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1.
Adv Exp Med Biol ; 1185: 215-219, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31884614

RESUMO

During the last 20 years, our group has focused on identifying the genes and mutations causative of inherited retinal dystrophies (IRDs). By applying massive sequencing approaches (NGS) in more than 500 familial and sporadic cases, we attained high diagnostic efficiency (85%) with a custom target gene panel and over 75% using whole exome sequencing (WES). Close to 40% of pathogenic alleles are novel mutations, which demand specific in silico tests and in vitro assays. Notably, missense variants are by far the most common type of mutation identified (around 40%), with small in-frame indels being less frequent (2%). To fill the gap of unsolved cases, when no candidate gene or only a single pathogenic allele has been identified, additional scientific and technical issues remain to be addressed. Reliable detection of genomic rearrangements and copy number variants (partial or complete), deep intronic mutations, variants that cause aberrant splicing events in retina-specific transcripts, functional assessment of hypomorphic missense alleles, mutations in regulatory sequences, the contribution of modifier genes to the IRD phenotype, and detection of low heteroplasmy mtDNA mutations are among the new challenges to be met.


Assuntos
Distrofias Retinianas/diagnóstico , Distrofias Retinianas/genética , Alelos , Variações do Número de Cópias de DNA , DNA Mitocondrial/genética , Humanos , Íntrons , Mutação de Sentido Incorreto , Fenótipo
2.
Invest Ophthalmol Vis Sci ; 60(10): 3456-3467, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31398255

RESUMO

Purpose: To describe foveal sparing (FS) in central retinal dystrophies (RD). Methods: Participants for this retrospective study were identified from the retinal dystrophy database of the Department of Ophthalmology at Radboud University Medical Center. FS was defined as an intact foveal structure surrounded by at least 180° of chorioretinal atrophy, and a best-corrected visual acuity (BCVA) of <1.0 logMAR (>20/200 Snellen). Eligible eyes were identified using fundus autofluorescence (FAF) images, and FS was confirmed using near-infrared reflectance (NIR) imaging and spectral-domain optical coherence tomography when available. Clinical and demographic data were extracted from medical records. We performed quantification of FS and chorioretinal atrophic areas using semiautomated software on fundus autofluorescence and NIR images. We calculated the chronologic change using eye-wise linear regression. Results: We identified 36 patients (56 eyes) with FS. RDs included: Stargardt disease (STGD1;20 patients), central areolar choroidal dystrophy (CACD; 7 patients), mitochondrial retinal dystrophy (MRD; 6 patients), pseudo-Stargardt pattern dystrophy (PSPD; 3 patients). Median age at first presentation was 60 (interquartile range [IQR] 54-63) years. Median BCVA at first presentation ranged from 20/25 Snellen in STGD1, to 20/38 Snellen in MRD. Progression of the chorioretinal atrophic area ranged from 0.26 (0.25-0.28) mm/year in PSPD, to 0.14 (0.11-0.22) in CACD. Change in FS area over time was similar between the different dystrophies. Conclusions: The presence of FS in different RDs suggests a disease-independent mechanism that prolongs the survival of the fovea. The associated preservation of BCVA is important for the individual prognosis and has implications for the design of therapeutic trials for RDs.


Assuntos
Fóvea Central/fisiologia , Distrofias Retinianas/diagnóstico , Progressão da Doença , Eletrorretinografia , Feminino , Angiofluoresceinografia/métodos , Fóvea Central/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Distrofias Retinianas/fisiopatologia , Estudos Retrospectivos , Tomografia de Coerência Óptica/métodos , Acuidade Visual/fisiologia
4.
Arch. Soc. Esp. Oftalmol ; 94(4): 160-164, abr. 2019. tab
Artigo em Espanhol | IBECS | ID: ibc-183299

