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1.
Genes (Basel) ; 15(6)2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38927662

RESUMO

Inherited cone disorders (ICDs) are a heterogeneous sub-group of inherited retinal disorders (IRDs), the leading cause of sight loss in children and working-age adults. ICDs result from the dysfunction of the cone photoreceptors in the macula and manifest as the loss of colour vision and reduced visual acuity. Currently, 37 genes are associated with varying forms of ICD; however, almost half of all patients receive no molecular diagnosis. This review will discuss the known ICD genes, their molecular function, and the diseases they cause, with a focus on the most common forms of ICDs, including achromatopsia, progressive cone dystrophies (CODs), and cone-rod dystrophies (CORDs). It will discuss the gene-specific therapies that have emerged in recent years in order to treat patients with some of the more common ICDs.


Assuntos
Defeitos da Visão Cromática , Distrofias de Cones e Bastonetes , Células Fotorreceptoras Retinianas Cones , Humanos , Defeitos da Visão Cromática/genética , Distrofias de Cones e Bastonetes/genética , Células Fotorreceptoras Retinianas Cones/patologia , Células Fotorreceptoras Retinianas Cones/metabolismo , Distrofia de Cones/genética , Cegueira/genética , Animais , Terapia Genética/métodos
2.
Doc Ophthalmol ; 148(3): 173-182, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38630375

RESUMO

BACKGROUND: KCNV2-associated retinopathy causes a phenotype reported as "cone dystrophy with nyctalopia and supernormal rod responses (CDSRR; OMIM# 610356)," featuring pathognomonic findings on electroretinography (ERG). Here, we report the clinical courses of two siblings with CDSRR. CASE REPORTS: Patient 1: A 3-year-old boy with intermittent exophoria was referred to our hospital. The patient's decimal best-corrected visual acuity (BCVA) at age 6 was 0.7 and 0.7 in the right and left eyes, respectively. Photophobia and night blindness were also observed. Because the ERG showed a delayed and supernormal b-wave with a "squaring (trough-flattened)" a-wave in the DA-30 ERG, and CDSRR was diagnosed. The patient's vision gradually worsened, and faint bilateral bull's eye maculopathy was observed at the age of 27 years, although the fundi were initially unremarkable. Genetic examination revealed a homozygous missense variant, c.529T > C (p.Cys177Arg), in the KCNV2 gene. Patient 2: The second patient was Patient 1's younger sister, who was brought to our hospital at 3 years of age. The patient presented with exotropia, mild nystagmus, photophobia, night blindness, and color vision abnormalities. The patients' decimal BCVA at age 13 was 0.6 and 0.4 in the right and left eyes, respectively, and BCVA gradually decreased until the age of 24 years. The fundi were unremarkable. The siblings had similar ERG findings and the same homozygous missense variant in the KCNV2 gene. CONCLUSIONS: The siblings had clinical findings typical of CDSRR. High-intense flash ERG is recommended for identifying pathognomonic "squaring" a-waves in patients with CDSRR.


Assuntos
Eletrorretinografia , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Irmãos , Acuidade Visual , Humanos , Masculino , Pré-Escolar , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Acuidade Visual/fisiologia , Tomografia de Coerência Óptica , Feminino , Mutação de Sentido Incorreto , Distrofia de Cones/genética , Retina/fisiopatologia , Linhagem , Fenótipo , Análise Mutacional de DNA , DNA/genética
3.
Clin Exp Ophthalmol ; 52(5): 528-544, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38443311

