RESUMO
Retinitis pigmentosa 11 is an untreatable, dominantly inherited retinal disease caused by heterozygous mutations in pre-mRNA processing factor 31 PRPF31. The expression level of PRPF31 is linked to incomplete penetrance in affected families; mutation carriers with higher PRPF31 expression can remain asymptomatic. The current study explores an antisense oligonucleotide exon skipping strategy to treat RP11 caused by truncating mutations within PRPF31 exon 12 since it does not appear to encode any domains essential for PRPF31 protein function. Cells derived from a patient carrying a PRPF31 1205C>A nonsense mutation were investigated; PRPF31 transcripts encoded by the 1205C>A allele were undetectable due to nonsense-mediated mRNA decay, resulting in a 46% reduction in PRPF31 mRNA, relative to healthy donor cells. Antisense oligonucleotide-induced skipping of exon 12 rescued the open reading frame with consequent 1.7-fold PRPF31 mRNA upregulation in the RP11 patient fibroblasts. The level of PRPF31 upregulation met the predicted therapeutic threshold of expression inferred in a non-penetrant carrier family member harbouring the same mutation. This study demonstrated increased PRPF31 expression and retention of the nuclear translocation capability for the induced PRPF31 isoform. Future studies should evaluate the function of the induced PRPF31 protein on pre-mRNA splicing in retinal cells to validate the therapeutic approach for amenable RP11-causing mutations.
Assuntos
Oligonucleotídeos Antissenso , Precursores de RNA , Retinose Pigmentar , Humanos , Precursores de RNA/genética , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/uso terapêutico , Fases de Leitura Aberta , Mutação , Códon sem Sentido , Proteínas do Olho/genética , Proteínas do Olho/metabolismo , LinhagemRESUMO
Peripapillary hyperreflective ovoid mass-like structures (PHOMS) are a laterally bulging herniation of distended axons into the peripapillary region above the level of Bruch's membrane opening. Increased use of enhanced depth imaging-optical coherence tomography (EDI-OCT) in our evaluation of the optic nerve head (ONH) and greater recognition of the vast range of optic nerve pathologies with which PHOMS is associated provides convincing evidence that PHOMS is not just buried optic disc drusen (ODD) as previously described. The frequent coexistence of PHOMS with ODD, papilloedema, anterior ischaemic optic neuropathy, tilted optic disc syndrome, inflammatory demyelinating disorders and other diseases associated with axoplasmic stasis provides insight into its underlying pathophysiology. The present review will discuss the role of key imaging modalities in the differential diagnosis of PHOMS, explore the current literature on the relationship between PHOMS and common neuro-ophthalmic conditions, and highlight the gaps in our knowledge, with respect to disease classification and prognosis, to pave the way for future directions of research.
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Drusas do Disco Óptico , Disco Óptico , Papiledema , Humanos , Disco Óptico/patologia , Drusas do Disco Óptico/complicações , Papiledema/complicações , Papiledema/diagnóstico , Papiledema/patologia , Tomografia de Coerência Óptica/métodos , Imagem MultimodalRESUMO
PURPOSE: To characterize the genotypic and phenotypic spectrum of foveal hypoplasia (FH). DESIGN: Multicenter, observational study. PARTICIPANTS: A total of 907 patients with a confirmed molecular diagnosis of albinism, PAX6, SLC38A8, FRMD7, AHR, or achromatopsia from 12 centers in 9 countries (n = 523) or extracted from publicly available datasets from previously reported literature (n = 384). METHODS: Individuals with a confirmed molecular diagnosis and availability of foveal OCT scans were identified from 12 centers or from the literature between January 2011 and March 2021. A genetic diagnosis was confirmed by sequence analysis. Grading of FH was derived from OCT scans. MAIN OUTCOME MEASURES: Grade of FH, presence or absence of