RESUMO

Antecedentes y objetivo: El diagnóstico de las distrofias retinianas es complejo y se basa en estudio oftalmológico completo, estudio genético y los estudios electrofisiológicos (EEF). En este estudio pretendemos evaluar el papel de las pruebas electrofisiológicas y del médico solicitante en el diagnóstico de las distrofias de retina. Materiales y métodos: Estudio observacional retrospectivo. Se seleccionaron 50 pacientes atendidos en el Servicio de Neurofisiología del Hospital Universitario Virgen Macarena. Se valoró el sexo, la edad, el hospital de origen, motivo por el que se solicitó los EEF, diagnóstico de presunción tras examen oftalmológico, EEF realizados, estudio genético y el diagnóstico definitivo tras realización de EEF. Se elaboró un sistema de clasificación que otorga a cada caso un valor comprendido entre 0 y 2, en función de la contribución de las pruebas electrofisiológicas al diagnóstico final. Resultados: La edad media fue 44,34 ± 18,03 años (60% mujeres). Retinosis pigmentaria, neuropatía óptica y enfermedad de Stargardt fueron los diagnósticos más frecuentes. Los EEF modificaron el diagnóstico de presunción en el 48% de los casos, confirmaron el diagnóstico en el 44% y no aportaron información en el 8%. La contribución de los EEF fue mayor en pacientes atendidos en el Hospital Universitario Virgen Macarena y cuando se solicitaban por hallazgos en la exploración (p = 0,001). Los falsos positivos para distrofia retiniana fueron del 60% en pacientes no valorados en dicho hospital. Conclusiones: Las pruebas electrofisiológicas y el manejo especializado de los pacientes con distrofias retinianas desempeñan un papel importante en el diagnóstico de estas patologías


Background and objective; The diagnosis of retinal dystrophies is complex and is based on complete ophthalmological study, genetic study and electrophysiological studies (EPS). In this study, we intend to evaluate the role of electrophysiological and medical tests in the diagnosis of retinal dystrophies. Material and methods: A retrospective observational study was conducted on 50 selected patients that attended the Neurophysiology Department of the University Hospital Virgen Macarena. An analysis was made of the variables that included, gender, age, referral hospital, reason for which the EPS was requested, applied EPS, genetic study, presumed diagnosis, and definitive diagnosis after EPS. A classification system was subsequently developed, which gives each case a value between 0 and 2, depending on the contribution of the electrophysiological tests to the final diagnosis. Results: The mean age was 44.34 ± 18.03 years (60% women). Retinitis pigmentosa (24%), optic neuropathy (12%), and Stargardt's disease (8%) were the most frequent diagnoses. The EPS modified the presumed diagnosis in 48% of the cases, confirmed the diagnosis in 44%, and did not provide any useful information in 8%. The contribution of the EPS was greater in patients seen in the HUVM and when requested by findings in the examination (P = .001). The false positives in the diagnosis of retinal dystrophy were 60% in patients not evaluated by the University Hospital Virgen Macarena. Conclusions: Electrophysiological test and specialised management of patients with retinal dystrophies play an important role in the diagnosis of these conditions


Assuntos
Humanos , Masculino , Feminino , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Eletrofisiologia/métodos , Distrofias Retinianas/diagnóstico , Distrofias Retinianas/fisiopatologia , Distrofias Retinianas/classificação , Estudos Retrospectivos
5.
Acta Ophthalmol ; 97(6): e877-e886, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30925032

RESUMO

PURPOSE: To identify the accurate clinical diagnosis of rare syndromic inherited retinal diseases (IRDs) based on the combination of clinical and genetic analyses. METHODS: Four unrelated families with various autosomal recessive syndromic inherited retinal diseases were genetically investigated using whole-exome sequencing (WES). RESULTS: Two affected subjects in family MOL0760 presented with a distinctive combination of short stature, developmental delay, congenital mental retardation, microcephaly, facial dysmorphism and retinitis pigmentosa (RP). Subjects were clinically diagnosed with suspected Kabuki syndrome. WES revealed a homozygous nonsense mutation (c.5492dup, p.Asn1831Lysfs*8) in VPS13B that is known to cause Cohen syndrome. The index case of family MOL1514 presented with both RP and liver dysfunction, suspected initially to be related. WES identified a homozygous frameshift mutation (c.1787_1788del, p.His596Argfs*47) in AGBL5, associated with nonsyndromic RP. The MOL1592 family included three affected subjects with crystalline retinopathy, skin ichthyosis, short stature and congenital adrenal hypoplasia, and were found to harbour a homozygous nonsense mutation (c.682C>T, p.Arg228Cys) in ALDH3A2, reported to cause Sjögren-Larsson syndrome (SLS). In the fourth family, SJ002, two siblings presented with hypotony, psychomotor delay, dysmorphic facial features, pathologic myopia, progressive external ophthalmoplegia and diffuse retinal atrophy. Probands were suspected to have atypical Kearns-Sayre syndrome, but were diagnosed with combined oxidative phosphorylation deficiency-20 due to a novel suspected missense variant (c.1691C>T, p.Ala564Val) in VARS2. CONCLUSION: Our findings emphasize the important complement of WES and thorough clinical investigation in establishing precise clinical diagnosis. This approach constitutes the basis for personalized medicine in rare IRDs.


