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1.
Can J Ophthalmol ; 54(1): 51-59, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30851774

RESUMO

OBJECTIVE: To identify the disease-causing variants in 2 families with autosomal recessive inherited retinal dystrophies (IRDs) and to characterize phenotypic variability across the affected family members. DESIGN: Exome sequencing and ophthalmic clinical examination study. PARTICIPANTS: Six members from 2 consanguineous Jordanian families with IRD. METHODS: Ophthalmic examinations and whole-exome sequencing (WES) were performed to identify IRD-causing variants in affected individuals from each family, followed by segregation analysis of candidate variants in affected and unaffected family members by Sanger sequencing. RESULTS: We identified 2 different homozygous deletion variants in CERKL in each family: a novel pathogenic variant, c.450_451delAT, and a known variant, c.1187_1188delTG. Both variants co-segregated with the disease in all affected family members. The resulting phenotypes further supported that CERKL is associated with cone-rod dystrophy (CRD) rather than retinitis pigmentosa (RP), as originally established. CONCLUSION: Our study expands the genotypic spectra of CERKL variants, providing insights into the relevant pathogenesis of RP/CRD. We also confirm that the WES approach is a valuable tool for the molecular diagnosis of retinopathies.


Assuntos
Consanguinidade , DNA/genética , Mutação , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Distrofias Retinianas/genética , Adolescente , Adulto , Análise Mutacional de DNA , Exoma , Feminino , Genótipo , Humanos , Jordânia , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Distrofias Retinianas/congênito , Distrofias Retinianas/metabolismo , Adulto Jovem
3.
Prog Retin Eye Res ; 59: 53-96, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28363849

RESUMO

The identification of the genes underlying monogenic diseases has been of interest to clinicians and scientists for many years. Using inherited retinal dystrophies as an example of monogenic disease we describe the history of molecular genetic techniques that have been pivotal in the discovery of disease causing genes. The methods that were developed in the 1970's and 80's are still in use today but have been refined and improved. These techniques enabled the concept of the Human Genome Project to be envisaged and ultimately realised. When the successful conclusion of the project was announced in 2003 many new tools and, as importantly, many collaborations had been developed that facilitated a rapid identification of disease genes. In the post-human genome project era advances in computing power and the clever use of the properties of DNA replication has allowed the development of next-generation sequencing technologies. These methods have revolutionised the identification of disease genes because for the first time there is no need to define the position of the gene in the genome. The use of next generation sequencing in a diagnostic setting has allowed many more patients with an inherited retinal dystrophy to obtain a molecular diagnosis for their disease. The identification of novel genes that have a role in the development or maintenance of retinal function is opening up avenues of research which will lead to the development of new pharmacological and gene therapy approaches. Neither of which can be used unless the defective gene and protein is known. The continued development of sequencing technologies also holds great promise for the advent of truly personalised medicine.


Assuntos
Biologia Molecular/métodos , Retina/patologia , Distrofias Retinianas , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Distrofias Retinianas/congênito , Distrofias Retinianas/diagnóstico , Distrofias Retinianas/genética
4.
Semin Ophthalmol ; 32(4): 428-437, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27082703

RESUMO

PURPOSE: We aimed to assess psychiatric manifestations, health-related quality of life (HRQoL), and associated illness perceptions in patients with inherited retinal dystrophies (IRD). METHODS: In 48 IRD patients, we assessed a wide range of psychological distress symptoms (Symptom Distress Checklist-90-R), depressive symptom severity (PHQ-9), generic HRQoL (WHOQOL-BREF), and Illness Perceptions (B-IPQ). Ninety-six alleged healthy participants matched for age, sex, and education served as healthy controls and 331 patients with rheumatological disorders served as disease controls. RESULTS: IRD patients exhibited elevated symptoms of phobic anxiety (p=0.049) and paranoid ideation (p=0.028) compared to healthy and disease controls and were less satisfied with their general health (p<0.001) compared to disease controls. They shared, however, similar levels on all other aspects of psychiatric manifestations and HRQoL. The majority of patients acknowledged the hereditary and chronic nature of the illness. They also attributed more symptoms to their disease (illness identity) compared to people with rheumatological disorders (p<0.001), and this attribution was associated with paranoid ideation (p<0.05) and phobic anxiety (p<0.001). CONCLUSIONS: Broadening our view of the psychological variables which should be assessed in IRD patients may help to better identify those psychological parameters which impair the patients' well-being and yet may be amenable to treatment. The design of psycho-educational therapies targeting illness representations may have a beneficial effect upon the IRD patients' psychological distress and HRQoL.