photoreceptor specialization (PRS+ vs. PRS-), molecular diagnosis, and visual acuity (VA). RESULTS: The most common genetic etiology for typical FH in our cohort was albinism (67.5%), followed by PAX6 (21.8%), SLC38A8 (6.8%), and FRMD7 (3.5%) variants. AHR variants were rare (0.4%). Atypical FH was seen in 67.4% of achromatopsia cases. Atypical FH in achromatopsia had significantly worse VA than typical FH (P < 0.0001). There was a significant difference in the spectrum of FH grades based on the molecular diagnosis (chi-square = 60.4, P < 0.0001). All SLC38A8 cases were PRS- (P = 0.003), whereas all FRMD7 cases were PRS+ (P < 0.0001). Analysis of albinism subtypes revealed a significant difference in the grade of FH (chi-square = 31.4, P < 0.0001) and VA (P = 0.0003) between oculocutaneous albinism (OCA) compared with ocular albinism (OA) and Hermansky-Pudlak syndrome (HPS). Ocular albinism and HPS demonstrated higher grades of FH and worse VA than OCA. There was a significant difference (P < 0.0001) in VA between FRMD7 variants compared with other diagnoses associated with FH. CONCLUSIONS: We characterized the phenotypic and genotypic spectrum of FH. Atypical FH is associated with a worse prognosis than all other forms of FH. In typical FH, our data suggest that arrested retinal development occurs earlier in SLC38A8, OA, HPS, and AHR variants and later in FRMD7 variants. The defined time period of foveal developmental arrest for OCA and PAX6 variants seems to demonstrate more variability. Our findings provide mechanistic insight into disorders associated with FH and have significant prognostic and diagnostic value.
Assuntos
Albinismo Ocular , Albinismo Oculocutâneo , Albinismo , Defeitos da Visão Cromática , Albinismo Ocular/diagnóstico , Albinismo Ocular/genética , Albinismo Oculocutâneo/diagnóstico , Albinismo Oculocutâneo/genética , Defeitos da Visão Cromática/diagnóstico , Defeitos da Visão Cromática/genética , Proteínas do Citoesqueleto , Fóvea Central/anormalidades , Humanos , Proteínas de Membrana , Transtornos da Visão/diagnósticoRESUMO
Type 2 idiopathic macular telangiectasia (MacTel-2) is a progressive adult-onset macular disease associated with bilateral perifoveal vascular changes, Muller cell degeneration and increased blood-retinal barrier permeability. The pathophysiological mechanisms of MacTel-2 remain unclear, however it was previously reported that anti-retinal antibodies in MacTel-2 patients are a significant feature of the disease. In this study, we aimed to compare the prevalence of anti-retinal antibodies in patients MacTel-2, healthy controls and patients with other retinal diseases. MacTel-2 patients diagnosed with multimodal imaging were enrolled and their disease severities were graded using spectral-domain optical coherence tomography. For comparison, patients with age-related macular degeneration (AMD), inherited retinal diseases (IRDs) or no retinal disease (healthy controls) were recruited as controls. Blood serum samples were screened for immunoglobulin G anti-retinal antibodies by western blotting, followed by densitometry analysis. Odds ratios (OR) with 95% confidence intervals (CI) were calculated and p < 0.05 considered statistically significant. Overall, anti-retinal antibody-positive cases were older (64 ± 15 vs 53 ± 17 years, p < 0.001) and females were more likely to develop anti-retinal antibodies (OR: 2.41, CI: 1.12-5.18). The frequency of anti-retinal antibody detection in MacTel-2 patients (n = 42, 36%) was not significantly different from healthy controls (n = 52, 25%) or IRD patients (n = 18, 25%) and the majority of MacTel-2 patients had no anti-retinal antibodies. In contrast, the frequency of anti-retinal antibody detection was significantly higher in patients with AMD (n = 15, 73%, p < 0.001). The lack of a greater anti-retinal antibody frequency or specificity in the MacTel-2 cohort suggests that antibody mediated immunological mechanisms may play a less significant role in MacTel-2 disease pathogenesis.