Assuntos
Carboxipeptidases/genética , DNA/genética , Mutação , Retina/patologia , Distrofias Retinianas/genética , Sequenciamento Completo do Exoma/métodos , Adulto , Carboxipeptidases/metabolismo , Análise Mutacional de DNA , Eletroculografia , Eletrorretinografia , Exoma , Feminino , Homozigoto , Humanos , Masculino , Linhagem , Distrofias Retinianas/diagnóstico , Tomografia de Coerência Óptica , Adulto Jovem
8.
Doc Ophthalmol ; 138(2): 147-152, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30701423

RESUMO

PURPOSE: Mitochondrial encephalopathy with lactic acid and stroke-like episodes (MELAS) is caused by mutations in the mitochondrial DNA. Approximately 80% of MELAS patients have an A > G transition mutation at nucleotide pair 3243 in the mitochondrial DNA, m.3243A > G. There are also MELAS patients with a one-base deletion at nucleotide pair 3271 in the mitochondrial DNA, m.3271delT, but these cases are very rare. We report a case of MELAS with the m.3271delT and describe the retinal structure and electrophysiological alterations. METHODS: The retinal structure and function of a 37-year-old woman who was referred to our clinic for of nyctalopia were studied. Standard ophthalmological examinations including the medical history, measurements of the best-corrected visual acuity, intraocular pressures, and slit-lamp biomicroscopy, ophthalmoscopy, fluorescein angiography, fundus autofluorescence, spectral-domain optical coherence tomography (SD-OCT), full-field electroretinography (ERG), and multifocal electroretinography (mfERG) were performed. RESULTS: Fundus examination showed bilateral hypopigmentary changes of the retinal pigment epithelium which extended from the posterior pole to the equator. Fluorescein angiography showed patchy hyperfluorescence due to window defects at the atrophic areas. Fundus autofluorescence demonstrated mild hyperfluorescent lesions in both eyes. SD-OCT showed that the interdigitation zone was indistinct in both eyes, and the inner nuclear layer was slightly thinner. The amplitudes of the rod, cone, and 30-Hz flicker ERGs were severely reduced, and the implicit times were prolonged. The a- and b-waves of the bright-flash mixed rod-cone ERGs were also reduced. The dark-adapted oscillatory potentials were reduced. The amplitudes of the mfERGs were severely depressed except at the fovea in both eyes. CONCLUSIONS: These findings indicate that the RPE atrophy was wider and the rod dysfunction was more severe affected than that of previously reported MELAS cases with the m.3243A > G mutation.


Assuntos
DNA Mitocondrial/genética , Síndrome MELAS/genética , Distrofias Retinianas/genética , Deleção de Sequência , Adulto , Sequência de Bases , Análise Mutacional de DNA , Eletrorretinografia , Feminino , Angiofluoresceinografia , Humanos , Oftalmoscopia , Retina/fisiopatologia , Células Fotorreceptoras Retinianas Cones/fisiologia , Distrofias Retinianas/diagnóstico , Distrofias Retinianas/fisiopatologia , Epitélio Pigmentado da Retina/patologia , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia
9.
Arch Soc Esp Oftalmol ; 94(4): 160-164, 2019 Apr.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-30711256