RESUMO

BACKGROUND: KCNV2-associated retinopathy is an autosomal recessive inherited retinal disease classically named cone dystrophy with supernormal rod response (CDSRR). This study aims to identify the best biomarker for evaluating the condition. METHODS: A retrospective review of eight patients from seven families with genetically confirmed KCNV2-associated retinopathy was performed. The best corrected visual acuity (BCVA), full-field electroretinogram (ffERG), pattern ERG (pERG), fundus imaging: retinal photograph and fundus autofluorescence (FAF), and optical coherence tomography (OCT) were analysed. RESULTS: There was a disproportionate increase in b-wave amplitude with a relatively small light intensity increase, especially between the two dimmest stimuli of DA 0.002 and 0.01 (-2.7 and -2.0 log cd.s/m2). The a-wave amplitude was normal. The a-wave peak time was delayed in all stimuli. The b-wave peak time was delayed compared to normal, but the gap tightened as intensity increased. The b:a wave ratio was above or at the upper limit for the reference values. FAF bull's eye maculopathy pattern was prominent and variable foveal disruption on OCT was apparent in all patients. Legal blindness was reached before the age of 25. CONCLUSIONS: We identified three potential electrophysiology biomarkers to assist in evaluating future therapies: the disproportionate b-wave amplitude jump, delayed a-wave and b-wave peak time, and the higher than normal b:a wave ratio. Any of these biomarkers found with photoreceptor ellipsoid zone foveal-perifoveal disruption should prompt consideration for KCNV2 retinopathy. The BCVA natural history data suggests the probable optimum therapeutic window in the first three decades of life.


Assuntos
Biomarcadores , Eletrorretinografia , Tomografia de Coerência Óptica , Acuidade Visual , Humanos , Masculino , Feminino , Tomografia de Coerência Óptica/métodos , Estudos Retrospectivos , Adulto , Acuidade Visual/fisiologia , Biomarcadores/metabolismo , Adulto Jovem , Adolescente , Pessoa de Meia-Idade , Criança , Angiofluoresceinografia/métodos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Distrofia de Cones/genética , Distrofia de Cones/diagnóstico , Distrofia de Cones/fisiopatologia , Mutação
4.
JAMA Ophthalmol ; 142(4): 301-308, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38421662

RESUMO

Importance: Reliable biomarkers with diagnostic and prognostic values are needed for upcoming gene therapy trials for spinocerebellar ataxias. Objective: To identify ophthalmological biomarkers in a sample of spinocerebellar ataxia type 7 (SCA7) carriers. Design, Setting, and Participants: This article presents baseline data from a cross-sectional natural history study conducted in Paris, France, reference centers for rare diseases from May 2020 to April 2021. Data were analyzed from September to December 2022. Fifteen adult ATXN7 pathogenic expansion carriers (9 with preataxia and 6 with ataxia) were included, all with a Scale for the Assessment and Rating of Ataxia (SARA) score of 15 of 40 or lower. Patients were recruited at the Paris Brain Institute, and all contacted patients accepted to participate in the study. Main Outcomes and Measures: Three visits (baseline, 6 months, and 12 months) were planned, including neurological examination (SARA and Composite Cerebellar Functional Severity Score), ophthalmological examination (best-corrected visual acuity, microperimetry, full-field electroretinogram, optical coherence tomography, and fundus autofluorescence imaging), and neurofilament light chain (NfL) measurements. Here we report the baseline ophthalmic data from the cohort and determine whether there is a correlation between disease scores and ophthalmic results. Results: Among the 15 included SCA7 carriers (median [range] age, 38 [18-60] years; 8 women and 7 men), 12 displayed cone or cone-rod dystrophy, with the number of CAG repeats correlating with disease severity (ρ, 0.73, 95% CI, 0.34 to 0.90; P < .001). Two patients with cone-rod dystrophy exhibited higher repeat numbers and greater ataxia scores (median [range] SARA score, 9 [7-15]) compared to those with only cone dystrophy (median [range] SARA score, 2 [0-5]). A correlation emerged for outer nuclear layer thickness with SARA score (ρ, -0.88; 95% CI, -0.96 to -0.59; P < .001) and NfL levels (ρ, -0.87; 95% CI, -0.86 to 0.96; P < .001). Moreover, ataxia severity was correlated with visual acuity (ρ: 0.89; 95% CI, 0.68 to 0.96; P < .001) and retinal sensitivity (ρ, -0.88; 95% CI, -0.96 to 0.59; P < .001). Conclusions and Relevance: In this cross-sectional study, retinal abnormalities were found at preataxic stages of the disease. Most of the carriers presented with cone dystrophy and preserved rod function. The outer nuclear layer thickness correlated with SARA score and plasma NfL levels suggesting nuclear layer thickness to be a biomarker of disease severity. These findings contribute to understanding the dynamics of SCA7-related retinal dystrophy and may help lay the groundwork for future therapeutic intervention monitoring and clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT04288128.


