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Sterile alpha motif domain containing 7 (SAMD7) is a component of the Polycomb repressive complex 1, which inhibits transcription of many genes, including those activated by the transcription factor Cone-Rod Homeobox (CRX). Here we report bi-allelic mutations in SAMD7 as a cause of autosomal-recessive macular dystrophy with or without cone dysfunction. Four of these mutations affect splicing, while another mutation is a missense variant that alters the repressive effect of SAMD7 on CRX-dependent promoter activity, as shown by in vitro assays. Immunostaining of human retinal sections revealed that SAMD7 is localized in the nuclei of both rods and cones, as well as in those of cells belonging to the inner nuclear layer. These results place SAMD7 as a gene crucial for human retinal function and demonstrate a significant difference in the role of SAMD7 between the human and the mouse retina.
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Anomalías del Ojo , Degeneración Macular , Ratones , Animales , Humanos , Transactivadores/genética , Proteínas de Homeodominio/genética , Retina , Mutación/genética , Degeneración Macular/genéticaRESUMEN
North Carolina macular dystrophy (NCMD) is a rare autosomal-dominant disease affecting macular development. The disease is caused by non-coding single-nucleotide variants (SNVs) in two hotspot regions near PRDM13 and by duplications in two distinct chromosomal loci, overlapping DNase I hypersensitive sites near either PRDM13 or IRX1. To unravel the mechanisms by which these variants cause disease, we first established a genome-wide multi-omics retinal database, RegRet. Integration of UMI-4C profiles we generated on adult human retina then allowed fine-mapping of the interactions of the PRDM13 and IRX1 promoters and the identification of eighteen candidate cis-regulatory elements (cCREs), the activity of which was investigated by luciferase and Xenopus enhancer assays. Next, luciferase assays showed that the non-coding SNVs located in the two hotspot regions of PRDM13 affect cCRE activity, including two NCMD-associated non-coding SNVs that we identified herein. Interestingly, the cCRE containing one of these SNVs was shown to interact with the PRDM13 promoter, demonstrated in vivo activity in Xenopus, and is active at the developmental stage when progenitor cells of the central retina exit mitosis, suggesting that this region is a PRDM13 enhancer. Finally, mining of single-cell transcriptional data of embryonic and adult retina revealed the highest expression of PRDM13 and IRX1 when amacrine cells start to synapse with retinal ganglion cells, supporting the hypothesis that altered PRDM13 or IRX1 expression impairs interactions between these cells during retinogenesis. Overall, this study provides insight into the cis-regulatory mechanisms of NCMD and supports that this condition is a retinal enhanceropathy.
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Distrofias Hereditarias de la Córnea , Tomografía de Coherencia Óptica , Adulto , Animales , Humanos , Linaje , Retina/metabolismo , Xenopus laevis/genéticaRESUMEN
Leber hereditary optic neuropathy (LHON) is an important example of mitochondrial blindness with the m.11778G>A mutation in the MT-ND4 gene being the most common disease-causing mtDNA variant worldwide. The REFLECT phase 3 pivotal study is a randomized, double-masked, placebo-controlled trial investigating the efficacy and safety of bilateral intravitreal injection of lenadogene nolparvovec in patients with a confirmed m.11778G>A mutation, using a recombinant adeno-associated virus vector 2, serotype 2 (rAAV2/2-ND4). The first-affected eye received gene therapy; the fellow (affected/not-yet-affected) eye was randomly injected with gene therapy or placebo. The primary end point was the difference in change from baseline of best-corrected visual acuity (BCVA) in second-affected/not-yet-affected eyes treated with lenadogene nolparvovec versus placebo at 1.5 years post-treatment, expressed in logarithm of the minimal angle of resolution (LogMAR). Forty-eight patients were treated bilaterally and 50 unilaterally. At 1.5 years, the change from baseline in BCVA was not statistically different between second-affected/not-yet-affected eyes receiving lenadogene nolparvovec and placebo (primary end point). A statistically significant improvement in BCVA was reported from baseline to 1.5 years in lenadogene nolparvovec-treated eyes: -0.23 LogMAR for the first-affected eyes of bilaterally treated patients (P < 0.01); and -0.15 LogMAR for second-affected/not-yet-affected eyes of bilaterally treated patients and the first-affected eyes of unilaterally treated patients (P < 0.05). The mean improvement in BCVA from nadir to 1.5 years was -0.38 (0.052) LogMAR and -0.33 (0.052) LogMAR in first-affected and second-affected/not-yet-affected eyes treated with lenadogene nolparvovec, respectively (bilateral treatment group). A mean improvement of -0.33 (0.051) LogMAR and -0.26 (0.051) LogMAR was observed in first-affected lenadogene nolparvovec-treated eyes and second-affected/not-yet-affected placebo-treated eyes, respectively (unilateral treatment group). The proportion of patients with one or both eyes on-chart at 1.5 years was 85.4% and 72.0% for bilaterally and unilaterally treated patients, respectively. The gene therapy was well tolerated, with no systemic issues. Intraocular inflammation, which was mostly mild and well controlled with topical corticosteroids, occurred in 70.7% of lenadogene nolparvovec-treated eyes versus 10.2% of placebo-treated eyes. Among eyes treated with lenadogene nolparvovec, there was no difference in the incidence of intraocular inflammation between bilaterally and unilaterally treated patients. Overall, the REFLECT trial demonstrated an improvement of BCVA in LHON eyes carrying the m.11778G>A mtDNA mutation treated with lenadogene nolparvovec or placebo to a degree not reported in natural history studies and supports an improved benefit/risk profile for bilateral injections of lenadogene nolparvovec relative to unilateral injections.