RESUMO

BACKGROUND AND OBJECTIVE: The diagnosis of retinal dystrophies is complex and is based on complete ophthalmological study, genetic study and electrophysiological studies (EPS). In this study, we intend to evaluate the role of electrophysiological and medical tests in the diagnosis of retinal dystrophies. MATERIAL AND METHODS: A retrospective observational study was conducted on 50 selected patients that attended the Neurophysiology Department of the University Hospital Virgen Macarena. An analysis was made of the variables that included, gender, age, referral hospital, reason for which the EPS was requested, applied EPS, genetic study, presumed diagnosis, and definitive diagnosis after EPS. A classification system was subsequently developed, which gives each case a value between 0 and 2, depending on the contribution of the electrophysiological tests to the final diagnosis. RESULTS: The mean age was 44.34 ±18.03 years (60% women). Retinitis pigmentosa (24%), optic neuropathy (12%), and Stargardt's disease (8%) were the most frequent diagnoses. The EPS modified the presumed diagnosis in 48% of the cases, confirmed the diagnosis in 44%, and did not provide any useful information in 8%. The contribution of the EPS was greater in patients seen in the HUVM and when requested by findings in the examination (P=.001). The false positives in the diagnosis of retinal dystrophy were 60% in patients not evaluated by the University Hospital Virgen Macarena. CONCLUSIONS: Electrophysiological test and specialised management of patients with retinal dystrophies play an important role in the diagnosis of these conditions.


Assuntos
Distrofias Retinianas/diagnóstico , Adulto , Técnicas de Diagnóstico Oftalmológico , Fenômenos Eletrofisiológicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Distrofias Retinianas/fisiopatologia , Estudos Retrospectivos
10.
Invest Ophthalmol Vis Sci ; 60(1): 274-281, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30657522

RESUMO

Purpose: To investigate the green and red fluorescence emission component of hyperautofluorescent flecks in patients with ABCA4-related retinopathy. Methods: A confocal light-emitting diode (LED)-based retinal imaging system (EIDON) was used for image acquisition of patients with genetically confirmed ABCA4 mutations. Using 450-nm excitation wavelengths, spectrally resolved retinal autofluorescence images were acquired in two wavelength ranges: green emission fluorescent component (GEFC, 500-560 nm), and red emission fluorescent component (REFC, 560-700 nm). Image analysis included comparison of the two emission spectra, correlation with confocal EIDON LED color fundus images, and spectral-domain optical coherence tomography (OCT). Results: Eighty eyes of 40 patients with ABCA4-related retinopathy were examined. A characteristic distribution of flecks with distinct pattern of fluorescence emission components was detected and quantified. Independent from disease manifestation, different proportions of GEFC and REFC were identified within single flecks. Centrally located flecks showed a higher proportion of GEFC and were characterized by local disruption of outer retinal bands in OCT. More peripheral flecks were more prominent in the REFC and correlated to subretinal hyperreflective deposits with only minor pathologic alterations of outer retinal layers. Individual flecks even showed spatial differences of the predominant fluorescent component. Conclusions: Spectrally resolved fundus autofluorescence intensity images feature characteristic distribution of GEFC and REFC in flecks, highlighting the heterogeneity of fluorophore distribution and providing more insight into the pathogenesis of ABCA4-related retinopathy. In view of upcoming therapeutic trials, longitudinal analysis of fluorescent components might facilitate monitoring of subtle disease progression and/or treatment effects.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Mutação , Imagem Óptica , Distrofias Retinianas/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Estudos Transversais , Feminino , Angiofluoresceinografia , Fundo de Olho , Humanos , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Oftalmoscopia , Distrofias Retinianas/genética , Epitélio Pigmentado da Retina/patologia , Tomografia de Coerência Óptica
11.
Graefes Arch Clin Exp Ophthalmol ; 257(2): 273-278, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30470876

RESUMO

PURPOSE: To evaluate the efficacy of intravitreal anti-VEGF injections in choroidal neovascularization (CNV) related to pattern dystrophy-like deposit in pseudoxanthoma elasticum (PXE). METHODS: One-year prospective, interventional study. Nine eyes were recruited in the ophthalmology departments of San Raffaele University and University of Barcelona. Each patient underwent best corrected visual acuity (BCVA) measurement on ETDRS chart, slit-lamp biomicroscopy, fluorescein angiography (FA), indocyanine green angiography (ICGA), and optical coherence tomography (OCT). The protocol included a first anti-VEGF injection, followed by monthly evaluations with re-treatments based on new funduscopic hemorrhages, fluid on OCT or leakage on FA and/or ICGA. Primary outcome measures were the mean BCVA changes. Secondary outcomes included central macular thickness (CMT) variations and the number of injections needed. RESULTS: At month 12, mean BCVA significantly improved from 20/45 to 20/35 Snellen equivalent, with 3 eyes gaining at least 3 ETDRS lines. Mean CMT decreased from 297 ± 22 to 262 ± 13 µm, after 5.5 ± 4.0 injections. No leakage was observed at the end of follow-up. CONCLUSIONS: Intravitreal anti-VEGF injections represent an effective treatment for CNV related to pattern dystrophy-like deposit in PXE, with an improvement of BCVA and CMT. Mean injection number is in line with other studies performed in CNV secondary to angioid streaks.