Assuntos
Adaptação Psicológica , Nível de Saúde , Qualidade de Vida , Distrofias Retinianas/psicologia , Estresse Psicológico/psicologia , Inquéritos e Questionários , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Distrofias Retinianas/complicações , Distrofias Retinianas/congênito , Índice de Gravidade de Doença , Estresse Psicológico/etiologia
5.
Acta Ophthalmol ; 95(3): 252-261, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27682439

RESUMO

PURPOSE: To evaluate the relationship between the peripapillary metabolic alterations [retinal vessel Oximetry (RO)] and the structural findings [retinal vessel diameter and retinal nerve fibre layer thickness (RNFL)] in patients with inherited retinal dystrophies (IRD). METHODS: Patients with IRD [24 patients with rod-cone dystrophy (RCD), 15 patients with cone-rod dystrophy, 13 patients with inherited maculopathy] and 18 age-matched controls, who underwent RO imaging and spectral domain optical coherence tomography, were included. The average and quadrant oxygen saturation in all four major peripapillary retinal arterioles (A-SO2 ) and venules (V-SO2 ) were measured, and their difference (A-V SO2 ) was calculated. The corresponding retinal vessel diameter of these arterioles (D-A) and venules (D-V) was measured. The data were compared to the peripapillary RNFL thickness within the IRD subgroups and to the data obtained in the controls. RESULTS: In general, patients with IRD had higher average V-SO2 values when compared to controls (p ≤ 0.029). Rod-cone dystrophy (RCD) patients differed from controls, but also from patients with other IRDs, when the average and quadrant oxygen saturation values (A-SO2 and V-SO2 ) were evaluated (p ≤ 0.026). Within the RCD group, the correlations of RNFL thickness to V-SO2 , A-V SO2 , D-A and D-V were significant (p ≤ 0.030), thus indicating a different relationship between the RNFL thickness and the examined parameters, when compared to the other groups. CONCLUSION: It becomes evident from our combined metabolic-structural approach that a prediction model, to identify which individual is at risk of developing a photoreceptor degeneration of RCD type, can be proposed. It will take into account the peripapillary retinal oxygen saturation, the retinal vessel diameter and the RNFL thickness values.


Assuntos
Fibras Nervosas/patologia , Consumo de Oxigênio , Oxigênio/metabolismo , Distrofias Retinianas/metabolismo , Células Ganglionares da Retina/patologia , Vasos Retinianos/diagnóstico por imagem , Adulto , Estudos Transversais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Disco Óptico/patologia , Oximetria , Estudos Prospectivos , Distrofias Retinianas/congênito , Distrofias Retinianas/diagnóstico , Vasos Retinianos/metabolismo , Fatores de Tempo , Tomografia de Coerência Óptica
6.
s.l; España. Ministerio de Sanidad, Servicios Sociales e Igualdad. Servicio de Evaluación del Servicio Canario de la Salud; 2017. ilus.
Não convencional em Espanhol | BIGG | ID: biblio-914068

RESUMO

Esta Guía de Práctica Clínica aborda la asistencia proporcionada desde Atención Primaria y Atención especializada a las personas afectadas de alguna Distrofia Hereditaria de Retina en el diagnóstico, la evaluación estandarizada de la enfermedad, el abordaje terapéutico general, la rehabilitación de la baja visión, el seguimiento clínico, el manejo de las complicaciones asociadas, el embarazo, aspectos psicoeducativos y necesidades de información por parte de los pacientes.


Assuntos
Humanos , Serviços de Reabilitação , Distrofias Retinianas/congênito , Distrofias Retinianas/diagnóstico , Atenção Primária à Saúde
7.
Br J Ophthalmol ; 100(6): 829-33, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26359340

RESUMO

BACKGROUND: Conorenal syndrome is a systemic skeletal ciliopathy characterised by skeletal and renal findings and caused by biallelic mutations in the gene intraflagellar transport 140 Chlamydomonas homologue (IFT140). Most studies have focused on syndromic features and are by non-ophthalmologists. We highlight the ophthalmic phenotype. METHODS: Retrospective consecutive case series (2010-2014). RESULTS: Twelve subjects with confirmed homozygous mutations were identified (11 consanguineous families; 7 boys; assessed at age 10 months to 20 years, average and median age 6.5 and 4 years). All were homozygous for the same IFT140 mutation (c.1990G>A; p.Glu664Lys) except one who was homozygous for c.1541_1542delinsAA. All had poor vision and nystagmus since birth, with visual acuity after 5 years old of hand motions or light perception. In early childhood, nine were noted to stare at lights, four were noted to have a happy demeanour, high hyperopia was typical, and electroretinography was non-recordable. Fundus appearance was grossly normal before the age of 1 year but thereafter appeared dystrophic. Eight children had developmental delay, two had short stubby fingers, and one had renal disease, but four had no evident extraocular disease, including one aged 18 years who also had two older affected siblings in their twenties who remained non-syndromic and were excelling academically. CONCLUSIONS: Recessive IFT140 mutations cause a severe congenital retinal dystrophy with high hyperopia and often early photophilia. Developmental delay is common but not universal and not all patients have obvious extraocular findings. The c.1990G>A mutation represents a founder effect or mutational hotspot on the Arabian Peninsula.