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Atrofia Óptica Hereditaria de Leber , Humanos , ADN Mitocondrial/genética , Terapia Genética , Inflamación/etiología , Mutación/genética , Atrofia Óptica Hereditaria de Leber/genética , Atrofia Óptica Hereditaria de Leber/terapiaRESUMEN
PURPOSE: Gyrate atrophy of the choroid and retina (GACR) is an autosomal recessive inherited metabolic disorder (IMD) characterised by progressive retinal degeneration, leading to severe visual impairment. The rapid developments in ophthalmic genetic therapies warrant knowledge on clinical phenotype of eligible diseases such as GACR to define future therapeutic parameters in clinical trials. METHODS: Retrospective chart analysis was performed in nineteen patients. Data were analysed using IBM SPSS Statistics version 28.0.1.1. RESULTS: Nineteen patients were included with a mean age of 32.6 years (range 8-58). Mean age at onset of ophthalmic symptoms was 7.9 years (range 3-16). Median logMAR of visual acuity at inclusion was 0.26 (range -0.18-3.00). Mean age at cataract surgery was 28.8 years (n = 11 patients). Mean spherical equivalent of the refractive error was -8.96 (range -20.87 to -2.25). Cystoid maculopathy was present in 68% of patients, with a loss of integrity of the foveal ellipsoid zone (EZ) in 24/38 eyes. Of the 14 patients treated with dietary protein restriction, the four patients who started the diet before age 10 showed most benefit. CONCLUSION: This study demonstrates the severe ophthalmic disease course associated with GACR, as well as possible benefit of early dietary treatment. In addition to visual loss, patients experience severe myopia, early-onset cataract, and CME. There is a loss of foveal EZ integrity at a young age, emphasising the need for early diagnosis enabling current and future therapeutic interventions.
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PURPOSE: Evaluating the presence of class 3, 4, and 5 genetic variants in inherited retinal disease (IRD) genes in patients with retinopathy of unknown origin (RUO). METHODS: Multicentric retrospective study of RUO cases diagnosed between January 2012 and February 2022. General and ophthalmologic history, complete ophthalmologic examination, antiretinal antibodies, and IRD gene panel results were analyzed in every patient. Four RUO categories were defined: nonparaneoplastic autoimmune retinopathy, unilateral pigmentary retinopathy, asymmetrical pigmentary retinopathy, and acute zonal occult outer retinopathy. RESULTS: The authors included 12 patients (9 females) across these four RUO categories. Mean age at inclusion was 45.6 years (20-68 years). Seven patients demonstrated class 3 variants in IRD genes. Of these, two also demonstrated class 5 variants in other IRD genes. The remaining five patients had negative panel results. IRD gene panel analysis allowed diagnosis refinement in 1 (8.3%) nonparaneoplastic autoimmune retinopathy patient in the RUO cohort. When considering the nonparaneoplastic autoimmune retinopathy subpopulation only, a higher diagnostic yield of 20% (1/5 patients) was achieved. CONCLUSION: Every suspected nonparaneoplastic autoimmune retinopathy patient should benefit from gene panel testing to not overlook undiagnosed IRDs. By contrast, unilateral pigmentary retinopathy, asymmetrical pigmentary retinopathy, and acute zonal occult outer retinopathy subpopulations did not benefit from genetic testing in this study.