Assuntos
Bevacizumab/administração & dosagem , Neovascularização de Coroide/tratamento farmacológico , Pseudoxantoma Elástico/complicações , Distrofias Retinianas/diagnóstico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Acuidade Visual , Idoso , Inibidores da Angiogênese/administração & dosagem , Neovascularização de Coroide/diagnóstico , Neovascularização de Coroide/etiologia , Feminino , Angiofluoresceinografia/métodos , Seguimentos , Fundo de Olho , Humanos , Injeções Intravítreas , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Pseudoxantoma Elástico/diagnóstico , Pseudoxantoma Elástico/tratamento farmacológico , Distrofias Retinianas/complicações , Distrofias Retinianas/tratamento farmacológico , Fatores de Tempo , Tomografia de Coerência Óptica/métodos
12.
Doc Ophthalmol ; 138(1): 55-70, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30446867

RESUMO

PURPOSE: Mutation of the CLN3 gene, associated with juvenile neuronal ceroid lipofuscinosis, has recently been associated with late-onset, non-syndromic retinal dystrophy. Herein we describe the multimodal imaging, immunological and systemic features of an adult with compound heterozygous CLN3 mutations. METHODS: A 50-year-old female with non-syndromic retinal dystrophy from the age of 36 years underwent multimodal retinal imaging, electroretinography, neuroimaging, immunological studies and genetic testing. CLN3 transcripts were amplified from patient leukocytes by reverse transcriptase polymerase chain reaction and characterized by Sanger sequencing. RESULTS: Visual acuity declined to 6/12 and 6/76 due to asymmetrical central scotoma. ERG responses became electronegative and patient's serum contained anti-retinal antibodies. Final visual acuity stabilized at 6/60 bilaterally 3 years after peri-ocular steroid and rituximab infusion. Genetic testing revealed compound heterozygous CLN3 mutations: the 1.02 kb deletion and a novel missense mutation (c.175G>A). In silico, analyses predicted the c.175G>A mutation disrupted an exonic splice enhancer site in exon 3. In patient leukocytes, CLN3 expression was reduced and novel CLN3 transcripts lacking exon 3 were detected. CONCLUSIONS: Our case study shows that (1) non-syndromic CLN3 disease leads to rod and delayed primary cone degeneration resulting in constricting peripheral field and enlarging central scotoma and, (2) the c.175G>A CLN3 mutation, altered splicing of the CLN3 gene. Overall, we provide comprehensive clinical characterization of a patient with non-syndromic CLN3 disease.


Assuntos
Glicoproteínas de Membrana/genética , Chaperonas Moleculares/genética , Mutação de Sentido Incorreto , Lipofuscinoses Ceroides Neuronais/genética , Distrofias Retinianas/genética , Autoanticorpos/sangue , Autoantígenos/imunologia , Western Blotting , Eletrorretinografia , Éxons , Feminino , Humanos , Pessoa de Meia-Idade , Imagem Multimodal , Lipofuscinoses Ceroides Neuronais/diagnóstico , Lipofuscinoses Ceroides Neuronais/imunologia , Lipofuscinoses Ceroides Neuronais/fisiopatologia , Linhagem , Retina/imunologia , Retina/fisiopatologia , Distrofias Retinianas/diagnóstico , Distrofias Retinianas/imunologia , Distrofias Retinianas/fisiopatologia , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Acuidade Visual/fisiologia
13.
Graefes Arch Clin Exp Ophthalmol ; 257(1): 9-22, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30324420

