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1.
Am J Hum Genet ; 111(3): 594-613, 2024 03 07.
Artículo en Inglés | MEDLINE | ID: mdl-38423010

RESUMEN

The endosomal sorting complex required for transport (ESCRT) machinery is essential for membrane remodeling and autophagy and it comprises three multi-subunit complexes (ESCRT I-III). We report nine individuals from six families presenting with a spectrum of neurodevelopmental/neurodegenerative features caused by bi-allelic variants in SNF8 (GenBank: NM_007241.4), encoding the ESCRT-II subunit SNF8. The phenotypic spectrum included four individuals with severe developmental and epileptic encephalopathy, massive reduction of white matter, hypo-/aplasia of the corpus callosum, neurodevelopmental arrest, and early death. A second cohort shows a milder phenotype with intellectual disability, childhood-onset optic atrophy, or ataxia. All mildly affected individuals shared the same hypomorphic variant, c.304G>A (p.Val102Ile). In patient-derived fibroblasts, bi-allelic SNF8 variants cause loss of ESCRT-II subunits. Snf8 loss of function in zebrafish results in global developmental delay and altered embryo morphology, impaired optic nerve development, and reduced forebrain size. In vivo experiments corroborated the pathogenicity of the tested SNF8 variants and their variable impact on embryo development, validating the observed clinical heterogeneity. Taken together, we conclude that loss of ESCRT-II due to bi-allelic SNF8 variants is associated with a spectrum of neurodevelopmental/neurodegenerative phenotypes mediated likely via impairment of the autophagic flux.


Asunto(s)
Epilepsia Generalizada , Atrofia Óptica , Animales , Humanos , Niño , Pez Cebra/genética , Atrofia Óptica/genética , Fenotipo , Complejos de Clasificación Endosomal Requeridos para el Transporte/genética
2.
Ophthalmic Res ; 67(1): 301-310, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38705136

RESUMEN

INTRODUCTION: Retinitis pigmentosa (RP), a heterogeneous inherited retinal disorder causing gradual vision loss, affects over 1 million people worldwide. Pathogenic variants in CNGA1 and CNGB1 genes, respectively, accounting for 1% and 4% of cases, impact the cyclic nucleotide-gated channel in rod photoreceptor cells. The aim of this study was to describe and compare genotypic and clinical characteristics of a cohort of patients with CNGA1- or CNGB1-related RP and to explore potential genotype-phenotype correlations. METHODS: The following data from patients with CNGA1- or CNGB1-related RP, followed in five Italian inherited retinal degenerations services, were retrospectively collected: genetic variants in CNGA1 and CNGB1, best-corrected visual acuity (BCVA), ellipsoid zone (EZ) width, fundus photographs, and short-wavelength fundus autofluorescence (SW-AF) images. Comparisons and correlation analyses were performed by first dividing the cohort in two groups according to the gene responsible for the disease (CNGA1 and CNGB1 groups). In parallel, the whole cohort of RP patients was divided into two other groups, according to the expected impact of the variants at protein level (low and high group). RESULTS: In total, 29 patients were recruited, 11 with CNGA1- and 18 with CNGB1-related RP. In both CNGA1 and CNGB1, 5 novel variants in CNGA1 and 5 in CNGB1 were found. BCVA was comparable between CNGA1 and CNGB1 groups, as well as between low and high groups. CNGA1 group had a larger mean EZ width compared to CNGB1 group, albeit not statistically significant, while EZ width did not differ between low and high groups A statistically significant correlation between EZ width and BCVA as well as between EZ width and age were observed in the whole cohort of RP patients. Fundus photographs of all patients in the cohort showed classic RP pattern, and in SW-AF images an hyperautofluorescent ring was observed in 14/21 patients. CONCLUSION: Rod CNG channel-associated RP was demonstrated to be a slowly progressive disease in both CNGA1- and CNGB1-related forms, making it an ideal candidate for gene augmentation therapies.


Asunto(s)
Canales Catiónicos Regulados por Nucleótidos Cíclicos , Genotipo , Fenotipo , Retinitis Pigmentosa , Agudeza Visual , Humanos , Retinitis Pigmentosa/genética , Retinitis Pigmentosa/diagnóstico , Retinitis Pigmentosa/fisiopatología , Masculino , Femenino , Canales Catiónicos Regulados por Nucleótidos Cíclicos/genética , Estudios Retrospectivos , Persona de Mediana Edad , Adulto , Adulto Joven , Adolescente , Electrorretinografía , Tomografía de Coherencia Óptica/métodos , Anciano , Mutación , Niño , Células Fotorreceptoras Retinianas Bastones/metabolismo , Angiografía con Fluoresceína/métodos , Estudios de Asociación Genética , Análisis Mutacional de ADN , Linaje , ADN/genética
3.
Int J Mol Sci ; 25(15)2024 Jul 30.
Artículo en Inglés | MEDLINE | ID: mdl-39125883