Assuntos
Distrofia de Cones , Distrofias de Cones e Bastonetes , Ataxias Espinocerebelares , Adulto , Masculino , Humanos , Feminino , Estudos Transversais , Ataxias Espinocerebelares/diagnóstico , Cerebelo , Biomarcadores
5.
Ophthalmic Genet ; 45(1): 72-77, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37246743

RESUMO

PURPOSE: Patients with cone dystrophy (CD) can present with virtually normal retinal appearance, which may delay diagnosis. This study describes the inconspicuous clinical features of POC1B-associated CD in two Saudi families. METHODS: This is a retrospective case study. Clinical data analyzed included multimodal retinal imaging and electroretinography of the affected individuals. Genetic analysis was done for all probands. RESULTS: Three affected males from two Saudi families with POC1B-associated CD were included. The ages at presentation ranged from 18 to 34 years. Ophthalmic examination showed decreased Snellen visual acuities (range: 20/100-20/300) and color vision bilaterally. Fundus examination showed only mild vascular attenuation. Macular optical coherence tomography showed reduced reflectivity of the external limiting membrane, ellipsoid, and interdigitation zones. Full-field electroretinography demonstrated undetectable light-adapted responses and normal dark-adapted responses in all patients. Next-generation sequencing showed one proband to be homozygous for a previously unpublished nonsense variant in POC1B (NM_172240):c.672C>G; p(Tyr224*). Whole exome sequencing for the second proband showed a novel homozygous frameshifting variant in POC1B: c.991del; p(Arg331Glufs*13). CONCLUSION: We described two novel variants in POC1B and the associated subtle, yet significant retinal features. POC1B-associated CD is a rare cause of visual loss in patients with relatively normal fundus appearance. Deep phenotyping is necessary in formulating appropriate differential diagnosis.


Assuntos
Distrofia de Cones , Masculino , Humanos , Distrofia de Cones/diagnóstico , Estudos Retrospectivos , Transtornos da Visão/diagnóstico , Fundo de Olho , Homozigoto , Eletrorretinografia , Tomografia de Coerência Óptica , Mutação , Linhagem , Fenótipo , Proteínas de Ciclo Celular/genética
6.
Ophthalmic Genet ; 45(1): 84-94, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37158316

RESUMO

BACKGROUND: Ectrodactyly is a rare congenital limb malformation characterized by a deep median cleft of the hand and/or foot due to the absence of central rays. It could be isolated or depicts a part of diverse syndromic forms. Heterozygous pathogenic variants in the TP63 gene are responsible for at least four rare syndromic human disorders associated with ectrodactyly. Among them, ADULT (Acro-Dermato-Ungual-Lacrimal-Tooth) syndrome is characterized by ectodermal dysplasia, excessive freckling, nail dysplasia, and lacrimal duct obstruction, in addition to ectrodactyly and/or syndactyly. Ophthalmic findings are very common in TP63-related disorders, consisting mainly of lacrimal duct hypoplasia. Absent meibomian glands have also been well documented in EEC3 (Ectrodactyly Ectodermal dysplasia Cleft lip/palate) syndrome but not in ADULT syndrome. METHODS: We report a case of syndromic ectrodactyly consistent with ADULT syndrome, with an additional ophthalmic manifestation of agenesis of meibomian glands. The proband, as well as her elder sister, presented with congenital cone dystrophy.The molecular investigation was performed in the proband using Whole Exome Sequencing. Family segregation of the identified variants was confirmed by Sanger sequencing. RESULTS: Two clinically relevant variants were found in the proband: the novel de novo heterozygous missense c.931A > G (p.Ser311Gly) in the TP63 gene classified as pathogenic, and the homozygous nonsense pathogenic c.1810C > T (p.Arg604Ter) in the CNGB3 gene. The same homozygous CNGB3 variation was also found in the sister, explaining the cone dystrophy in both cases. CONCLUSIONS: Whole Exome Sequencing allowed dual molecular diagnoses: de novo TP63-related syndromic ectrodactyly and familial CNGB3-related congenital cone dystrophy.