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Enfermedades de la Retina , Humanos , Femenino , Estudios Retrospectivos , Masculino , Persona de Mediana Edad , Adulto , Enfermedades de la Retina/genética , Enfermedades de la Retina/diagnóstico , Anciano , Adulto Joven , Pruebas Genéticas/métodos , Mutación , Proteínas del Ojo/genéticaRESUMEN
INTRODUCTION: The purpose of this project was to explore the current standards of clinical care genetic testing and counseling for patients with inherited retinal diseases (IRDs) from the perspective of leading experts in selected European countries. Also, to gather opinions on current bottlenecks and future solutions to improve patient care. METHODS: On the initiative of the European Vision Institute, a survey questionnaire with 41 questions was designed and sent to experts in the field from ten European countries. Each participant was asked to answer with reference to the situation in their own country. RESULTS: Sixteen questionnaires were collected by November 2023. IRD genetic tests are performed in clinical care settings for 80% or more of tested patients in 9 countries, and the costs of genetic tests in clinical care are covered by the public health service to the extent of 90% or more in 8 countries. The median proportion of patients who are genetically tested, the median rate of genetically solved patients among those who are tested, and the median proportion of patients receiving counseling are 51-70%, 61-80%, and 61-80%, respectively. Improving the education of healthcare professionals who facilitate patient referrals to specialized centers, improving access of patients to more thorough genotyping, and increasing the number of available counselors were the most advocated solutions. CONCLUSION: There is a significant proportion of IRD patients who are not genetically tested, whose genetic testing is inconclusive, or who do not receive counseling. Educational programs, greater availability of state-of-the-art genotyping and genetic counselors could improve healthcare for IRD patients.
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Pruebas Genéticas , Enfermedades de la Retina , Humanos , Pruebas Genéticas/métodos , Europa (Continente) , Enfermedades de la Retina/genética , Enfermedades de la Retina/diagnóstico , Encuestas y Cuestionarios , Asesoramiento GenéticoRESUMEN
BACKGROUND: Biallelic pathogenic variants in the ATP-binding cassette subfamily C member 6 (ABCC6) gene cause pseudoxanthoma elasticum, a multisystemic ectopic calcification disorder, while heterozygous ABCC6 variants are associated with an increased risk of cardiovascular and cerebrovascular disease. As the prevalence of pathogenic ABCC6 variants in the general population is estimated at ~1%, identifying additional ABCC6-related (sub)clinical manifestations in heterozygous carriers is of the utmost importance to reduce this burden of disease. Here, we present a large Belgian cohort of heterozygous ABCC6 carriers with comprehensive clinical, biochemical and imaging data. Based on these results, we formulate clinical practice guidelines regarding screening, preventive measures and follow-up of ABCC6 carriers. METHODS: The phenotype of 56 individuals carrying heterozygous pathogenic ABCC6 variants was assessed using clinical (eg, detailed ophthalmological examinations), biochemical, imaging (eg, cardiovascular and abdominal ultrasound) and genetic data. Clinical practice guidelines were then drawn up. RESULTS: We found that ABCC6 heterozygosity is associated with distinct retinal alterations ('comet-like') (24%), high prevalence of hypercholesterolaemia (>75%) and diastolic dysfunction (33%), accelerated lower limb atherosclerosis and medial vascular disease, abdominal organ calcification (26%) and testicular microlithiasis (28%), though with highly variable expression. CONCLUSION: In this study, we delineated the multisystemic ABCC6 heterozygosity phenotype characterised by retinal alterations, aberrant lipid metabolism, diastolic dysfunction and increased vascular, abdominal and testicular calcifications. Our clinical practice guidelines aimed to improve early diagnosis, treatment and follow-up of ABCC6-related health problems.