RESUMEN

Bardet-Biedl syndrome (BBS) is a rare recessive multisystem disorder characterized by retinitis pigmentosa, obesity, postaxial polydactyly, cognitive deficits, and genitourinary defects. BBS is clinically variable and genetically heterogeneous, with 26 genes identified to contribute to the disorder when mutated, the majority encoding proteins playing role in primary cilium biogenesis, intraflagellar transport, and ciliary trafficking. Here, we report on an 18-year-old boy with features including severe photophobia and central vision loss since childhood, hexadactyly of the right foot and a supernumerary nipple, which were suggestive of BBS. Genetic analyses using targeted resequencing and exome sequencing failed to provide a conclusive genetic diagnosis. Whole-genome sequencing (WGS) allowed us to identify compound heterozygosity for a missense variant and a large intragenic deletion encompassing exon 12 in BBS9 as underlying the condition. We assessed the functional impact of the identified variants and demonstrated that they impair BBS9 function, with significant consequences for primary cilium formation and morphology. Overall, this study further highlights the usefulness of WGS in the diagnostic workflow of rare diseases to reach a definitive diagnosis. This report also remarks on a requirement for functional validation analyses to more effectively classify variants that are identified in the frame of the diagnostic workflow.


Asunto(s)
Síndrome de Bardet-Biedl , Secuenciación Completa del Genoma , Síndrome de Bardet-Biedl/genética , Síndrome de Bardet-Biedl/diagnóstico , Humanos , Masculino , Adolescente , Cilios/patología , Cilios/genética , Proteínas del Citoesqueleto
4.
Graefes Arch Clin Exp Ophthalmol ; 260(5): 1525-1534, 2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-35048199

RESUMEN

PURPOSE: To compare macular atrophy (MA) secondary to age-related macular degeneration (AMD) and Stargardt disease (STGD) using the choroidal vascularity index (CVI). METHODS: In this multicentric retrospective study, two distinct cohorts were collected: patients with MA secondary to AMD and MA secondary to STGD. All patients were investigated using a multimodal imaging approach, including CVI in the subfoveal 1000 µm area. Of note, the CVI is not influenced by aging, which allows comparisons between different cohorts. RESULTS: Seventy eyes were included: 35 eyes of 35 patients (mean age 78 ± 7 years) in the AMD group and 35 eyes of 35 patients (mean age 41 ± 16 years, p < 0.001) in the STGD group. Choroidal thickness was significantly lower in the AMD group in comparison to the STGD group (151 ± 80 µm vs 353 ± 105 µm, p < 0.001). The total choroidal area (TCA) was significantly greater in the STGD group in comparison to the AMD group (1.734 ± 0.958 mm2 vs 0.538 ± 0.391 mm2, respectively, p < 0.001). Interestingly, the CVI was significantly lower in AMD patients in comparison to STGD patients (27.322 ± 15.320% vs 49.880 ± 7.217%, respectively, p < 0.001), and this difference was confirmed in the subgroup of patients over 50 years old. CONCLUSION: Our results corroborate the hypothesis that large choroidal vessels were impaired to a greater extent in AMD than in STGD. CVI may help in differentiating AMD from STGD in the presence of MA, better understanding of the pathogenesis, and monitoring of therapeutic response.


Asunto(s)
Degeneración Macular , Tomografía de Coherencia Óptica , Adulto , Anciano , Anciano de 80 o más Años , Atrofia/diagnóstico , Coroides/patología , Angiografía con Fluoresceína/métodos , Humanos , Degeneración Macular/complicaciones , Degeneración Macular/diagnóstico , Degeneración Macular/patología , Persona de Mediana Edad , Estudios Retrospectivos , Enfermedad de Stargardt , Tomografía de Coherencia Óptica/métodos
5.
Int J Mol Sci ; 23(23)2022 Nov 24.
Artículo en Inglés | MEDLINE | ID: mdl-36498982