RESUMO

PURPOSE: To evaluate the clinical phenotype of autosomal recessive NR2E3-related retinal dystrophy. METHODS: We retrospectively studied 11 patients carrying out at least 2 NR2E3 mutations; they had undergone comprehensive ophthalmological examination, fundus photography, optical coherence tomography, electrophysiological testing, and visual field at the Regional Reference Center for Hereditary Retinal Degenerations of the Eye Clinic in Florence. RESULTS: Five females and six males with a diagnosis of NR2E3-related retinal dystrophy were included in the study. All patients complained of nyctalopia. Visual acuity ranged from 0.00 logMAR to hand motion. Two patients presented bull's eye maculopathy, and one of these was characterized by a triple hyper-autofluorescent ring at the fundus autofluorescence examination. Three patients showed small yellowish dots and spots at the mid-periphery. One patient was characterized by widespread subretinal drusenoid deposits (SDD) at the posterior pole. Four patients showed vitreous abnormalities. Optical coherence tomography (OCT) examinations detected variable degrees of abnormal retinal lamination and schitic changes. Seven patients were compound heterozygous and four were homozygous for mutations in NR2E3. CONCLUSIONS: Our study confirmed high variable phenotype in autosomal recessive NR2E3-related retinal dystrophy. Bull's eye maculopathy, subretinal drusenoid deposits, and foveal hypoplasia represent novel clinical findings in NR2E3-related retinal dystrophy. Macular involvement was detectable in all the patients, and the abnormal foveal avascular zone (FAZ) supports the role of NR2E3 in retinal development.


Assuntos
DNA/genética , Mutação , Receptores Nucleares Órfãos/genética , Retina/patologia , Distrofias Retinianas/diagnóstico , Adolescente , Adulto , Idoso , Criança , Análise Mutacional de DNA , Feminino , Angiofluoresceinografia , Seguimentos , Fundo de Olho , Humanos , Masculino , Pessoa de Meia-Idade , Receptores Nucleares Órfãos/metabolismo , Fenótipo , Distrofias Retinianas/genética , Distrofias Retinianas/metabolismo , Estudos Retrospectivos , Tomografia de Coerência Óptica , Adulto Jovem
14.
Am J Ophthalmol ; 199: 58-70, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30268864

RESUMO

PURPOSE: To delineate the natural history of visual parameters over time in individuals with biallelic RPE65 mutation-associated inherited retinal dystrophy (IRD); describe the range of causative mutations; determine potential genotype/phenotype relationships; and describe the variety of clinical diagnoses. DESIGN: Global, multicenter, retrospective chart review. METHODS: Study Population: Seventy individuals with biallelic RPE65 mutation-associated IRD. PROCEDURES: Data were extracted from patient charts. MEASUREMENTS: Visual acuity (VA), Goldmann visual field (GVF), optical coherence tomography, color vision testing, light sensitivity testing, and electroretinograms (retinal imaging and fundus photography were collected and analyzed when available). RESULTS: VA decreased with age in a nonlinear, positive-acceleration relationship (P < .001). GVF decreased with age (P < .0001 for both V4e and III4e), with faster GVF decrease for III4e stimulus vs V4e (P = .0114, left eye; P = .0076, right eye). On average, a 1-year increase in age decreased III4e GVF by ∼25 sum total degrees in each eye while V4e GVF decreased by ∼37 sum total degrees in each eye, although individual variability was observed. A total of 78 clinical diagnoses and 56 unique RPE65 mutations were recorded, without discernible RPE65 mutation genotype/phenotype relationships. CONCLUSIONS: The number of clinical diagnoses and lack of a consistent RPE65 mutation-to-phenotype correlation underscore the need for genetic testing. Significant relationships between age and worsening VA and GVF highlight the progressive loss of functional retina over time. These data may have implications for optimal timing of treatment for IRD attributable to biallelic RPE65 mutations.