Assuntos
Retinopatia Diabética , Degeneração Macular , Telangiectasia Retiniana , Adulto , Retinopatia Diabética/patologia , Feminino , Humanos , Imunoglobulina G , Degeneração Macular/patologia , Retina/patologia , Telangiectasia Retiniana/diagnóstico , Telangiectasia Retiniana/patologia , Tomografia de Coerência Óptica/métodosRESUMO
PURPOSE: To investigate retinal sensitivity changes in eyes with pure cuticular drusen. METHODS: Multimodal imaging and microperimetry (37-loci grid) data were examined retrospectively to evaluate functional changes in eyes with pure cuticular drusen. Mean sensitivity in the cuticular drusen cohort was compared to age-matched normals. An age- and loci-specific normative reference was created to analyse localised sensitivity deviation. RESULTS: The mean number loci with relative scotoma in the cuticular drusen cohort (n = 27, mean [SD] age: 48.5 [12.4] years) referenced to normal eyes (n = 80, 53.5 [14.6] years) was 5.5 (95% confidence interval 3.0 to 8.1). However, mean sensitivity was not statistically different to the age-matched normal cohort (95% CI, - 2.3 to + 3.4 dB). The 37-loci grid was stratified into three rings of the approximately same number of loci, and the percentage of cuticular drusen eyes with pointwise deviation was significantly lower in the inner compared to the middle ring (12.3 [5.3]% vs. 17.3 [5.1]%, p < 0.05). CONCLUSIONS: Eyes with cuticular drusen demonstrated relative scotoma, but mean sensitivity was not affected. Pointwise sensitivity provides a more robust measure of retinal sensitivity than mean sensitivity in cuticular drusen and should be assessed both in the clinic and in future clinical trials.
Assuntos
Drusas Retinianas , Escotoma , Lâmina Basilar da Corioide/patologia , Oftalmopatias Hereditárias , Humanos , Pessoa de Meia-Idade , Drusas Retinianas/diagnóstico , Estudos Retrospectivos , Escotoma/diagnóstico , Escotoma/etiologia , Tomografia de Coerência Óptica/métodosRESUMO
PURPOSE: To investigate concordance in symptom onset, area of dark autofluorescence (DAF), and growth rate (GR) between Stargardt disease siblings at an age-matched time point. METHODS: In this retrospective longitudinal study of sibling pairs with identical biallelic ABCA4 variants, age at symptom onset, best-corrected visual acuity, atrophy area, and effective radius of DAF on ultra-widefield fundus autofluorescence were recorded. Absolute intersibling differences for both eyes were compared with absolute interocular differences using the Mann-Whitney test. RESULTS: Overall 39 patients from 19 families were recruited. In 16 families, age-matched best-corrected visual acuity and DAF were compared between siblings. In 8 families, DAF GR was compared. The median (range) absolute difference in age at symptom onset between siblings was 3 (0-35) years. Absolute intersibling differences in age-matched best-corrected visual acuity were greater than interocular differences ( P = 0.01). Similarly, absolute intersibling differences in DAF area and radius were greater than interocular differences ( P = 0.04 for area and P = 0.001 for radius). Differences between absolute interocular and intersibling GR were not statistically significant ( P = 0.44 for area GR and P = 0.61 for radius GR). CONCLUSION: There was significant discordance in age-matched best-corrected visual acuity and DAF beyond the expected limits of interocular asymmetry. Lack of significant intersibling differences in GR warrants further investigation.