Assuntos
Anodontia , Mama , Fenda Labial , Fissura Palatina , Distrofia de Cones , Displasia Ectodérmica , Obstrução dos Ductos Lacrimais , Deformidades Congênitas dos Membros , Unhas Malformadas , Transtornos da Pigmentação , Adulto , Feminino , Humanos , Mama/anormalidades , Fenda Labial/diagnóstico , Fenda Labial/genética , Fissura Palatina/genética , Canais de Cátion Regulados por Nucleotídeos Cíclicos/genética , Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/genética , Sequenciamento do Exoma , Glândulas Tarsais , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética
7.
Int J Mol Sci ; 24(23)2023 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-38069202

RESUMO

Sequencing of the low-complexity ORF15 exon of RPGR, a gene correlated with retinitis pigmentosa and cone dystrophy, is difficult to achieve with NGS and Sanger sequencing. False results could lead to the inaccurate annotation of genetic variants in dbSNP and ClinVar databases, tools on which HGMD and Ensembl rely, finally resulting in incorrect genetic variants interpretation. This paper aims to propose PacBio sequencing as a feasible method to correctly detect genetic variants in low-complexity regions, such as the ORF15 exon of RPGR, and interpret their pathogenicity by structural studies. Biological samples from 75 patients affected by retinitis pigmentosa or cone dystrophy were analyzed with NGS and repeated with PacBio. The results showed that NGS has a low coverage of the ORF15 region, while PacBio was able to sequence the region of interest and detect eight genetic variants, of which four are likely pathogenic. Furthermore, molecular modeling and dynamics of the RPGR Glu-Gly repeats binding to TTLL5 allowed for the structural evaluation of the variants, providing a way to predict their pathogenicity. Therefore, we propose PacBio sequencing as a standard procedure in diagnostic research for sequencing low-complexity regions such as RPGRORF15, aiding in the correct annotation of genetic variants in online databases.


Assuntos
Distrofia de Cones , Doenças Genéticas Ligadas ao Cromossomo X , Retinose Pigmentar , Humanos , Mutação , Proteínas do Olho/genética , Linhagem , Doenças Genéticas Ligadas ao Cromossomo X/genética , Retinose Pigmentar/diagnóstico , Retinose Pigmentar/genética , Retinose Pigmentar/metabolismo
9.
Doc Ophthalmol ; 147(3): 203-209, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37642804

RESUMO

PURPOSE: Biallelic mutations in the CEP290 gene cause early onset retinal dystrophy or syndromic disease such as Senior-Loken or Joubert syndrome. Here, we present an unusual non-syndromic case of a juvenile retinal dystrophy caused by biallelic CEP290 mutations imitating initially the phenotype of achromatopsia or slowly progressing cone dystrophy. METHODS: We present 13 years of follow-up of a female patient who presented first with symptoms and findings typical for achromatopsia. The patient underwent functional and morphologic examinations, including fundus autofluorescence imaging, spectral-domain optical coherence tomography, electroretinography, color vision and visual field testing. RESULTS: Diagnostic genetic testing via whole genome sequencing and virtual inherited retinal disease gene panel evaluation finally identified two compound heterozygous variants c.4452_4455del;p.(Lys1484Asnfs*4) and c.2414T > C;p.(Leu805Pro) in the CEP290 gene. CONCLUSIONS: CEP290 mutation causes a wide variety of clinical phenotypes. The presented case shows a phenotype resembling achromatopsia or early onset slowly progressing cone dystrophy.


