual field decreased more rapidly in subjects carrying MYO7A mutations than in those carrying USH2A mutations (mean annual exponential rates of decline of 3.92 vs. 3.44% and of 8.52 vs. 4.97%, respectively), and the former patients reached legal blindness on average 15 years earlier than the latter. CONCLUSION: The current study confirmed a more severe progression of the retinal disease in USH1 patients rather than in USH2 patients. Furthermore, most visual symptoms (i.e., night blindness, visual acuity worsening) occurred at an earlier age in USH1 patients carrying mutations in MYO7A.
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ADN/genética , Proteínas de la Matriz Extracelular/genética , Mutación , Miosinas/genética , Síndromes de Usher/genética , Agudeza Visual , Campos Visuales , Adolescente , Adulto , Análisis Mutacional de ADN , Progresión de la Enfermedad , Electrorretinografía , Proteínas de la Matriz Extracelular/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Miosina VIIa , Miosinas/metabolismo , Fenotipo , Retina/diagnóstico por imagen , Retina/fisiopatología , Estudios Retrospectivos , Factores de Tiempo , Tomografía de Coherencia Óptica , Síndromes de Usher/diagnóstico , Síndromes de Usher/fisiopatología , Adulto JovenRESUMEN
In this paper, the authors describe a case of high serum levels of ubiquitin and proteasome in a woman under an acute attack of autoimmune uveitis. The woman was 52 years old, diagnosed as positive for the Human leukocyte antigen-B27 gene, and came to our observation in January 2013 claiming a severe uveitis attack that involved the right eye. During the acute attack of uveitis, this woman had normal serum biochemical parameters but higher levels of serum ubiquitin and proteasome 20S subunit, with respect to a healthy volunteer matched for age and sex. These levels correlated well with the clinical score attributed to uveitis. After the patient was admitted to therapy, she received oral prednisone in a de-escalation protocol (doses from 50 to 5 mg/day) for four weeks. Following this therapy, she had an expected reduction of clinical signs and score for uveitis, but concomitantly she had a reduction of the serum levels of ubiquitin, poliubiquitinated proteins (MAb-FK1) and proteasome 20S activity. Therefore, a role for ubiquitin and proteasome in the development of human autoimmune uveitis has been hypothesized.
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Antígeno HLA-B27/genética , Antígeno HLA-B27/inmunología , Complejo de la Endopetidasa Proteasomal/sangre , Ubiquitina/sangre , Uveítis/sangre , Uveítis/etiología , Enfermedades Autoinmunes/sangre , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Persona de Mediana Edad , Fenotipo , Uveítis/diagnóstico , Uveítis/tratamiento farmacológicoRESUMEN
Autosomal recessive Stargardt disease (STGD1, MIM 248200) is caused by mutations in the ABCA4 gene. Complete sequencing of ABCA4 in STGD patients identifies compound heterozygous or homozygous disease-associated alleles in 65-70% of patients and only one mutation in 15-20% of patients. This study was designed to find the missing disease-causing ABCA4 variation by a combination of next-generation sequencing (NGS), array-Comparative Genome Hybridization (aCGH) screening, familial segregation and in silico analyses. The entire 140 kb ABCA4 genomic locus was sequenced in 114 STGD patients with one known ABCA4 exonic mutation revealing, on average, 200 intronic variants per sample. Filtering of these data resulted in 141 candidates for new mutations. Two variants were detected in four samples, two in three samples, and 20 variants in two samples, the remaining 117 new variants were detected only once. Multimodal analysis suggested 12 new likely pathogenic intronic ABCA4 variants, some of which were specific to (isolated) ethnic groups. No copy number variation (large deletions and insertions) was detected in any patient suggesting that it is a very rare event in the ABCA4 locus. Many variants were excluded since they were not conserved in non-human primates, were frequent in African populations and, therefore, represented ancestral, and not disease-associated, variants. The sequence variability in the ABCA4 locus is extensive and the non-coding sequences do not harbor frequent mutations in STGD patients of European-American descent. Defining disease-associated alleles in the ABCA4 locus requires exceptionally well characterized large cohorts and extensive analyses by a combination of various approaches.
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Transportadoras de Casetes de Unión a ATP/genética , Sitios Genéticos , Variación Genética , Degeneración Macular/congénito , Mutación , Alelos , Población Negra , Estudios de Casos y Controles , Hibridación Genómica Comparativa , Exones , Femenino , Expresión Génica , Genes Recesivos , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Homocigoto , Humanos , Intrones , Degeneración Macular/etnología , Degeneración Macular/genética , Degeneración Macular/patología , Masculino , Linaje , Enfermedad de Stargardt , Población BlancaRESUMEN
We report on an experimental prototype of a low-cost silicon photonic reconfigurable optical add/drop multiplexer (ROADM). The device is able to operate with up to 12 wavelength division multiplexing channels. In order to control the polarization of the multi-wavelength signal at the input of the device, an integrated polarization controller is investigated as an alternative to the polarization diversity device architecture. The integrated ROADM is equipped with optical switches for the selection of the path direction and variable optical attenuators for optical power control. We demonstrate the polarization insensitive routing of 10 Gb/s channels between two ROADM nodes with error-free transmission.
RESUMEN
BACKGROUND: To evaluate the functional recovery of patients with symptomatic vitreomacular traction (VMT) after Ocriplasmin treatment. METHODS: Prospective, single centre, consecutive case series. Patients were treated with a single intravitreal injection of Ocriplasmin (Jetrea, Thrombogenics Inc, USA, Alcon/Novartis EU). The following outcome measures are considered: resolution of VMT, evaluated through the use of optical coherence tomography (SD-OCT), functional recovery evidenced by multifocal-electroretinogram (mfERG) and microperimetry (MP1) after treatment with Ocriplasmin. RESULTS: Four eyes of four patients were treated with Ocriplasmin injection. We observed a VMT non-surgical resolution in all patients. The longitudinal statistical analysis showed a significant improvement of best corrected visual acuity (BCVA) in the treated eye of about 0.97 letters/week (p = 0.033). No significant difference was observed in mean sensitivity (p > 0.05) assessed by MP1 in both eyes, while improvement in fixation stability was assessed in treated eyes (ß = 0.39; p = 0.029). In the four treated eyes mfERG revealed an increased foveal peak response over the follow-up. The longitudinal analysis of mfERG data shows a significant increase of N1 and P1 amplitude in the first rings and a significant decrease of N1 and P1 implicit time in most rings. CONCLUSIONS: We report on four cases with resolution of VMT after Ocriplasmin treatment. Our preliminary results demonstrate that Ocriplasmin is safe and effective in the treatment of VMT, because it not only leads to a morphological recovery but mostly to a restoration of macular functionality, evaluated through the use of different objective tests, such as MP1 and mfERG over a six-month follow-up.