RESUMEN

Inherited retinal degeneration (IRD) represents a clinically variable and genetically heterogeneous group of disorders characterized by photoreceptor dysfunction. These diseases typically present with progressive severe vision loss and variable onset, ranging from birth to adulthood. Genomic sequencing has allowed to identify novel IRD-related genes, most of which encode proteins contributing to photoreceptor-cilia biogenesis and/or function. Despite these insights, knowledge gaps hamper a molecular diagnosis in one-third of IRD cases. By exome sequencing in a cohort of molecularly unsolved individuals with IRD, we identified a homozygous splice site variant affecting the transcript processing of TUB, encoding the first member of the Tubby family of bipartite transcription factors, in a sporadic case with retinal dystrophy. A truncating homozygous variant in this gene had previously been reported in a single family with three subjects sharing retinal dystrophy and obesity. The clinical assessment of the present patient documented a slightly increased body mass index and no changes in metabolic markers of obesity, but confirmed the occurrence of retinal detachment. In vitro studies using patient-derived fibroblasts showed the accelerated degradation of the encoded protein and aberrant cilium morphology and biogenesis. These findings definitely link impaired TUB function to retinal dystrophy and provide new data on the clinical characterization of this ultra-rare retinal ciliopathy.


Asunto(s)
Ciliopatías , Distrofias Retinianas , Humanos , Adulto , Cilios/genética , Retina , Ciliopatías/genética , Distrofias Retinianas/genética , Proteínas/genética , Obesidad , Mutación , Linaje
6.
Graefes Arch Clin Exp Ophthalmol ; 259(5): 1297-1308, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33415352

RESUMEN

PURPOSE: To study whether there is a correlation between the macular and optic nerve morphological condition and the retinal ganglion cells (RGCs) and visual pathways' function, and to investigate whether visual acuity (VA) changes might be related to the morpho-functional findings in chronic non-arteritic ischemic optic neuropathy (NAION). METHODS: In this retrospective study, 22 patients (mean age 62.12 ± 6.87) with chronic unilateral NAION providing 22 affected and 22 fellow eyes without NAION (NAION-FE), and 20 (mean age 61.20 ± 7.32) healthy control subjects were studied by spectral domain optical coherence tomography (Sd-OCT) for investigating macular thickness (MT) and volume (MV) of the whole (WR), inner (IR) and outer retina (OR), and the peripapillary retinal nerve fiber layer thickness (RNFL-T) measured overall and for all quadrants. Also, simultaneous 60' and 15' pattern electroretinogram (PERG) and visual evoked potentials (VEP) and VA were assessed. Differences of MT and MV of WR, IR, OR, and RNFL-T overall and for all quadrants, PERG amplitude (A), VEP implicit time (IT), and A and VA values between NAION eyes and controls were assessed by one-way analysis of variance. Pearson's test was used for regression analysis. A p value < 0.01 was considered as significant. RESULTS: In NAION eyes as compared to NAION-FE eyes and controls, significant (p < 0.01) changes of MT, MV of WR and IR, RNFL-T, 60' and 15' PERG A, VEP IT and A, and VA were found. No significant (p > 0.01) OR changes were observed between groups. In NAION eyes, significant (p < 0.01) correlations between MV of WR and IR and 15' PERG A were found. Overall, RNFL-T values were significantly correlated (p < 0.01) with those of 60' PERG A and VEP IT and A; temporal RNFL-T values were correlated (p < 0.01) with 15' PERG A and VEP IT and A ones. Temporal RNFL-T, MV-IR, and 15' PERG A as well as VEP IT were significantly (p < 0.01) correlated with VA. Significant (p < 0.01) linear correlations between 60' and 15' PERG A findings and the corresponding values of 60' and 15' VEP A were also found. CONCLUSION: Our findings suggest that in chronic NAION, there is a morpho-functional impairment of the IR, with OR structural sparing. VA changes are related to the impaired morphology and function of IR, to the temporal RNFL-T reduction and to the dysfunction of both large and small axons forming the visual pathway.


Asunto(s)
Neuropatía Óptica Isquémica , Potenciales Evocados Visuales , Humanos , Persona de Mediana Edad , Neuropatía Óptica Isquémica/diagnóstico , Células Ganglionares de la Retina , Estudios Retrospectivos , Tomografía de Coherencia Óptica
7.
Hum Mol Genet ; 27(24): 4204-4217, 2018 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-30184081