Assuntos
Defeitos da Visão Cromática , Distrofia de Cones , Distrofias Retinianas , Humanos , Feminino , Distrofia de Cones/diagnóstico , Distrofia de Cones/genética , Defeitos da Visão Cromática/diagnóstico , Defeitos da Visão Cromática/genética , Eletrorretinografia , Mutação , Fenótipo , Tomografia de Coerência Óptica
10.
Sci Rep ; 13(1): 11223, 2023 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-37433860

RESUMO

To report the association of autoimmune polyglandular syndrome type 1 (APS1) with cone dystrophy in a large Saudi family. This is a Retrospective chart review and prospective genetic testing and ophthalmic examination of a large multiplex consanguineous family. Genetic testing was performed on 14 family members, seven of whom had detailed ophthalmic examinations. Medical history, ocular history and evaluation, visual field testing, full-field electroretinogram (ERG), and Whole Exome Sequencing (WES) results were analyzed. Three family members were homozygous for c.205_208dupCAGG;p.(Asp70Alafs*148) in AIRE and homozygous for c.481-1G>A in PDE6C. One additional family member was homozygous for only the AIRE variant and another additional family member was homozygous for only the PDE6C variant. All patients with homozygosity for the PDE6C variant had cone dystrophy, and all patients with homozygosity for the AIRE variant had APS1. In addition, two of the family members who were homozygous for the PDE6C and AIRE variants had reduced rod function on ERG. We report the co-inheritance for APS1 and PDE6C-related cone dystrophy, an unusual example of two seemingly independent recessive conditions coinciding within a family. Dual molecular diagnosis must be taken into account by ophthalmologists facing unusual constellations of findings, especially in consanguineous families.


Assuntos
Distrofia de Cones , Humanos , Estudos Prospectivos , Estudos Retrospectivos , Testes Genéticos , Homozigoto
11.
Stem Cell Res ; 69: 103099, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37121194

RESUMO

Cone dystrophy with supernormal rod response (CDSRR) is associated with pathogenic variants of the KCNV2 gene that result in severe symptoms, including color vision defects, decreased visual acuity, and specific changes in electroretinogram responses. Two iPSC lines were obtained from two patients in the same family with different types of mutations in the KCNV2 gene. These lines could serve as a useful model for studying the pathogenetic mechanism and treatment development for CDSRR. PBMCs from donors have been reprogrammed into iPSC lines. Derived clones were characterized with mutation sequencing, analysis of common pluripotency-associated markers at the protein levels, and in vitro differentiation studies.


Assuntos
Distrofia de Cones , Células-Tronco Pluripotentes Induzidas , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Humanos , Células Fotorreceptoras Retinianas Bastonetes , Mutação/genética , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética
12.
Indian J Ophthalmol ; 71(1): 195-201, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36588235

RESUMO

Purpose: The aim of this study was to elucidate the type of low vision devices (LVDs) prescribed for patients with cone dystrophy, cone-rod dystrophy, and rod-cone dystrophy and to analyze the visual improvement with the devices. Methods: A retrospective review of 300 electronic medical records of patients with cone dystrophy, cone-rod dystrophy, and rod-cone dystrophy referred to the low vision care (LVC) clinic for the first time between 2014 and 2016 at a tertiary eye care center was done. Collected data included the demographic profile of patients, details of LVDs, and best-corrected vision. Results: Out of 300 patients, 62.6% (n = 188) were male and 37.3% (n = 112) were female. Of the cases, 50% (n = 150) had cone-rod dystrophy, 45% (n = 135) had cone dystrophy, and 5% (n = 15) had rod-cone dystrophy. The most commonly prescribed LVD was SEE-TV binocular telescope (n = 6, 2.0%) for distance and dome magnifier (n = 60, 20%) for near. ET-40 dark grey tint (20.6%) was preferred for managing photophobia. There was a statistically significant difference in both distance and near visual acuities with LVDs (P < 0.05) in all categories, except rod-cone dystrophy. Conclusion: Early diagnosis with appropriate prescription of LVDs including tints helps in achieving good quality of vision in patients with cone-related dystrophies.