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Seudoxantoma Elástico , Bélgica/epidemiología , Estudios de Cohortes , Heterocigoto , Humanos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Fenotipo , Seudoxantoma Elástico/diagnóstico , Seudoxantoma Elástico/epidemiología , Seudoxantoma Elástico/genéticaRESUMEN
PURPOSE: To describe the natural course, phenotype, and genotype of patients with X-linked retinoschisis (XLRS). DESIGN: Retrospective cohort study. PARTICIPANTS: Three hundred forty patients with XLRS from 178 presumably unrelated families. METHODS: This multicenter, retrospective cohort study reviewed medical records of patients with XLRS for medical history, symptoms, visual acuity (VA), ophthalmoscopy, full-field electroretinography, and retinal imaging (fundus photography, spectral-domain [SD] OCT, fundus autofluorescence). MAIN OUTCOME MEASURES: Age at onset, age at diagnosis, severity of visual impairment, annual visual decline, and electroretinography and imaging findings. RESULTS: Three hundred forty patients were included with a mean follow-up time of 13.2 years (range, 0.1-50.1 years). The median ages to reach mild visual impairment and low vision were 12 and 25 years, respectively. Severe visual impairment and blindness were observed predominantly in patients older than 40 years, with a predicted prevalence of 35% and 25%, respectively, at 60 years of age. The VA increased slightly during the first 2 decades of life and subsequently transitioned into an average annual decline of 0.44% (P < 0.001). No significant difference was found in decline of VA between variants that were predicted to be severe and mild (P = 0.239). The integrity of the ellipsoid zone (EZ) as well as the photoreceptor outer segment (PROS) length in the fovea on SD OCT correlated significantly with VA (Spearman's ρ = -0.759 [P < 0.001] and -0.592 [P = 0.012], respectively). Fifty-three different RS1 variants were found. The most common variants were the founder variant c.214GâA (p.(Glu72Lys)) (101 patients [38.7%]) and a deletion of exon 3 (38 patients [14.6%]). CONCLUSIONS: Large variabilities in phenotype and natural course of XLRS were seen in this study. In most patients, XLRS showed a slow deterioration starting in the second decade of life, suggesting an optimal window of opportunity for treatment within the first 3 decades of life. The integrity of EZ as well as the PROS length on SD OCT may be important in choosing optimal candidates for treatment and as potential structural end points in future therapeutic studies. No clear genotype-phenotype correlation was found.
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Proteínas del Ojo/genética , Retinosquisis/diagnóstico , Retinosquisis/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Ceguera/diagnóstico , Ceguera/fisiopatología , Niño , Preescolar , Electrorretinografía , Femenino , Estudios de Seguimiento , Estudios de Asociación Genética , Humanos , Lactante , Masculino , Persona de Mediana Edad , Oftalmoscopía , Imagen Óptica , Retina/diagnóstico por imagen , Retina/fisiopatología , Segmento Externo de las Células Fotorreceptoras Retinianas/patología , Retinosquisis/fisiopatología , Estudios Retrospectivos , Tomografía de Coherencia Óptica , Baja Visión/diagnóstico , Baja Visión/fisiopatología , Agudeza Visual/fisiologíaRESUMEN
Until recently, there was no approved treatment for a retinal degenerative disease. Subretinal injection of a recombinant adeno-associated virus (AAV) delivering the normal copy of the human RPE65 cDNA led to reversal of blindness first in animal models and then in humans. This led to the first US Food and Drug Administration (FDA)-approved gene therapy product for a genetic disease, voretigene neparvovec-rzyl (Luxturna). Luxturna was then approved by the European Medicines Association and is now available in the US through Spark Therapeutics and worldwide through Novartis. Not only has treatment with Luxturna changed the lives of people previously destined to live a life of blindness, but it has fueled interest in developing additional gene therapy reagents targeting numerous other genetic forms of inherited retinal disease. This review describes many of the considerations for administration of Luxturna and describes how lessons from experience with Luxturna could lead to additional gene-based treatments of blindness.
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Terapia Genética , Distrofias Retinianas/genética , Distrofias Retinianas/terapia , cis-trans-Isomerasas/genética , Dependovirus/genética , Aprobación de Drogas , Desarrollo de Medicamentos , Terapia Genética/métodos , Vectores Genéticos/administración & dosificación , Vectores Genéticos/genética , Humanos , Estados Unidos , United States Food and Drug Administration , cis-trans-Isomerasas/metabolismoRESUMEN
The recent approval of voretigene neparvovec (Luxturna®) for patients with biallelic RPE65 mutation-associated inherited retinal dystrophy with viable retinal cells represents an important step in the development of ocular gene therapies. Herein, we review studies investigating the episomal persistence of different recombinant adeno-associated virus (rAAV) vector genomes and the pre-clinical and clinical evidence of long-term effects of different RPE65 gene replacement therapies. A targeted review of articles published between 1974 and January 2021 in Medline®, Embase®, and other databases, was conducted, followed by a descriptive longitudinal analysis of the clinical trial outcomes of voretigene neparvovec. Following an initial screening, 14 publications examining the episomal persistence of different rAAV genomes and 71 publications evaluating gene therapies in animal models were included. Viral genomes were found to persist for at least 22 months (longest study follow-up) as transcriptionally active episomes. Treatment effects lasting almost a decade were reported in canine disease models, with more pronounced effects the earlier the intervention. The clinical trial outcomes of voretigene neparvovec are consistent with pre-clinical findings and reveal sustained results for up to 7.5 years for the full-field light sensitivity threshold test and 5 years for the multi-luminance mobility test in the Phase I and Phase III trials, respectively. In conclusion, the therapeutic effect of voretigene neparvovec lasts for at least a decade in animal models and 7.5 years in human subjects. Since retinal cells can retain functionality over their lifetime after transduction, these effects may be expected to last even longer in patients with a sufficient number of outer retinal cells at the time of intervention.