RESUMEN

Guanylate Cyclase-Activating Protein 1 (GCAP1) regulates the enzymatic activity of the photoreceptor guanylate cyclases (GC), leading to inhibition or activation of the cyclic guanosine monophosphate (cGMP) synthesis depending on its Ca2+- or Mg2+-loaded state. By genetically screening a family of patients diagnosed with cone-rod dystrophy, we identified a novel missense mutation with autosomal dominant inheritance pattern (c.332A>T; p.(Glu111Val); E111V from now on) in the GUCA1A gene coding for GCAP1. We performed a thorough biochemical and biophysical investigation of wild type (WT) and E111V human GCAP1 by heterologous expression and purification of the recombinant proteins. The E111V substitution disrupts the coordination of the Ca2+ ion in the high-affinity site (EF-hand 3, EF3), thus significantly decreasing the ability of GCAP1 to sense Ca2+ (∼80-fold higher Kdapp compared to WT). Both WT and E111V GCAP1 form dimers independently on the presence of cations, but the E111V Mg2+-bound form is prone to severe aggregation over time. Molecular dynamics simulations suggest a significantly increased flexibility of both the EF3 and EF4 cation binding loops for the Ca2+-bound form of E111V GCAP1, in line with the decreased affinity for Ca2+. In contrast, a more rigid backbone conformation is observed in the Mg2+-bound state compared to the WT, which results in higher thermal stability. Functional assays confirm that E111V GCAP1 interacts with the target GC with a similar apparent affinity (EC50); however, the mutant shifts the GC inhibition out of the physiological [Ca2+] (IC50E111V ∼10 µM), thereby leading to the aberrant constitutive synthesis of cGMP under conditions of dark-adapted photoreceptors.


Asunto(s)
Distrofias de Conos y Bastones/genética , Proteínas Activadoras de la Guanilato-Ciclasa/genética , Células Fotorreceptoras Retinianas Conos/química , Degeneración Retiniana/genética , Fenómenos Biofísicos , Calcio/metabolismo , Distrofias de Conos y Bastones/patología , GMP Cíclico/biosíntesis , GMP Cíclico/química , Regulación de la Expresión Génica/genética , Proteínas Activadoras de la Guanilato-Ciclasa/química , Humanos , Magnesio/metabolismo , Simulación de Dinámica Molecular , Mutación Missense/genética , Linaje , Agregación Patológica de Proteínas/genética , Unión Proteica , Células Fotorreceptoras Retinianas Conos/metabolismo , Células Fotorreceptoras Retinianas Conos/patología , Degeneración Retiniana/patología
8.
J Transl Med ; 17(1): 330, 2019 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-31570112

RESUMEN

BACKGROUND: Best vitelliform macular dystrophy (BVMD) is an autosomal dominant macular degeneration. The typical central yellowish yolk-like lesion usually appears in childhood and gradually worsens. Most cases are caused by variants in the BEST1 gene which encodes bestrophin-1, an integral membrane protein found primarily in the retinal pigment epithelium. METHODS: Here we describe the spectrum of BEST1 variants identified in a cohort of 57 Italian patients analyzed by Sanger sequencing. In 13 cases, the study also included segregation analysis in affected and unaffected relatives. We used molecular mechanics to calculate two quantitative parameters related to calcium-activated chloride channel (CaCC composed of 5 BEST1 subunits) stability and calcium-dependent activation and related them to the potential pathogenicity of individual missense variants detected in the probands. RESULTS: Thirty-six out of 57 probands (63% positivity) and 16 out of 18 relatives proved positive to genetic testing. Family study confirmed the variable penetrance and expressivity of the disease. Six of the 27 genetic variants discovered were novel: p.(Val9Gly), p.(Ser108Arg), p.(Asn179Asp), p.(Trp182Arg), p.(Glu292Gln) and p.(Asn296Lys). All BEST1 variants were assessed in silico for potential pathogenicity. Our computational structural biology approach based on 3D model structure of the CaCC showed that individual amino acid replacements may affect channel shape, stability, activation, gating, selectivity and throughput, and possibly also other features, depending on where the individual mutated amino acid residues are located in the tertiary structure of BEST1. Statistically significant correlations between mean logMAR best-corrected visual acuity (BCVA), age and modulus of computed BEST1 dimerization energies, which reflect variations in the in CaCC stability due to amino acid changes, permitted us to assess the pathogenicity of individual BEST1 variants. CONCLUSIONS: Using this computational approach, we designed a method for estimating BCVA progression in patients with BEST1 variants.


Asunto(s)
Bestrofinas/química , Bestrofinas/genética , Biología Computacional , Mutación/genética , Distrofia Macular Viteliforme/genética , Adolescente , Adulto , Anciano , Niño , Femenino , Humanos , Italia , Masculino , Persona de Mediana Edad , Modelos Moleculares , Linaje , Subunidades de Proteína/química , Subunidades de Proteína/genética , Análisis de Regresión , Adulto Joven
9.
Ophthalmology ; 126(7): 1033-1044, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30822445