Assuntos
Distrofia de Cones , Distrofias de Cones e Bastonetes , Baixa Visão , Humanos , Masculino , Feminino , Baixa Visão/epidemiologia , Acuidade Visual , Fotofobia , Eletrorretinografia
13.
Eye (Lond) ; 37(12): 2461-2469, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-36509996

RESUMO

PURPOSE: In this study, we described a large family presenting different manifestations of cone dystrophy at different ages associated with GUCY2D gene mutation. METHOD: Sixty-three individuals of a single kindred, including 23 affected with cone dystrophies, were recruited and received ocular examinations, including best corrected visual acuity, intraocular pressure, slit-lamp biomicroscopy, color fundus photograph (CFP), fundus autofluorescence, optical coherence tomography, fluorescence fundus angiography, color vision testing, full-field electroretinography, and electro-oculogram. Whole exome sequencing (WES) and Sanger sequencing were performed for underlying mutations associated with cone dystrophy. RESULT: There were 23 affected family members. Clinical analysis showed that the proband and other patients had impaired visual acuity ranging from 20/800 to 20/50 with impaired color vision. Fundus photograph showed retinal pigment epithelium (RPE) granular abnormalities with depressed macular reflex in young patients and macular or retinochoriodal atrophy in older patients. OCT examination confirmed the reduced outer retinal thickness or inner retinal thickness, absence of the ellipsoid zone (EZ) and retinal atrophy to varying degrees. Electroretinography revealed a reduced cone response combined with a relatively maintained rod response. WES and Sanger sequencing revealed a heterozygous variant c.2512C>T in the GUCY2D gene of the affected family members. CONCLUSIONS: We reported cone dystrophy in 23 affected individuals in a five-generation family and demonstrated different macular abnormalities in OCT scans and CFP at different ages. The multimodal ocular records in our study provide physicians and ophthalmologists with a better understanding of cone dystrophy associated with GUCY2D mutation.


Assuntos
Distrofia de Cones , Degeneração Retiniana , Humanos , Idoso , Distrofia de Cones/patologia , Degeneração Retiniana/diagnóstico , Células Fotorreceptoras Retinianas Cones , Mutação , Eletrorretinografia , Atrofia/patologia , Tomografia de Coerência Óptica , Linhagem , Fenótipo
14.
Mol Genet Genomic Med ; 11(3): e2120, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36479642

RESUMO

BACKGROUND: Biallelic pathogenic variants in the neuroblastoma-amplified sequence (NBAS) gene manifest in a broad spectrum of disorders, including, but not limited to recurrent acute liver failure, skeletal dysmorphism, susceptibility to infections, and SOPH syndrome with its cardinal symptoms of short stature, optic atrophy, and Pelger-Huët anomaly. We aimed to present clinical and genetic characteristics of two sisters (20 and 15 years old) who were diagnosed with optic atrophy and cone dystrophy in childhood. Genome sequencing revealed two novel variants in NBAS in compound heterozygous state in both sisters, namely a 1-bp deletion predicted to result in a premature termination codon (c.5104del; p.(Met1702*)), and a non-canonical splice site variant of unclear significance (c.886-5T>A; p.?). RESULTS: Clinical examination and history revealed cone dystrophy, optic atrophy, and Pelger-Huët anomaly, but no short stature, recurrent acute liver failure, or susceptibility to infections. RNA analysis revealed that the c.886-5T>A variant results in two aberrant transcripts that are predicted to lead to in frame amino acid changes in the ß-propeller region of the protein. CONCLUSION: We hypothesize that the phenotype of our subjects, which appears to be at the end of the spectrum of NBAS-related disorders, could be explained by residual protein function mediated by the non-canonical splice site variant c.886-5T>A. Our study contributes to the existing knowledge on the genotypic and phenotypic spectrum of NBAS-related disorders.


Assuntos
Distrofia de Cones , Nanismo , Falência Hepática Aguda , Neuroblastoma , Atrofia Óptica , Anomalia de Pelger-Huët , Humanos , Anomalia de Pelger-Huët/diagnóstico , Anomalia de Pelger-Huët/genética , Anomalia de Pelger-Huët/patologia , Atrofia Óptica/genética , Falência Hepática Aguda/diagnóstico , Falência Hepática Aguda/genética , Nanismo/genética , Fenótipo
15.
Ophthalmic Genet ; 44(4): 389-395, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-36094084