Assuntos
Eletrorretinografia , Degeneração Macular , Doença de Stargardt , Transportadores de Cassetes de Ligação de ATP/genética , Adolescente , Adulto , Atrofia , Criança , Pré-Escolar , Angiofluoresceinografia , Fundo de Olho , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Degeneração Macular/diagnóstico , Degeneração Macular/genética , Estudos Retrospectivos , Irmãos , Doença de Stargardt/diagnóstico , Doença de Stargardt/genética , Tomografia de Coerência Óptica , Acuidade Visual , Adulto JovemRESUMO
PURPOSE: The c.1430A > G (Asp477Gly) variant in RPE65 has been reported in Irish and Scottish families with either an autosomal dominant retinal dystrophy (adRD) that resembles choroideremia, a vitelliform macular dystrophy or an isolated macular atrophy. We report novel features on multimodal imaging and the natural history of a family harbouring this variant in combination with the BEST1 c.37C > T (Arg13Cys) variant. METHODS: Members of a family with an adRD were examined clinically to ascertain phenotype and underwent genetic testing. Multimodal imaging included widefield colour fundus photography, quantitative autofluorescence (qAF) and spectral domain optical coherence tomography. Electrophysiology and microperimetry were also performed. RESULTS: Vision loss was attributed to foveal atrophy in the proband and choroidal neovascularisation and a vitello-eruptive lesion in one affected son. Peripheral retinal white dots corresponding to subretinal deposits were seen in three patients. The median qAF8 values in the proband (I:1) were low (40 and 101 in OD and OS) at age 79. Similarly, the qAF8 values for the middle son (II:2) were also low (100 and 87 in ODS and OS) at age 60. Electrophysiology showed disproportionate reduction in Arden ratio prior to the gradual loss of full-field responses. Microperimetry demonstrated an enlarging scotoma in the proband. CONCLUSIONS: The coexistence of the pathogenic BEST1 c.37C > T variant may modify clinical features observed in RPE65 adRD. This study expands our understanding of RPE65 adRD as a retinoid cycle disorder supported by the reduced qAF, fine white retinal dots and corresponding subretinal deposits on OCT in affected members.
Assuntos
Bestrofinas , Distrofias Retinianas , Distrofia Macular Viteliforme , cis-trans-Isomerases , Idoso , Bestrofinas/genética , Eletrorretinografia , Angiofluoresceinografia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Fenótipo , Distrofias Retinianas/diagnóstico , Distrofias Retinianas/genética , Tomografia de Coerência Óptica , cis-trans-Isomerases/genéticaRESUMO
PURPOSE: To establish a mutation-specific age-dependent ultra-widefield fundus autofluorescence (UWF-FAF) trajectory in a large Stargardt disease (STGD1) cohort using total lesion size (TLS) and to develop a clinical method for variant classification. METHODS: A retrospective study of patients with biallelic ABCA4 mutations that were evaluated with UWF-FAF. Boundaries of TLS, defined by stippled hyper/hypoautofluorescence, were outlined manually. Pathogenicity was assessed according to ACMG/AMP criteria, and mutation severities were classified based on the current literature. Age-dependent trajectories in TLS were examined in patients with nullizygous, mild, and intermediate mutations. Mutations of uncertain severities were classified using a clinical criterion based on age of symptom onset and TLS. RESULTS: Eighty-one patients with STGD1 (mean age = 42 ± 20 years and mean visual acuity = 20/200) were recruited from 65 unrelated families. Patients with biallelic null/severe variants (n = 6) demonstrated an increase in TLS during their second decade reaching a mean ± SD of 796 ± 29 mm2 by age 40. Those harboring mild mutations c.5882G>A or c.5603A>T had lesions confined to the posterior pole with a mean ± SD TLS of 30 ± 39 mm2. Intermediate mutations c.6079C>T or c.[2588G>C;5603A>T] in trans with a null/severe mutation had a mean ± SD TLS of 397 ± 29 mm2. Thirty-two mutations were predicted to cause severe (n = 22), intermediate (n = 6), and mild (n = 5) impairment of ABCA4 function based on age of symptom onset and TLS. CONCLUSION: Age-dependent TLS showed unique ABCA4 mutation-specific trajectories. Our novel clinical criterion using age of symptom onset and TLS to segregate ABCA4 mutations into three severity groups requires further molecular studies to confirm its validity.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Análise Mutacional de DNA/classificação , Mutação/genética , Doença de Stargardt/diagnóstico por imagem , Doença de Stargardt/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Eletrorretinografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Imagem Óptica , Estudos Retrospectivos , Índice de Gravidade de Doença , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia , Adulto JovemRESUMO
Stargardt disease (STGD1) is an autosomal recessive retinal dystrophy, characterised by bilateral progressive central vision loss and subretinal deposition of lipofuscin-like substances. Recent advances in molecular diagnosis and therapeutic options are complemented by the increasing recognition of new multimodal imaging biomarkers that may predict genotype and disease progression. Unique non-invasive imaging features of STDG1 are useful for gene variant interpretation and may even provide insight into the underlying molecular pathophysiology. In addition, pathognomonic imaging features of STGD1 have been used to train neural networks to improve time efficiency in lesion segmentation and disease progression measurements. This review will discuss the role of key imaging modalities, correlate imaging signs across varied STGD1 presentations and illustrate the use of multimodal imaging as an outcome measure in determining the efficacy of emerging STGD1 specific therapies.