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Biallelic mutations in G-Protein coupled receptor kinase 1 (GRK1) cause Oguchi disease, a rare subtype of congenital stationary night blindness (CSNB). The purpose of this study was to identify disease causing GRK1 variants and use in-depth bioinformatic analyses to evaluate how their impact on protein structure could lead to pathogenicity. Patients' genomic DNA was sequenced by whole genome, whole exome or focused exome sequencing. Disease associated variants, published and novel, were compared to nondisease associated missense variants. The impact of GRK1 missense variants at the protein level were then predicted using a series of computational tools. We identified twelve previously unpublished cases with biallelic disease associated GRK1 variants, including eight novel variants, and reviewed all GRK1 disease associated variants. Further structure-based scoring revealed a hotspot for missense variants in the kinase domain. In addition, to aid future clinical interpretation, we identified the bioinformatics tools best able to differentiate disease associated from nondisease associated variants. We identified GRK1 variants in Oguchi disease patients and investigated how disease-causing variants may impede protein function in-silico.
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Enfermedades Hereditarias del Ojo , Quinasa 1 del Receptor Acoplado a Proteína-G , Ceguera Nocturna , Enfermedades Hereditarias del Ojo/genética , Quinasa 1 del Receptor Acoplado a Proteína-G/genética , Humanos , Ceguera Nocturna/genéticaRESUMEN
PURPOSE: To determine whether functional vision and visual function improvements after voretigene neparvovec (VN; Luxturna [Spark Therapeutics, Inc]) administration in patients with biallelic RPE65 mutation-associated inherited retinal disease are maintained at 3 to 4 years and to review safety outcomes. DESIGN: Open-label, randomized, controlled phase 3 trial. PARTICIPANTS: Thirty-one individuals were enrolled and randomized 2:1 to intervention (n = 21) or control (n = 10). One participant from each group withdrew before, or at, randomization. METHODS: Patients in the original intervention (OI) group received bilateral subretinal VN injections. Delayed intervention (DI) patients served as control participants for 1 year then received VN. MAIN OUTCOME MEASURES: Change from injection baseline in bilateral performance on the multiluminance mobility test (MLMT), a measure of ambulatory navigation, and change from injection baseline in full-field light sensitivity threshold white light, visual field (VF), and visual acuity (VA). RESULTS: Mean bilateral MLMT change scores at year 4 for OI patients and year 3 for DI patients were 1.7 and 2.4, respectively, with 71% of patients with a year 3 visit able to pass MLMT at the lowest light level. Mean change in full-field light sensitivity threshold white light, averaged over both eyes at year 4 for OI patients and year 3 for DI patients, was -1.90 log10(cd.s/m2) and -2.91 log10(cd.s/m2), respectively. Mean change in Goldmann kinetic VF III4e sum total degrees, averaged across both eyes, was 197.7 at year 4 for OI patients and 157.9 at year 3 for DI patients. Mean change in VA (Holladay scale), averaged across both eyes, was -0.003 logarithm of the minimum angle of resolution (logMAR) at year 4 for OI patients and -0.06 logMAR at year 3 for DI patients. One OI patient experienced retinal detachment at approximately year 4 that impacted VA for the OI group. No product-related serious adverse events (AEs) occurred, nor did any deleterious immune responses. CONCLUSIONS: Improvements in ambulatory navigation, light sensitivity, and VF were consistent in both intervention groups. Overall, improvements were maintained up to 3 to 4 years, with ongoing observation. The safety profile of VN was consistent with vitrectomy and the subretinal injection procedure and was similar between intervention groups, with no product-related serious AEs reported.