RESUMEN

PURPOSE: To assess changes of retinal ganglion cells (RGCs) and visual pathways' function in patients with Leber's hereditary optic neuropathy (LHON) during 12 months of follow-up of the chronic phase. DESIGN: Retrospective case series. PARTICIPANTS: Twenty-two patients with LHON (mean age, 36.3±9.3 years) in the "chronic phase" of the disease, providing 42 eyes (LHON group) with different pathogenic mitochondrial DNA mutations (group 11778: 21 eyes; group 3460: 4 eyes; group 14484: 13 eyes; and group 14568: 4 eyes) were enrolled. Twenty-five age-similar healthy participants, providing 25 eyes, served as controls. METHODS: Pattern electroretinogram (PERG) and visual evoked potentials (VEP), in response to 60' and 15' checks visual stimuli, were recorded at baseline in all subjects and after 6 and 12 months of follow-up in patients with LHON. At baseline, in all LHON eyes for each PERG and VEP parameter (amplitude and implicit time), the 95% confidence limit (CL) of test-retest variability was calculated. The PERG and VEP mean values observed in LHON eyes were compared (1-way analysis of variance [ANOVA]) with those of controls. During the follow-up, the PERG and VEP differences observed with respect to baseline were evaluated by ANOVA. MAIN OUTCOME MEASURES: Changes of individual and mean absolute values of 60' and 15' PERG amplitude and VEP amplitude and implicit time at each time point compared with baseline values in the LHON group. RESULTS: At baseline, mean values of PERG and VEP parameters detected in the LHON group were significantly (P < 0.01) different with respect to control values. In the LHON group, at 6 and 12 months of follow-up, the majority of eyes showed unmodified (within 95% CL) PERG and VEP values, and mean absolute values of these measures were not significantly (P > 0.01) different from baseline values. CONCLUSIONS: In our untreated patients with chronic LHON, with different specific pathogenic mutations, RGCs and visual pathways function were not significantly modified during 12 months of follow-up. This should be considered in the disease natural history when attempts for treatments are proposed in chronic LHON.


Asunto(s)
Atrofia Óptica Hereditaria de Leber/fisiopatología , Células Ganglionares de la Retina/fisiología , Vías Visuales/fisiología , Adulto , Análisis de Varianza , Estudios de Casos y Controles , Electrorretinografía , Potenciales Evocados Visuales/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad
10.
Mol Ther ; 26(9): 2282-2294, 2018 09 05.
Artículo en Inglés | MEDLINE | ID: mdl-30196853

RESUMEN

This study evaluated the safety and tolerability of ocular RS1 adeno-associated virus (AAV8-RS1) gene augmentation therapy to the retina of participants with X-linked retinoschisis (XLRS). XLRS is a monogenic trait affecting only males, caused by mutations in the RS1 gene. Retinoschisin protein is secreted principally in the outer retina, and its absence results in retinal cavities, synaptic dysfunction, reduced visual acuity, and susceptibility to retinal detachment. This phase I/IIa single-center, prospective, open-label, three-dose-escalation clinical trial administered vector to nine participants with pathogenic RS1 mutations. The eye of each participant with worse acuity (≤63 letters; Snellen 20/63) received the AAV8-RS1 gene vector by intravitreal injection. Three participants were assigned to each of three dosage groups: 1e9 vector genomes (vg)/eye, 1e10 vg/eye, and 1e11 vg/eye. The investigational product was generally well tolerated in all but one individual. Ocular events included dose-related inflammation that resolved with topical and oral corticosteroids. Systemic antibodies against AAV8 increased in a dose-related fashion, but no antibodies against RS1 were observed. Retinal cavities closed transiently in one participant. Additional doses and immunosuppressive regimens are being explored to pursue evidence of safety and efficacy (ClinicalTrials.gov: NCT02317887).


Asunto(s)
Proteínas del Ojo/metabolismo , Terapia Genética/métodos , Retinosquisis/terapia , Adulto , Anciano , Proteínas del Ojo/genética , Femenino , Humanos , Inyecciones Intravítreas , Masculino , Persona de Mediana Edad , Mutación/genética , Retina/metabolismo , Retina/patología , Retinosquisis/genética , Retinosquisis/metabolismo , Adulto Joven
11.
Int J Mol Sci ; 20(22)2019 Nov 14.
Artículo en Inglés | MEDLINE | ID: mdl-31739639

RESUMEN

Inherited retinal dystrophies (IRDs) are a group of clinically and genetically heterogeneous degenerative disorders. To date, mutations have been associated with IRDs in over 270 disease genes, but molecular diagnosis still remains elusive in about a third of cases. The methodologic developments in genome sequencing techniques that we have witnessed in this last decade have represented a turning point not only in diagnosis and prognosis but, above all, in the identification of new therapeutic perspectives. The discovery of new disease genes and pathogenetic mechanisms underlying IRDs has laid the groundwork for gene therapy approaches. Several clinical trials are ongoing, and the recent approval of Luxturna, the first gene therapy product for Leber congenital amaurosis, marks the beginning of a new era. Due to its anatomical and functional characteristics, the retina is the organ of choice for gene therapy, although there are quite a few difficulties in the translational approaches from preclinical models to humans. In the first part of this review, an overview of the current knowledge on methodological issues and future perspectives of gene therapy applied to IRDs is discussed; in the second part, the state of the art of clinical trials on the gene therapy approach in IRDs is illustrated.