Assuntos
Distrofias Retinianas , Tomografia de Coerência Óptica , Angiofluoresceinografia , Humanos , Lipofuscina , Doença de StargardtRESUMO
PURPOSE: To present the distribution of time to retinal redetachment in eyes undergoing retinal detachment surgery, using a method for adjusting time to outcome in eyes with silicone oil or heavy liquid tamponade ("oil-filled eyes"). METHODS: Data from two Australian centers were used. Adjusted time to outcome was measured from the date of tamponade removal in oil-filled eyes, unless failure was diagnosed with tamponade in situ. RESULTS: 188/1257 failures were identified (15.0%). Using unadjusted time to outcome, failures in oil-filled eyes occurred later than non-oil-filled eyes (median time to failure 57 vs. 28 days, P < 0.001). After adjustment, the distribution of time to failure was similar for oil-filled and non-oil-filled eyes (median 25 vs. 28 days, P = 0.68). Larger detachments, eyes with ≥Grade B proliferative vitreoretinopathy and eyes receiving surgery for recurrent detachments were more likely to fail, but the time to failure was similar regardless of risk. CONCLUSION: Adjustment of time to outcome resulted in a similar distribution of time to failure in oil-filled and non-oil filled eyes and was similar in low- and high-risk eyes. The use of adjusted time to outcome will support consistent collection and interpretation of outcomes across different jurisdictions where time to oil removal may vary.
Assuntos
Tamponamento Interno , Descolamento Retiniano/cirurgia , Recurvamento da Esclera , Vitrectomia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Descolamento Retiniano/fisiopatologia , Óleos de Silicone/administração & dosagem , Fatores de Tempo , Falha de Tratamento , Acuidade Visual/fisiologiaRESUMO
The application of artificial intelligence in medicine, particularly in relation to screening and diagnosis of disease through imaging analysis, will have a profound impact over the next decade. This communication discusses regulatory challenges that should be considered by physicians and how potential issues may be mitigated using a collaborative approach, drawing on the combined expertise of relevant stakeholders.
Assuntos
Medicina , Médicos , Inteligência Artificial , HumanosRESUMO
AIM: There has been an increased use of heated humidified high flow nasal canula (HFNC) in premature babies (PBs) admitted to our neonatal unit. The aim of this study is to identify clinical characteristics in PBs < 29 weeks gestational age (GA) that distinguish between those who did not or did receive HFNC. METHODS: This study compared prospectively collected data from 2010 to 2012. Comparisons were undertaken between PBs<29 weeks GA who received continuous positive airway pressure (CPAP: 44/72 (61.1%)) to those who received both CPAP and HFNC (28/72 (38.9%)). Data were analysed using general linear models. RESULTS: There were no significant differences in baseline characteristics between the groups (GA: 27.6 ± 1.1 vs. 27.5 ± 1.1 (weeks), birth weight: 1066 ± 209 vs. 1057 ± 304 (grams) respectively). When analysing outcome measures with multivariate analysis, we found the corrected GA to cease CPAP and oxygen were significantly longer in the HFNC group (31.2 ± 2.1 vs. 32.7 ± 2.0 weeks, P = 0.01 and 32.8 ± 3.5 vs. 36.5 ± 2.8 weeks, P < 0.0001 respectively). CONCLUSIONS: Increased use of HFNC has been associated with increased oxygen requirements. These findings highlight the need to review the use of HFNC in small PBs.