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Terapia Genética/métodos , Vectores Genéticos/administración & dosificación , Mutación , Distrofias Retinianas/tratamiento farmacológico , Agudeza Visual , cis-trans-Isomerasas/administración & dosificación , Adolescente , Adulto , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Inyecciones Intraoculares , Masculino , Retina , Distrofias Retinianas/genética , Distrofias Retinianas/metabolismo , Factores de Tiempo , Resultado del Tratamiento , Campos Visuales , Adulto Joven , cis-trans-Isomerasas/genética , cis-trans-Isomerasas/metabolismoRESUMEN
PURPOSE: Cancer-associated retinal ON bipolar cell dysfunction (CARBD), which includes melanoma-associated retinopathy (MAR), has been reported to be caused by autoantibodies against the molecules expressed in ON bipolar cells, including TRPM1. The purpose of this study was to determine the antigenic regions of the autoantibodies against TRPM1 in the sera of CARBD patients, in whom we previously detected anti-TRPM1 autoantibodies. METHODS: The antigenic regions against TRPM1 in the sera of eight CARBD patients were examined by Western blots using HEK293T cells transfected with the plasmids expressing FLAG-tagged TRPM1 fragments. The clinical course of these patients was also documented. RESULTS: The clinical course differed among the patients. The electroretinograms (ERGs) and symptoms were improved in three patients, deteriorated in one patient, remained unchanged for a long time in one patient, and were not followable in three patients. Seven of the eight sera possessed multiple antigenic regions: two sera contained at least four antigen recognition regions, and three sera had at least three regions. The antigen regions were spread over the entire TRPM1 protein: five sera in the N-terminal intracellular domain, six sera in the transmembrane-containing region, and six sera in the C-terminal intracellular domain. No significant relationship was observed between the location of the antigen epitope and the patients' clinical course. CONCLUSIONS: The antigenic regions of anti-TRPM1 autoantibodies in CARBD patients were present not only in the N-terminal intracellular domain, which was reported in an earlier report, but also in the transmembrane-containing region and in the C-terminal intracellular domain. In addition, the antigenic regions for TRPM1 were found to vary among the CARBD patients examined, and most of the sera had multiple antigenic regions.
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Autoanticuerpos/sangre , Síndromes Paraneoplásicos Oculares/inmunología , Células Bipolares de la Retina/metabolismo , Canales Catiónicos TRPM/inmunología , Anciano , Western Blotting , Electrorretinografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndromes Paraneoplásicos Oculares/metabolismo , Síndromes Paraneoplásicos Oculares/patología , Células Bipolares de la Retina/patología , Estudios Retrospectivos , Células Tumorales CultivadasRESUMEN
PURPOSE: To describe an isolated maculopathy and an intermediate rod-cone dystrophy phenotype as the milder end of the RDH12-related retinal dystrophy spectrum. METHODS: Seven patients (17-34 years of age) underwent an extensive ophthalmic workup including psychophysical and electrophysiological testing and multimodal imaging. RESULTS: Three patients have isolated macular disease. Best-corrected visual acuity (BCVA) ranges from 20/125 to 20/40 with normal visual fields or only limited central, relative scotomata, and normal full-field ERGs. Both optical coherence tomography scans and autofluorescent imaging hint at relatively better-preserved foveal quality initially. An intermediate rod-cone phenotype in four patients is characterized by a central retinal dystrophy extending just beyond the vascular arcades, characteristic peripapillary sparing, and additional scattered atrophic patches. Again, foveal quality is initially better on optical coherence tomography scans. Best-corrected visual acuity ranges from counting fingers to 20/32. Goldmann visual fields vary from central scotomata to severe generalized abnormalities. ERGs range between mild and severe rod-cone dysfunction. Nine distinct RDH12 pathogenic variants, two of which are novel, are identified. CONCLUSION: The classic phenotype of RDH12-related early-onset retinal dystrophy is expanded to include an isolated maculopathy and intermediate dystrophy phenotype, characterized by its later onset and milder course with a fair visual potential until much later in life, emphasizing the phenotypic heterogeneity of RDH12-related retinopathy.