Asunto(s)
Terapia Genética , Distrofias Retinianas/genética , Distrofias Retinianas/terapia , Animales , Modelos Animales de Enfermedad , Edición Génica , Técnicas de Transferencia de Gen , Predisposición Genética a la Enfermedad , Terapia Genética/métodos , Vectores Genéticos/genética , Humanos , Distrofias Retinianas/diagnóstico , Transgenes , Resultado del Tratamiento
12.
Ophthalmic Res ; 60(3): 169-175, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30078014

RESUMEN

AIM: To characterize by multimodal approach the phenotype of patients from a 3 generations pedigree, affected by autosomal dominant cone-rod dystrophy (CRD), found to carry a novel pathogenic variant in the cone-rod homeobox-containing (CRX) gene. METHODS: Examination of the adult patients included the following tests: visual acuity, multicolour imaging, spectral domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF) and OCT angiography (OCT-A) recordings. In a 2.5-year-old child, cycloplegic refraction, fundoscopy, ocular motility evaluation and electrophysiological exams were performed. Next Generation Sequencing of patients' DNA has been carried out. RESULTS: A novel CRX pathogenic variant has been identified in our patients. The 2.5-year-old child in the third generation was found to have inherited the variant, with no clinical signs of the condition, but electroretinographic abnormalities in the scotopic component. In the adult patients, diffuse atrophy of the retinal pigment epithelium/photoreceptor complex in the macular region was evident at the OCT and FAF, while OCT-A showed choriocapillaris density reduction. CONCLUSIONS: Multimodal study allowed the characterization of a peculiar form of CRD. The novel pathogenic variant seems to have a different effect on the phenotype if compared with a previously described similar one, giving an insight into the pathogenic mechanism of CRX-related retinal dystrophies and offering valuable information that could lead to the development of possible future therapies.


Asunto(s)
Canales Catiónicos Regulados por Nucleótidos Cíclicos/genética , Proteínas de Homeodominio/genética , Distrofias Retinianas/diagnóstico por imagen , Distrofias Retinianas/genética , Transactivadores/genética , Adulto , Preescolar , Electrorretinografía , Femenino , Humanos , Masculino , Imagen Multimodal , Visión Nocturna/fisiología , Fenotipo , Retina/patología , Distrofias Retinianas/patología , Agudeza Visual/fisiología
13.
Graefes Arch Clin Exp Ophthalmol ; 255(12): 2481-2486, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28831547

RESUMEN

PURPOSE: To assess whether infantile visual deprivation induced by developmental cataract may influence the cone-driven retinal function in humans. METHODS: A total of 14 patients with history of bilateral developmental cataract (DC), who had undergone uncomplicated cataract extraction surgery and intraocular lens implant, and 14 healthy subjects (HS) were enrolled. All patients underwent complete ophthalmological and orthoptic evaluations and best-corrected visual acuity measurement. Light-adapted full-field electroretinograms (ERG) and photopic negative responses (PhNR) were recorded to obtain a reliable measurement of the outer/inner retinal function and of the retinal ganglion cells' function, respectively. RESULT: Mean values of light-adapted ERG a- and b-wave implicit times were slightly delayed when compared to HS values. Light-adapted ERG a-wave amplitude mean values showed borderline values (p = 0.001), whereas a-wave amplitude analysis at 5 ms, b-wave and PhNR amplitude mean values showed no significant differences when compared to control values. No significant correlations were found when age at surgery, time elapsed from surgery, duration of the visual deprivation, age at examination, age at first detection of the opacity, BCVA and electrophysiological parameters were plotted together. Coherently with morphological studies, the extremely light bioelectrical impairment of the cone pathway in our cohort of patients describes minimal functional abnormalities of a well-structured retina that is not completely mature. CONCLUSIONS: Our present results, combined to those of our previous work on congenital cataracts, allow us to enhance the comprehension of functional developmental mechanisms of children's retinas and highlight the relevance of the timely treatment of lens opacities during infancy.