Assuntos
Oftalmopatias Hereditárias/diagnóstico , Oftalmopatias Hereditárias/genética , Mutação , Distrofias Retinianas/diagnóstico , Distrofias Retinianas/genética , cis-trans-Isomerases/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos Transversais , Eletrorretinografia , Oftalmopatias Hereditárias/fisiopatologia , Feminino , Estudos de Associação Genética , Humanos , Lactente , Internacionalidade , Masculino , Distrofias Retinianas/fisiopatologia , Estudos Retrospectivos , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia , Testes de Campo Visual , Campos Visuais/fisiologia , Adulto Jovem
15.
Acta Ophthalmol ; 97(1): e116-e121, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30178525

RESUMO

PURPOSE: To assess choroidal structural changes in patients with retinal dystrophies using choroidal vascularity index (CVI), a novel optical coherence tomography (OCT) based tool. METHODS: This retrospective study included 26 patients with retinal dystrophies (17 with retinitis pigmentosa, four with Stargardt disease, three with cone-rod dystrophy, one each with Best disease and Bietti crystalline dystrophy) and 32 healthy controls. Subfoveal OCT images were used for analysis. Mean CVI was compared between retinal dystrophy and control group, as well as among the retinal dystrophy subgroups. RESULTS: Mean CVI in eyes with retinal dystrophies was 52 ± 9% and it was significantly lower compared to that in normal eyes (70 ± 3%, p < 0.001). The differences among subgroups of retinal dystrophy were not statistically significant (p = 0.084). All types of retinal dystrophy were associated with lower CVI (all p < 0.001), after adjusting for age, gender, visual acuity and duration of symptoms. Older age was also shown to be independently associated with lower CVI (p = 0.012). Gender, visual acuity (VA) and duration of symptoms did not significantly affect CVI. CONCLUSION: Decreased choroidal vascularity was seen in eyes with retinal dystrophies. (CVI) may be a helpful tool in monitoring choroidal involvement in retinal dystrophies.


Assuntos
Corioide/patologia , Distrofias Retinianas/diagnóstico , Vasos Retinianos/patologia , Tomografia de Coerência Óptica/métodos , Acuidade Visual , Adulto , Estudos de Casos e Controles , Corioide/irrigação sanguínea , Feminino , Seguimentos , Humanos , Masculino , Microscopia Acústica , Pessoa de Meia-Idade , Distrofias Retinianas/fisiopatologia , Estudos Retrospectivos , Adulto Jovem
16.
Adv Exp Med Biol ; 1085: 245-259, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30578524

RESUMO

Genomic approaches to developing new diagnostic and therapeutic strategies in retinal dystrophies are among the most advanced applications of genetics (Tsang SH, Gouras P (1996) Molecular physiology and pathology of the retina. In: Duane TD, Tasman W, Jaeger AE (eds) Duane's clinical opthalmology. Lippincott-Raven, Philadelphia). The notion that "nothing can be done" for patients with retinal dystrophies is no longer true. Electrophysiological testing and autofluorescence imaging help to diagnose and predict the patient's course of disease. Better phenotyping can contribute to better-directed, cost-efficient genotyping. Combining fundoscopy, autofluorescent imaging, and electrophysiological testing is essential in approaching patients with retinal dystrophies. Emerging are new gene-based treatments for these devastating conditions.


Assuntos
Distrofias Retinianas/diagnóstico , Distrofias Retinianas/terapia , Humanos , Oftalmoscopia , Imagem Óptica , Retina
17.
Adv Exp Med Biol ; 1085: 261-268, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30578525

RESUMO

Genetic testing is a medical test that studies human DNA to discover genetic changes or mutations that could lead to genetic disease. Genetic testing is performed on samples of DNA that can be obtained from blood, hair, skin, saliva, amniotic fluid, or other tissues. The test results are then sent in writing to the doctor or the genetic counsellor for discussion with the patient and the family.


Assuntos
Testes Genéticos , Distrofias Retinianas/diagnóstico , Distrofias Retinianas/genética , DNA , Humanos , Mutação
18.
Mol Vis ; 24: 679-689, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30416334

RESUMO

Purpose: The aim of this study was to identify the molecular genetic basis of hereditary retinal dystrophies (HRDs) in five unrelated Iranian families. Methods: Whole exome sequencing and Sanger sequencing were performed in all families. Variants were analyzed using various bioinformatics databases and software. Results: Based on the selected strategies, we identified potentially causative variants in five families with HRDs: the novel homozygous deletion mutation c.586_589delTTTG (p.F196Sfs*56) in the TTC8 gene of family A, the novel homozygous missense mutation c.2389T>C (p.S797P) in the CRB1 gene in family B, the novel homozygous frameshift mutation c.2707dupA (p.S903Kfs*66) in the LRP5 gene in family C, the novel homozygous splice mutation c.584-1G>T in the MERTK gene in family D, and the novel homozygous missense mutation c.1819G>C (p.G607R) rs61749412 in the ABCA4 gene of family E. Conclusions: This study highlights the presence of five novel variants associated with retinal dystrophies in selected Iranian families with hereditary blindness.