Assuntos
Cânula/efeitos adversos , Ventilação não Invasiva/métodos , Oxigenoterapia/métodos , Pressão Positiva Contínua nas Vias Aéreas/efeitos adversos , Pressão Positiva Contínua nas Vias Aéreas/métodos , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Ventilação não Invasiva/efeitos adversos , Oxigenoterapia/efeitos adversos , Estudos Prospectivos , Desmame do Respirador/estatística & dados numéricosRESUMO
BACKGROUND: A previous randomised controlled trial (RCT) in babies born < 30 weeks gestation found the so-called CICADA method (ceasing continuous positive airways pressure (CPAP) with a view to remain off rather than slow weaning) significantly reduced CPAP time. Post-RCT we introduced the CICADA method and evaluated whether the improved outcomes of the CICADA method during the RCT were replicated in clinical practice. AIM: The aim of the study is to compare cardio-respiratory outcomes in PBs < 30 weeks GA over three epochs: (i) pre RCT, (ii) during RCT and (iii) post RCT implementation. METHODS: The study used prospective data to compare baseline characteristics and cardio-respiratory outcomes over the three epochs. RESULTS: There were 270/393(69%) PBs < 30 weeks GA who fulfilled the inclusion criteria over the three epochs. No significant differences were found in GA or birthweight between the three epochs (27.9 ± 1.3, 27.7 ± 1.4, 28.0 ± 1.3 (weeks ± 1 standard deviation); and 1100 ± 252, 1086 ± 251, 1094 ± 320 (grams ± 1 standard deviation)). There were significant decreases in CPAP days and corrected GA to cease CPAP post implementation (20.5 ± 2.1, 21.1 ± 2.1, 16.5 ± 1.8 (days ± SE); P = 0.006 and 33.3 ± 0.4, 33.5 ± 0.4, 32.6 ± 0.4 (weeks ± SE); P = 0.01). Compared with the pre RCT epoch, there were significant reductions in patent ductus arteriosus (36/78 (46%), 33/87 (37%), 18/103 (17%); P < 0.001) and chronic lung disease (40/78 (51%), 19/87 (21%), 30/103 (29%); P < 0.001). CONCLUSIONS: CPAP time, corrected GA to cease CPAP, patent ductus arteriosus and chronic lung disease significantly reduced following the introduction of the CICADA method. Early cessation of CPAP expedites the transition from neonatal intensive care to special care.
Assuntos
Pressão Positiva Contínua nas Vias Aéreas/métodos , Recém-Nascido Prematuro , Síndrome do Desconforto Respiratório do Recém-Nascido/terapia , Desmame do Respirador/normas , Índice de Apgar , Peso ao Nascer , Bases de Dados Factuais , Permeabilidade do Canal Arterial/complicações , Permeabilidade do Canal Arterial/diagnóstico , Feminino , Seguimentos , Idade Gestacional , Humanos , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Pneumopatias/complicações , Pneumopatias/diagnóstico , Masculino , Gravidez , Estudos Prospectivos , Síndrome do Desconforto Respiratório do Recém-Nascido/etiologia , Síndrome do Desconforto Respiratório do Recém-Nascido/fisiopatologia , Fatores de Tempo , Resultado do TratamentoAssuntos
Oftalmopatias/epidemiologia , Serviços de Saúde do Indígena/estatística & dados numéricos , Havaiano Nativo ou Outro Ilhéu do Pacífico/estatística & dados numéricos , Pessoas com Deficiência Visual/estatística & dados numéricos , Adulto , Idoso , Austrália/epidemiologia , Feminino , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Inquéritos Epidemiológicos , Humanos , MasculinoRESUMO
Inherited retinal diseases (IRDs) are the most common cause of blindness in working-age adults. Macular neovascularization (MNV) may be a presenting feature or occurs as a late-stage complication in several IRDs. We performed an extensive literature review on MNV associated with IRDs. MNV is a well-known complication of Sorsby fundus dystrophy and pseudoxanthoma elasticum. Those with late-onset Stargardt disease may masquerade as exudative age-related macular degeneration (AMD) when MNV is the presenting feature. Peripherinopathies may develop MNV that responds well to a short course of anti-vascular endothelial growth factor (anti-VEGF) therapy, while bestrophinopathies tend to develop MNV in the early stages of the disease without vision loss. Enhanced S-cone syndrome manifests type 3 MNV that typically regresses into a subfoveal fibrotic nodule. MNV is only a rare complication in choroideraemia and rod-cone dystrophies. Most IRD-related MNVs exhibit a favorable visual prognosis requiring less intensive regimens of anti-vascular endothelial growth factor therapy compared to age-related macular degeneration. We discuss the role of key imaging modalities in the diagnosis of MNV across a wide spectrum of IRDs and highlight the gaps in our knowledge with respect to the natural history and prognosis to pave the way for future directions of research.