Asunto(s)
Catarata/fisiopatología , Células Fotorreceptoras Retinianas Conos/fisiología , Agudeza Visual , Adolescente , Catarata/congénito , Extracción de Catarata , Niño , Preescolar , Visión de Colores , Electrorretinografía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Estimulación Luminosa , Células Ganglionares de la Retina/fisiología , Privación Sensorial , Factores de Tiempo , Adulto Joven
17.
Graefes Arch Clin Exp Ophthalmol ; 253(8): 1327-40, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26004075

RESUMEN

PURPOSE: To evaluate the retinal function and the neural conduction along the visual pathways after treatment with citicoline eye drops in patients with open angle glaucoma (OAG). METHODS: Fifty-six OAG patients (mean age 52.4 ± 4.72 years, IOP <18 mmHg with beta-blocker monotherapy only) were enrolled. Of these, 47 eyes completed the study: 24 OAG eyes were treated with topical citicoline (OMK1®, Omikron Italia, 3 drops/day) (GC eyes) over a 4-month period (month 4) followed by a 2-month period of citicoline wash-out (month 6), and another 23 OAG eyes were only treated with beta-blocker monotherapy (GP eyes). In GC and GP eyes, pattern electroretinogram (PERG) and visual evoked potentials (VEP) were assessed at baseline and at months 4 and 6 in both groups. RESULTS: At baseline, similar (ANOVA, p > 0.01) PERG and VEP values in GC and GP eyes were observed. After treatment with topical citicoline, a significant (p < 0.01) increase of PERG P50-N95 and VEP N75-P100 amplitudes, and a significant (p < 0.01) shortening of VEP P100 implicit times were found. In GC eyes, the shortening of VEP P100 implicit times was correlated significantly (p < 0.01) with the increase of PERG P50-N95 amplitudes. After a 2-month period of topical Citicoline wash-out, PERG and VEP values were similar (p > 0.01) to baseline ones. GP eyes showed not significant changes of PERG and VEP values during the entire follow-up. CONCLUSIONS: Topical treatment with citicoline in OAG eyes induces an enhancement of the retinal bioelectrical responses (increase of PERG amplitude) with a consequent improvement of the bioelectrical activity of the visual cortex (shortening and increase of VEP implicit time and amplitude, respectively).


Asunto(s)
Citidina Difosfato Colina/uso terapéutico , Glaucoma de Ángulo Abierto/tratamiento farmacológico , Conducción Nerviosa/fisiología , Nootrópicos/uso terapéutico , Retina/fisiología , Vías Visuales/fisiología , Antagonistas Adrenérgicos beta/uso terapéutico , Adulto , Método Doble Ciego , Electrorretinografía , Potenciales Evocados Visuales/fisiología , Femenino , Glaucoma de Ángulo Abierto/fisiopatología , Humanos , Presión Intraocular/efectos de los fármacos , Masculino , Persona de Mediana Edad , Soluciones Oftálmicas , Estudios Prospectivos , Tonometría Ocular , Agudeza Visual/fisiología
18.
Graefes Arch Clin Exp Ophthalmol ; 253(9): 1591-600, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25773998

RESUMEN

PURPOSE: To differentiate the bioelectrical cortical responses driven by axons from central and mid-peripheral retina in Leber's hereditary optic neuropathy (LHON) by using multifocal visual evoked potentials (mfVEP). METHODS: Seventeen genetically confirmed LHON patients (33.35 ± 8.4 years, 17 eyes) and 22 age-matched controls (C) (38.2 ± 6.0 years, 22 eyes) were studied by mfVEP and optical coherence tomography. MfVEP P1 implicit time (P1 IT, ms) and response amplitude density of the N1-P1 components (N1-P1 RAD, nV/deg(2)) of the second order binary kernel were measured for five concentric retinal areas between the fovea and mid-periphery: 0-20 degrees (R1 to R5). RESULTS: Mean mfVEP P1 ITs and N1-P1 RADs at all five foveal eccentricities were significantly different (p < 0.01) in LHON when compared to controls. In both groups, mean mfVEP responses obtained from R1 to R5 showed a progressive shortening of P1 ITs (linear fitting, LHON: r = -0.95; C: r = -0.98) and decrease of N1-P1 RADs (exponential fitting, LHON: r (2) = 0.94; C: r (2) = 0.93). The slope of the linear fitting between mean mfVEP P1 ITs in the two groups was about three times greater in LHON than in controls (LHON: y = -13.33x +182.03; C: y = -4.528x +108.1). MfVEP P1 ITs detected in R1 and R2 (0-5 degrees) were significantly correlated (p < 0.01) with the reduction of retinal nerve fiber layer thickness of the temporal quadrant. CONCLUSIONS: MfVEP identifies abnormal neural conduction along the visual pathways in LHON, discriminating a predominant involvement of axons driving responses from the central retina when compared to those serving the mid-peripheral retina.