RESUMO

PURPOSE: To report a case of cone dystrophy, associated with autosomal recessive homozygote POC1B gene variant, mimicking autoimmune retinopathy. CASE: A 45-year-old female presented with a complaint of decreased vision in both eyes. Her best corrected visual acuity was 20/32 in the right eye and 20/50 in the left eye. Anterior segment and dilated fundus examinations were unremarkable. Spectral domain optical coherence tomography showed a subfoveal blurred dome-shaped ellipsoid zone and an extinguished interdigitation zone affecting the entire macula. Full field electroretinography revealed reduced cone responses. The differential diagnosis included inflammatory chorioretinopathies, autoimmune retinopathies (paraneoplastic or nonparaneoplastic), and hereditary retinal dystrophies. No remarkable finding was observed on combined fluorescein and indocyanine green angiographies. Paraneoplastic autoimmune antibody panel revealed nothing; however, aldolase, enolase, pyruvate kinase M2, and glyceraldehyde-3-phosphate dehydrogenase antibodies were positive on autoimmune retinopathy panel. To exclude hereditary retinal dystrophies, whole-exome sequencing (WES) was applied. WES identified an autosomal recessive homozygote POC1B gene variant (c.680A>G, p.His227Arg). Cone dystrophy diagnosis was given. CONCLUSION: Cone dystrophy associated with POC1B gene variant may present without visible fundus abnormalities. It should be kept in mind that retinal autoantibodies may be positive in such a hereditary dystrophy case due to long-term exposure of the immune system to self-antigens. Therefore, autoimmune retinopathy is a diagnosis of exclusion and should not be diagnosed until all other causes, including hereditary dystrophies, have been ruled out.


Assuntos
Doenças Autoimunes , Distrofia de Cones , Distrofias Retinianas , Feminino , Humanos , Pessoa de Meia-Idade , Distrofia de Cones/diagnóstico , Retina , Células Fotorreceptoras Retinianas Cones , Distrofias Retinianas/diagnóstico , Distrofias Retinianas/genética , Eletrorretinografia , Tomografia de Coerência Óptica/métodos , Angiofluoresceinografia , Proteínas de Ciclo Celular/genética
16.
Mol Vis ; 29: 329-337, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38264610

RESUMO

Purpose: Autosomal recessive cone and cone-rod dystrophies (CD/CRD) are inherited forms of vison loss. Here, we report on and correlate the clinical phenotypes with the underlying genetic mutations. Methods: Clinical information was collected from subjects, including a family history with a chart review. They underwent a full ophthalmic examination, including best-corrected visual acuity, direct and indirect ophthalmoscopy, color vision testing, color fundus photography, contrast sensitivity, autofluorescence, and spectral domain-optical coherence tomography (SD-OCT), and full-field electroretinography. Next-generation panel-based genetic testing was used to identify DNA variants in subject buccal swab samples. Results: Genetic testing in two patients revealed three novel variants in the TTLL5 gene associated with CD/CRD: two missense variants (c.1433G>A;p.(Arg478Gln), c.241C>G;p.(Leu81Val), and one loss-of-function variant (c.2384_2387del;p.(Ala795Valfs*9). Based on in-silico analysis, structural modeling, and comparison to previously reported mutations, these novel variants are very likely to be disease-causing mutations. Combining retinal imaging with SD-OCT analysis, we observed an unusual sheen in the CD/CRD phenotypes. Conclusion: Based on the protein domain location of novel TTLL5 variants and the localization of TTLL5 to the connecting cilium, we conclude that the CD/CRD disease phenotype is characterized as a ciliopathy caused by protein tracking dysfunction. This initially affects cone photoreceptors, where photoreceptor cilia express a high level of TTLL5, but extends to rod photoreceptors over time. Fundus photography correlated with SD-OCT imaging suggests that the macular sheen characteristically seen with TTLL5 mutations derives from the photoreceptor's outer segments at the posterior pole.