Assuntos
Neovascularização de Coroide , Degeneração Macular , Degeneração Retiniana , Neovascularização Retiniana , Adulto , Humanos , Fatores de Crescimento Endotelial , Retina , Degeneração Macular/complicações , Degeneração Macular/diagnóstico , Degeneração Retiniana/complicações , Neovascularização Patológica , Angiofluoresceinografia , Tomografia de Coerência Óptica , Estudos Retrospectivos , Neovascularização Retiniana/complicaçõesRESUMO
PURPOSE: To evaluate the outer retinal bands using OCT in ABCA4- and PRPH2-associated retinopathy and develop a novel imaging biomarker to differentiate between these 2 genotypes. DESIGN: Multicenter case-control study. PARTICIPANTS: Patients with a clinical and genetic diagnosis of ABCA4- or PRPH2-associated retinopathy and an age-matched control group. METHODS: Macular OCT was used to measure the thickness of the outer retinal bands 2 and 4 by 2 independent examiners at 4 retinal loci. MAIN OUTCOME MEASURES: Outcome measures included the thicknesses of band 2, band 4, and the band 2/band 4 ratio. Linear mixed modeling was used to make comparisons across the 3 groups. Receiver operating characteristic (ROC) analysis determined the optimal cutoff for the band 2/band 4 ratio to distinguish PRPH2- from ABCA4-associated retinopathy. RESULTS: We included 45 patients with ABCA4 variants, 45 patients with PRPH2 variants, and 45 healthy controls. Band 2 was significantly thicker in patients with PRPH2 compared with ABCA4 (21.4 vs. 15.9 µm, P < 0.001) variants, whereas band 4 was thicker in patients with ABCA4 variants than those with PRPH2 variants (27.5 vs. 21.7 µm, P < 0.001). Similarly, the band 2/band 4 ratio was significantly different (1.0 vs. 0.6 for PRPH2 vs. ABCA4, P < 0.001). The area under the ROC curve was 0.87 for either band 2 (> 18.58 µm) or band 4 (< 26.17 µm) alone and 0.99 (95% confidence interval: 0.97-0.99) for the band 2/band 4 ratio with a cutoff threshold of 0.79, providing 100% specificity. CONCLUSIONS: We report an altered outer retinal band profile whereby the band 2/band 4 ratio was able to discriminate between PRPH2- and ABCA4-associated retinopathy. This may have future clinic utility in predicting the genotype and provide further insight into the anatomic correlate of band 2. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Assuntos
Degeneração Macular , Doenças Retinianas , Humanos , Degeneração Macular/diagnóstico , Estudos de Casos e Controles , Tomografia de Coerência Óptica/métodos , Transportadores de Cassetes de Ligação de ATP/genética , Doenças Retinianas/diagnóstico , Doenças Retinianas/genéticaRESUMO
Purpose: To describe the clinical, electrophysiological and genetic spectrum of inherited retinal diseases associated with variants in the PRPH2 gene. Methods: A total of 241 patients from 168 families across 15 sites in 9 countries with pathogenic or likely pathogenic variants in PRPH2 were included. Records were reviewed for age at symptom onset, visual acuity, full-field ERG, fundus colour photography, fundus autofluorescence (FAF), and SD-OCT. Images were graded into six phenotypes. Statistical analyses were performed to determine genotype-phenotype correlations. Results: The median age at symptom onset was 40 years (range, 4-78 years). FAF phenotypes included normal (5%), butterfly pattern dystrophy, or vitelliform macular dystrophy (11%), central areolar choroidal dystrophy (28%), pseudo-Stargardt pattern