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Oxidorreductasas de Alcohol/genética , Distrofias de Conos y Bastones/genética , Degeneración Macular/etiología , Mutación , Células Fotorreceptoras de Vertebrados/patología , Agudeza Visual , Campos Visuales/fisiología , Adolescente , Adulto , Oxidorreductasas de Alcohol/metabolismo , Distrofias de Conos y Bastones/diagnóstico , Distrofias de Conos y Bastones/metabolismo , Análisis Mutacional de ADN , Electrorretinografía/métodos , Femenino , Humanos , Degeneración Macular/diagnóstico , Degeneración Macular/genética , Masculino , Linaje , Fenotipo , Tomografía de Coherencia Óptica/métodos , Adulto JovenRESUMEN
PURPOSE: Leber congenital amaurosis due to CEP290 mutations (LCA10) is an inherited retinal disease that often results in severe visual impairment or blindness in early childhood. Currently, there are no approved treatments, highlighting the considerable unmet medical need associated with LCA10. We aimed to review the clinical characteristics of LCA10, its impact on patients and society, and the investigational treatment strategies currently in development. METHODS: Review of the current literature. RESULTS: LCA10 is an autosomal recessive ciliopathy, for which the CEP290 intronic variant c.2991+1655A>G (p.Cys998X) is the most common mutation. Usually diagnosed in early childhood, most patients with LCA10 have severe visual impairment during their first decade of life, which significantly affects the quality of life and development. LCA10 also has a significant societal burden (direct and indirect costs). RNA editing using antisense oligonucleotides or Staphylococcus aureus CRISPR-associated protein-9 nuclease is currently under investigation for treatment of p.Cys998X LCA10. Specifically, the antisense oligonucleotide therapy QR-110 (sepofarsen) has demonstrated encouraging safety and efficacy data in a first-in-human trial; a phase 3 clinical trial is ongoing. CONCLUSION: Interventions that can preserve or improve vision in patients with LCA10 have considerable potential to improve the patient quality of life and reduce burden of disease.
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Antígenos de Neoplasias/genética , Ceguera/etiología , Proteínas de Ciclo Celular/genética , Proteínas del Citoesqueleto/genética , ADN/genética , Manejo de la Enfermedad , Necesidades y Demandas de Servicios de Salud/normas , Amaurosis Congénita de Leber/genética , Antígenos de Neoplasias/metabolismo , Ceguera/diagnóstico , Ceguera/terapia , Proteínas de Ciclo Celular/metabolismo , Proteínas del Citoesqueleto/metabolismo , Análisis Mutacional de ADN , Humanos , Amaurosis Congénita de Leber/complicacionesRESUMEN
PURPOSE: To investigate the natural history of RHO-associated retinitis pigmentosa (RP). METHODS: A multicenter, medical chart review of 100 patients with autosomal dominant RHO-associated RP. RESULTS: Based on visual fields, time-to-event analysis revealed median ages of 52 and 79 years to reach low vision (central visual field <20°) and blindness (central visual field <10°), respectively. For the best-corrected visual acuity (BCVA), the median age to reach mild impairment (20/67 ≤ BCVA < 20/40) was 72 years, whereas this could not be computed for lower acuities. Disease progression was significantly faster in patients with a generalized RP phenotype (n = 75; 75%) than that in patients with a sector RP phenotype (n = 25; 25%), in terms of decline rates of the BCVA (P < 0.001) and V4e retinal seeing areas (P < 0.005). The foveal thickness of the photoreceptor-retinal pigment epithelium (PR + RPE) complex correlated significantly with BCVA (Spearman's ρ = 0.733; P < 0.001). CONCLUSION: Based on central visual fields, the optimal window of intervention for RHO-associated RP is before the 5th decade of life. Significant differences in disease progression are present between generalized and sector RP phenotypes. Our findings suggest that the PR + RPE complex is a potential surrogate endpoint for the BCVA in future studies.
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Proteínas de Fase Aguda/genética , Predicción , Epitelio Pigmentado de la Retina/patología , Retinitis Pigmentosa/diagnóstico , Agudeza Visual , Campos Visuales/fisiología , Proteínas de Fase Aguda/metabolismo , Anciano , Electrorretinografía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Retinitis Pigmentosa/sangre , Retinitis Pigmentosa/genética , Estudios Retrospectivos , Tomografía de Coherencia Óptica/métodosRESUMEN
Inactivating variants in the centrosomal CEP78 gene have been found in cone-rod dystrophy with hearing loss (CRDHL), a particular phenotype distinct from Usher syndrome. Here, we identified and functionally characterized the first CEP78 missense variant c.449T>C, p.(Leu150Ser) in three CRDHL families. The variant was found in a biallelic state in two Belgian families and in a compound heterozygous state-in trans with c.1462-1G>T-in a third German family. Haplotype reconstruction showed a founder effect. Homology modeling revealed a detrimental effect of p.(Leu150Ser) on protein stability, which was corroborated in patients' fibroblasts. Elongated primary cilia without clear ultrastructural abnormalities in sperm or nasal brushes suggest impaired cilia assembly. Two affected males from different families displayed sperm abnormalities causing infertility. One of these is a heterozygous carrier of a complex allele in SPAG17, a ciliary gene previously associated with autosomal recessive male infertility. Taken together, our data indicate that a missense founder allele in CEP78 underlies the same sensorineural CRDHL phenotype previously associated with inactivating variants. Interestingly, the CEP78 phenotype has been possibly expanded with male infertility. Finally, CEP78 loss-of-function variants may have an underestimated role in misdiagnosed Usher syndrome, with or without sperm abnormalities.