Asunto(s)
Axones/patología , Potenciales Evocados Visuales/fisiología , Atrofia Óptica Hereditaria de Leber/fisiopatología , Enfermedades de la Retina/fisiopatología , Células Ganglionares de la Retina/patología , Vías Visuales/fisiopatología , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Conducción Nerviosa/fisiología , Atrofia Óptica Hereditaria de Leber/diagnóstico , Enfermedades de la Retina/diagnóstico , Tomografía de Coherencia Óptica , Agudeza Visual/fisiología , Corteza Visual/fisiopatología , Pruebas del Campo Visual , Campos Visuales/fisiología , Adulto Joven
19.
Doc Ophthalmol ; 129(3): 177-89, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25294024

RESUMEN

PURPOSE: The aim of the present study was to evaluate the short-term effects of the vision trainer rehabilitation technique on retinal and post-retinal function in young amblyopic patients outside the critical visual developmental period. METHODS: Twenty-one patients (mean age 12.2 ± 2.7 years, ranging from 9.1 to 18 years) affected by unilateral anisometropic amblyopia were studied, providing 21 amblyopic eyes (AE) and 21 sound eyes (SE). Thirty eyes from 15 age-similar normal subjects served as controls. All subjects underwent extensive ophthalmologic characterization to exclude any disease not related to amblyopia. All AE were subjected to rehabilitation sessions performed by the Retimax vision trainer (VT) program. The protocol consisted of 2 sessions per week, each lasting 10 min, for 10 consecutive weeks. Before and after the rehabilitation, electrophysiological [pattern electroretinogram (PERG) and visual evoked potential (VEP)] and psychophysical [best corrected visual acuity (BCVA) and microperimetry] data were collected from AE and SE. RESULTS: When comparing baseline data with those collected at the end of the study, PERG P50-N95 amplitude and BCVA values from AE had improved significantly by the end of the study (p < 0.05). Our electrophysiological findings also showed some abnormalities in SE when the data were compared to control eyes. We found a significant correlation (p < 0.05) between PERG amplitude and VEP implicit time in SE after visual rehabilitation. CONCLUSIONS: Short-term visual rehabilitation performed by the VT program ameliorated the electrofunctional and psychophysical parameters of vision in children outside the critical developmental period, thus indicating that VT might be a potential adjuvant therapy of traditional patching treatment.


Asunto(s)
Ambliopía/rehabilitación , Anisometropía/rehabilitación , Electrorretinografía , Potenciales Evocados Visuales/fisiología , Células Ganglionares de la Retina/fisiología , Trastornos de la Visión/rehabilitación , Adolescente , Ambliopía/fisiopatología , Anisometropía/fisiopatología , Niño , Femenino , Humanos , Masculino , Trastornos de la Visión/fisiopatología , Agudeza Visual/fisiología , Pruebas del Campo Visual , Adulto Joven
20.
Adv Exp Med Biol ; 801: 559-66, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24664744

RESUMEN

Light-activated movement of transducin-α (Gαt1) from rod photoreceptor outer segments (ROS) into inner segments (IS) enables rods to rapidly adapt to changes in light intensity. The threshold light intensity at which Gαt1 translocates from ROS into IS is primarily determined by the rates of activation and inactivation of Gαt1. Loss- of- expression of the retina specific cell surface protein, retinoschsin (Rs1-KO), led to a dramatic 3-10 fold increase, depending on age, in the luminance threshold for transducin translocation from ROS into IS compared with wild-type control. In contrast, arrestin translocated from IS into ROS at the same light intensity both in WT and Rs1-KO mice. Biochemical changes, including reduced transducin protein levels and enhanced transducin GTPase activity, explain the shift in light intensity threshold for Gαt1 translocation in Rs1-KO mice. These changes in Rs1-KO mice were also associated with age related alterations in photoreceptor morphology and transcription factor expression that suggest delayed photoreceptor maturation.


Asunto(s)
Moléculas de Adhesión Celular/genética , Proteínas del Ojo/genética , Subunidades alfa de la Proteína de Unión al GTP/metabolismo , Células Fotorreceptoras Retinianas Bastones/patología , Retinosquisis/genética , Retinosquisis/patología , Transducina/metabolismo , Animales , Moléculas de Adhesión Celular/metabolismo , Modelos Animales de Enfermedad , Proteínas del Ojo/metabolismo , Humanos , Luz , Ratones , Ratones Noqueados , Segmento Interno de las Células Fotorreceptoras Retinianas/metabolismo , Segmento Interno de las Células Fotorreceptoras Retinianas/patología , Segmento Externo de las Células Fotorreceptoras Retinianas/metabolismo , Segmento Externo de las Células Fotorreceptoras Retinianas/patología , Células Fotorreceptoras Retinianas Bastones/metabolismo , Retinosquisis/metabolismo
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