dystrophy (41%), and retinitis pigmentosa (25%). Symptom onset was earlier in retinitis pigmentosa as compared with pseudo-Stargardt pattern dystrophy (34 vs 44 years; P = 0.004). The median visual acuity was 0.18 logMAR (interquartile range, 0-0.54 logMAR) and 0.18 logMAR (interquartile range 0-0.42 logMAR) in the right and left eyes, respectively. ERG showed a significantly reduced amplitude across all components (P < 0.001) and a peak time delay in the light-adapted 30-Hz flicker and single-flash b-wave (P < 0.001). Twenty-two variants were novel. The central areolar choroidal dystrophy phenotype was associated with 13 missense variants. The remaining variants showed marked phenotypic variability. Conclusions: We described six distinct FAF phenotypes associated with variants in the PRPH2 gene. One FAF phenotype may have multiple ERG phenotypes, demonstrating a discordance between structure and function. Given the vast spectrum of PRPH2 disease our findings are useful for future clinical trials.
Assuntos
Eletrorretinografia , Periferinas , Fenótipo , Distrofias Retinianas , Acuidade Visual , Humanos , Periferinas/genética , Pessoa de Meia-Idade , Adulto , Masculino , Feminino , Adolescente , Distrofias Retinianas/genética , Distrofias Retinianas/fisiopatologia , Distrofias Retinianas/diagnóstico , Idoso , Acuidade Visual/fisiologia , Criança , Adulto Jovem , Pré-Escolar , Tomografia de Coerência Óptica , Mutação , Angiofluoresceinografia , Estudos de Associação Genética , Estudos Retrospectivos , Análise Mutacional de DNA , DNA/genética , LinhagemRESUMO
BACKGROUND: To establish the proportion of patients with retinitis pigmentosa (RP) meeting the Australian fitness to drive (FTD) visual standards. METHODOLOGY: A prospective consecutive case series of patients with a clinical or genetic diagnosis of RP. Data on age at symptom onset, current driving status, inheritance pattern, better eye visual acuity (BEVA), binocular Esterman visual field (BEVF) parameters, genotype and ability to meet the driving standards based on BEVA and BEVF were collected. Outcome measures included the proportion of RP patients overall meeting the standards and clinical predictors for passing. A sub-analysis was performed on those RP patients who reported to drive. Change in BEVA and BEVF parameters across age in specific genotype groups was assessed. RESULTS: Overall, 228 patients with RP had a BEVF assessment. Only 39% (89/228) met the driving standards. Younger age at the time of testing was the only significant predictor (p < 0.01) for passing. Of the 55% of RP patients who reported to drive, 52% (65/125) met the standards, decreasing to 14% in the 56- to 65-year-old age group. RP patients harbouring mutations in HK1 or RHO genes may have slower rates of decline in their VF parameters. CONCLUSION: Nearly 40% of RP patients met the driving standards. However, almost 50% of RP drivers were unaware of their failure to meet the current standards. BEVF testing is essential in the assessment of RP patients who are still driving. Phenotype and genotype predictors for passing the standards warrant further investigation.Abbreviation: FTD, fitness to drive; IRD, inherited retinal disease; RP, retinitis pigmentosa; RHO, rhodopsin; HK1, hexokinase 1; PRPF31 pre-mRNA processing factor 31; RPGR, retinitis pigmentosa GTPase regulator; VF, visual field; BEVA, better eye visual acuity; BEVF, binocular Esterman visual field.