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Alelos , Proteínas de Ciclo Celular/genética , Distrofias de Conos y Bastones/genética , Efecto Fundador , Pérdida Auditiva/genética , Infertilidad Masculina/genética , Mutación Missense , Adolescente , Proteínas de Ciclo Celular/química , Cilios/metabolismo , Cilios/ultraestructura , Distrofias de Conos y Bastones/diagnóstico , Análisis Mutacional de ADN , Femenino , Fibroblastos/metabolismo , Genotipo , Pérdida Auditiva/diagnóstico , Humanos , Infertilidad Masculina/diagnóstico , Masculino , Persona de Mediana Edad , Modelos Moleculares , Linaje , Fenotipo , Conformación Proteica , Relación Estructura-Actividad , Síndrome , Secuenciación del ExomaRESUMEN
Pseudoxanthoma elasticum (PXE) is a rare autosomal recessive ectopic mineralization disorder, characterized by skin, eye and cardiovascular symptoms. The most devastating ocular complication is choroidal neovascularization, which is thought to be mediated by vascular endothelial growth factor (VEGF) signaling, a molecule encoded by the VEGFA gene. As early detection and treatment is essential to preserve vision, prioritization of patients at risk is crucial, but impossible because of wide phenotypic variability and a lack of genotype-phenotype correlations for PXE. This study aimed to validate the previously suggested association of five single nucleotide VEGFA variants (rs13207351, rs833061, rs699947, rs25648 and rs1413711) with a severe PXE retinopathy in an independent cohort. Direct Sanger sequencing was performed in 100 PXE patients, with a mild (56) or severe (44) PXE retinopathy. The inclusion criteria for severe retinopathy were a unilateral best-corrected visual acuity of <5/10 and/or the need for anti-angiogenic treatment. We found a significant association of three of five variants and borderline missed significance for one. These data further suggest the VEGFA gene to be a modifier gene for the PXE retinopathy. Hereby, we provide the necessary evidence to implement these variants in ocular risk stratification and individualized patient follow-up.
Asunto(s)
Marcadores Genéticos/genética , Polimorfismo de Nucleótido Simple/genética , Seudoxantoma Elástico/genética , Enfermedades de la Retina/genética , Factor A de Crecimiento Endotelial Vascular/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neovascularización Coroidal/genética , Estudios de Cohortes , Femenino , Estudios de Asociación Genética/métodos , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Piel/patología , Adulto JovenRESUMEN
Biallelic MFSD8 variants are an established cause of severe late-infantile subtype of neuronal ceroid lipofuscinosis (v-LINCL), a severe lysosomal storage disorder, but have also been associated with nonsyndromic adult-onset maculopathy. Here, we functionally characterized two novel MFSD8 variants found in a child with juvenile isolated maculopathy, in order to establish a refined prognosis. ABCA4 locus resequencing was followed by the analysis of other inherited retinal disease genes by whole exome sequencing (WES). Minigene assays and cDNA sequencing were used to assess the effect of a novel MFSD8 splice variant. MFSD8 expression was quantified with qPCR and overexpression studies were analyzed by immunoblotting. Transmission electron microscopy (TEM) was performed on a skin biopsy and ophthalmological and neurological re-examinations were conducted. WES revealed two novel MFSD8 variants: c.[590del];[439+3A>C] p.[Gly197Valfs*2];[Ile67Glufs*3]. Characterization of the c.439+3A>C variant via splice assays showed exon-skipping (p.Ile67Glufs*3), while overexpression studies of the corresponding protein indicated expression of a truncated polypeptide. In addition, a significantly reduced MFSD8 RNA expression was noted in patient's lymphocytes. TEM of a skin biopsy revealed typical v-LINCL lipopigment inclusions while neurological imaging of the proband displayed subtle cerebellar atrophy. Functional characterization demonstrated the pathogenicity of two novel MFSD8 variants, found in a child with an initial diagnosis of juvenile isolated maculopathy but likely evolving to v-LINCL with a protracted disease course. Our study allowed a refined neurological prognosis in the proband and expands the natural history of MFSD8-associated disease.