Assuntos
Distrofia de Cones , Distrofias de Cones e Bastonetes , Distrofias Retinianas , Humanos , Células Fotorreceptoras Retinianas Cones , Tomografia de Coerência Óptica , Tubulina (Proteína) , Fenótipo , Tirosina , Proteínas de Transporte
17.
Cell Mol Life Sci ; 79(8): 409, 2022 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-35810394

RESUMO

Inherited retinal diseases (IRDs) are a heterogeneous group of blinding disorders, which result in dysfunction or death of the light-sensing cone and rod photoreceptors. Despite individual IRDs (Inherited retinal disease) being rare, collectively, they affect up to 1:2000 people worldwide, causing a significant socioeconomic burden, especially when cone-mediated central vision is affected. This study uses the Pde6ccpfl1 mouse model of achromatopsia, a cone-specific vision loss IRD (Inherited retinal disease), to investigate the potential gene-independent therapeutic benefits of a histone demethylase inhibitor GSK-J4 on cone cell survival. We investigated the effects of GSK-J4 treatment on cone cell survival in vivo and ex vivo and changes in cone-specific gene expression via single-cell RNA sequencing. A single intravitreal GSK-J4 injection led to transcriptional changes in pathways involved in mitochondrial dysfunction, endoplasmic reticulum stress, among other key epigenetic pathways, highlighting the complex interplay between methylation and acetylation in healthy and diseased cones. Furthermore, continuous administration of GSK-J4 in retinal explants increased cone survival. Our results suggest that IRD (Inherited retinal disease)-affected cones respond positively to epigenetic modulation of histones, indicating the potential of this approach in developing a broad class of novel therapies to slow cone degeneration.


Assuntos
Defeitos da Visão Cromática , Distrofia de Cones , Animais , Defeitos da Visão Cromática/metabolismo , Distrofia de Cones/metabolismo , Modelos Animais de Doenças , Histonas/metabolismo , Humanos , Camundongos , Células Fotorreceptoras Retinianas Cones/metabolismo
18.
Zhonghua Yan Ke Za Zhi ; 58(5): 376-379, 2022 May 11.
Artigo em Chinês | MEDLINE | ID: mdl-35511665

RESUMO

The proband was an 8-year-old boy, complaining of progressively decreased vision in both eyes for 3 years. The electroretinogram was characterized by supernormal rod response. While the responses of the rod and cone system were reduced, the amplitudes of dark-adapted electroretinogram responses at a high intensity were supernormal. A homozygous non-frameshift deletion variant c.1002-1004del (p. L335del) in KCNV2 was found by the Next Generation Sequencing using a custom designed panel. His father was a heterozygous carrier of this variant. In silico analysis indicated the variant was harmful. The proband was diagnosed as cone dystrophy type 3B which also known as cone dystrophy with supernormal rod response.


Assuntos
Distrofia de Cones , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Retinose Pigmentar , Criança , Eletrorretinografia , Humanos , Masculino , Células Fotorreceptoras Retinianas Cones/fisiologia
20.
Eur J Ophthalmol ; 32(1): 664-672, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33706576

RESUMO

PURPOSE: To describe the clinical, electrophysiological, and genetic findings of three Portuguese families with a rare variant in the KCNV2 gene resulting in "cone dystrophy with supernormal rod responses" (CDSRR). METHODS: Retrospective clinical revision of five individuals from three unrelated families with CDSRR. Ophthalmological examination was described in all patients and included color vision testing, fundus photography, fundus autofluorescence (FAF) imaging, spectral domain-optical coherence tomography (SD-OCT), pattern electroretinogram (ERG), and full-field ERG. The mutational screening of the KCNV2 gene was performed with Sanger and Next Generation Sequencing. RESULTS: All patients showed childhood-onset photophobia and progressive visual acuity loss with varying degrees of severity. In multimodal imaging, various degrees of retinal pigment epithelium disturbances and outer retinal atrophy, which tend to be worst with advancing age, were observed. Molecular screening identified a rare presumed truncating variant (p.Glu209Ter) in homozygosity in two families and in compound heterozygosity in a third family. Three patients showed ERG changes characteristic of CDSRR, however, two patients presented with incomplete electrophysiological features of the disease. CONCLUSION: A rare variant in the KCNV2 gene was identified in five patients from three Portuguese families. This variant often leads to a severe and progressive form of retinopathy. Considerable variability in the ERG responses among patients with this KCNV2 variant was observed.


Assuntos
Distrofia de Cones , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Retinose Pigmentar , Eletrorretinografia , Humanos , Portugal , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Estudos Retrospectivos , Tomografia de Coerência Óptica
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