Assuntos
Oftalmopatias Hereditárias/diagnóstico , Predisposição Genética para Doença , Distrofias Retinianas/diagnóstico , Sequenciamento Completo do Exoma , Transportadores de Cassetes de Ligação de ATP/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Criança , Análise Mutacional de DNA , Oftalmopatias Hereditárias/genética , Proteínas do Olho/genética , Feminino , Humanos , Lactente , Irã (Geográfico) , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Masculino , Proteínas de Membrana/genética , Biologia Molecular , Proteínas do Tecido Nervoso/genética , Linhagem , Proteínas/genética , Distrofias Retinianas/genética , c-Mer Tirosina Quinase/genética
19.
Sci Rep ; 8(1): 15939, 2018 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-30374144

RESUMO

Among the Brazilian population, the frequency rates of inherited retinal dystrophies and their causative genes are underreported. To increase the knowledge about these dystrophies in our population, we retrospectively studied the medical records of 1,246 Brazilian patients with hereditary retinopathies during 20 years of specialized outpatient clinic care. Of these patients, 559 had undergone at least one genetic test. In this cohort, the most prevalent dystrophies were non-syndromic retinitis pigmentosa (35%), Stargardt disease (21%), Leber congenital amaurosis (9%), and syndromic inherited retinal dystrophies (12%). Most patients had never undergone genetic testing (55%), and among the individuals with molecular test results, 28.4% had negative or inconclusive results compared to 71.6% with a conclusive molecular diagnosis. ABCA4 was the most frequent disease-causing gene, accounting for 20% of the positive cases. Pathogenic variants also occurred frequently in the CEP290, USH2A, CRB1, RPGR, and CHM genes. The relative frequency rates of different inherited retinal dystrophies in Brazil are similar to those found globally. Although mutations in more than 250 genes lead to hereditary retinopathies, only 66 genes were responsible for 70% of the cases, which indicated that smaller and cheaper gene panels can be just as effective and provide more affordable solutions for implementation by the Brazilian public health system.


Assuntos
Distrofias Retinianas/diagnóstico , Transportadores de Cassetes de Ligação de ATP/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Antígenos de Neoplasias/genética , Brasil/epidemiologia , Proteínas do Olho/genética , Testes Genéticos , Humanos , Amaurose Congênita de Leber/diagnóstico , Amaurose Congênita de Leber/epidemiologia , Amaurose Congênita de Leber/genética , Degeneração Macular/congênito , Degeneração Macular/diagnóstico , Degeneração Macular/epidemiologia , Degeneração Macular/genética , Proteínas de Membrana/genética , Proteínas de Neoplasias/genética , Proteínas do Tecido Nervoso/genética , Polimorfismo Genético , Prevalência , Distrofias Retinianas/epidemiologia , Distrofias Retinianas/genética , Retinite Pigmentosa/diagnóstico , Retinite Pigmentosa/epidemiologia , Retinite Pigmentosa/genética , Estudos Retrospectivos
20.
Ophthalmologe ; 115(12): 1021-1027, 2018 Dec.
Artigo em Alemão | MEDLINE | ID: mdl-30259088

RESUMO

Hereditary retinal dystrophies represent a genetically and clinically heterogeneous group of diseases. A comprehensive characterization constitutes functional and high-resolution multimodal imaging. With the advent of novel treatment options the detection of the underlying gene causing the disease is becoming more important. Technical advances in molecular genetic diagnostics enable a classification of retinal dystrophies depending on the specific genetic cause of the disease, which is important particularly against the background of newly emerging therapy approaches. Targeted next generation sequencing (NGS), in particular is now an efficient method to accomplish this and can be especially helpful to identify rare and potentially new disease-causing variants. For the interpretation of the molecular genetic results a close collaboration between ophthalmologists and geneticists is essential.


Assuntos
Distrofias Retinianas , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Distrofias Retinianas/diagnóstico , Distrofias Retinianas/genética
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