Assuntos
Proteínas de Transporte/genética , Ciliopatias/genética , DNA/genética , Mutação , Distrofias Retinianas/congênito , Adolescente , Proteínas de Transporte/metabolismo , Criança , Pré-Escolar , Ciliopatias/etiologia , Ciliopatias/metabolismo , Análise Mutacional de DNA , Eletrorretinografia , Feminino , Genes Recessivos , Homozigoto , Humanos , Lactente , Masculino , Linhagem , Fenótipo , Retina/diagnóstico por imagem , Retina/fisiopatologia , Distrofias Retinianas/complicações , Distrofias Retinianas/genética , Estudos Retrospectivos , Adulto Jovem
8.
Invest Ophthalmol Vis Sci ; 56(2): 883-91, 2015 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-25574057

RESUMO

PURPOSE: To define the phenotypic manifestation, confirm the genetic basis, and delineate the pathogenic mechanisms underlying an oculoauricular syndrome (OAS). METHODS: Two individuals from a consanguineous family underwent comprehensive clinical phenotyping and electrodiagnostic testing (EDT). Genome-wide microarray analysis and Sanger sequencing of the candidate gene were used to identify the likely causal variant. Protein modelling, Western blotting, and dual luciferase assays were used to assess the pathogenic effect of the variant in vitro. RESULTS: Complex developmental ocular abnormalities of congenital cataract, anterior segment dysgenesis, iris coloboma, early-onset retinal dystrophy, and abnormal external ear cartilage presented in the affected family members. Genetic analyses identified a homozygous c.650A>C; p.(Gln217Pro) missense mutation within the highly conserved homeodomain of the H6 family homeobox 1 (HMX1) gene. Protein modelling predicts that the variant may have a detrimental effect on protein folding and/or stability. In vitro analyses were able to demonstrate that the mutation has no effect on protein expression but adversely alters function. CONCLUSIONS: Oculoauricular syndrome is an autosomal recessive condition that has a profound effect on the development of the external ear, anterior segment, and retina, leading to significant visual loss at an early age. This study has delineated the phenotype and confirmed HMX1 as the gene causative of OAS, enabling the description of only the second family with the condition. HMX1 is a key player in ocular development, possibly in both the pathway responsible for lens and retina development, and via the gene network integral to optic fissure closure.


Assuntos
Segmento Anterior do Olho/anormalidades , Catarata/genética , DNA/genética , Orelha/anormalidades , Anormalidades do Olho/genética , Proteínas de Homeodomínio/genética , Mutação , Distrofias Retinianas/diagnóstico , Anormalidades Múltiplas , Western Blotting , Catarata/congênito , Catarata/diagnóstico , Células Cultivadas , Pré-Escolar , Análise Mutacional de DNA , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/metabolismo , Testes Genéticos , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Fenótipo , Distrofias Retinianas/congênito , Distrofias Retinianas/genética
9.
Invest Ophthalmol Vis Sci ; 54(3): 2186-97, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23462753

RESUMO

PURPOSE: Hereditary retinal dystrophies (HRDs) are a group of monogenic diseases characterized by an irreversible loss of photoreceptors. HRDs exhibit significant genetic and clinical heterogeneities challenging traditional techniques for determining disease-causal mutations. This study aims to develop an efficient molecular diagnostic platform for HRDs, and to determine the genetic basis for 25 randomly collected Chinese families with a variety of HRDs. METHODS: We designed a high throughput sequence capture microarray targeting 179 genes associated with HRDs and 10 candidate genes. We combined sequence capture with next-generation sequencing (NGS) to screen for mutations in the cohort of Chinese families. Variants detected by NGS were filtered, validated, and prioritized by pathogenicity analysis. Genotypes and phenotypes were correlated. RESULTS: We identified four recurrent single mutations, two compound mutations, and eight novel putative causative mutations, including five putative pathogenic alleles (e.g., premature stop codons and frame shifts) and three novel missense variants that are very likely pathogenic. These findings provided specific genetic diagnoses in 14 of 25 families (56%). Among these, identification of a mutation in VCAN in a family with a complicated phenotype helped to finalize the clinical diagnosis as Wagner syndrome. In another five families, 11 potential novel pathogenic variants were identified. CONCLUSIONS: A substantial number of potential new genes and new mutations associated with HRDs remain to be discovered. Identification of the novel HRDs-causing mutations in our study not only provides a better understanding of genotype-phenotype relationships in these diseases, but also demonstrates that the approach described herein is an effective method for large scale mutation detection among diverse and complicated HRDs cases.


Assuntos
Análise Mutacional de DNA/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mutação/genética , Distrofias Retinianas/genética , Grupo com Ancestrais do Continente Asiático/genética , China , Estudos de Coortes , Predisposição Genética para Doença , Humanos , Análise em Microsséries , Linhagem , Distrofias Retinianas/congênito
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