74 results on '"Julie De Zaeytijd"'
Search Results
2. Combining a prioritization strategy and functional studies nominates 5’UTR variants underlying inherited retinal disease
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Alfredo Dueñas Rey, Marta del Pozo Valero, Manon Bouckaert, Katherine A Wood, Filip Van den Broeck, Malena Daich Varela, Huw B Thomas, Mattias Van Heetvelde, Marieke De Bruyne, Stijn Van de Sompele, Miriam Bauwens, Hanne Lenaerts, Quinten Mahieu, Dragana Josifova, Genomics England Research Consortium, Carlo Rivolta, Raymond T O’Keefe, Jamie Ellingford, Andrew R Webster, Gavin Arno, Carmen Ayuso, Julie De Zaeytijd, Bart P Leroy, Elfride De Baere, and Frauke Coppieters
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5’untranslated region (5’UTR) ,Upstream open reading frame (uORF) ,Non-coding variation ,Whole genome sequencing (WGS) ,Whole exome sequencing (WES) ,In silico prioritization ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background 5’ untranslated regions (5’UTRs) are essential modulators of protein translation. Predicting the impact of 5’UTR variants is challenging and rarely performed in routine diagnostics. Here, we present a combined approach of a comprehensive prioritization strategy and functional assays to evaluate 5’UTR variation in two large cohorts of patients with inherited retinal diseases (IRDs). Methods We performed an isoform-level re-analysis of retinal RNA-seq data to identify the protein-coding transcripts of 378 IRD genes with highest expression in retina. We evaluated the coverage of their 5’UTRs by different whole exome sequencing (WES) kits. The selected 5’UTRs were analyzed in whole genome sequencing (WGS) and WES data from IRD sub-cohorts from the 100,000 Genomes Project (n = 2397 WGS) and an in-house database (n = 1682 WES), respectively. Identified variants were annotated for 5’UTR-relevant features and classified into seven categories based on their predicted functional consequence. We developed a variant prioritization strategy by integrating population frequency, specific criteria for each category, and family and phenotypic data. A selection of candidate variants underwent functional validation using diverse approaches. Results Isoform-level re-quantification of retinal gene expression revealed 76 IRD genes with a non-canonical retina-enriched isoform, of which 20 display a fully distinct 5’UTR compared to that of their canonical isoform. Depending on the probe design, 3–20% of IRD genes have 5’UTRs fully captured by WES. After analyzing these regions in both cohorts, we prioritized 11 (likely) pathogenic variants in 10 genes (ARL3, MERTK, NDP, NMNAT1, NPHP4, PAX6, PRPF31, PRPF4, RDH12, RD3), of which 7 were novel. Functional analyses further supported the pathogenicity of three variants. Mis-splicing was demonstrated for the PRPF31:c.-9+1G>T variant. The MERTK:c.-125G>A variant, overlapping a transcriptional start site, was shown to significantly reduce both luciferase mRNA levels and activity. The RDH12:c.-123C>T variant was found in cis with the hypomorphic RDH12:c.701G>A (p.Arg234His) variant in 11 patients. This 5’UTR variant, predicted to introduce an upstream open reading frame, was shown to result in reduced RDH12 protein but unaltered mRNA levels. Conclusions This study demonstrates the importance of 5’UTR variants implicated in IRDs and provides a systematic approach for 5’UTR annotation and validation that is applicable to other inherited diseases.
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- 2024
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3. Expanding the Spectrum of Alkali Retinopathy: Maculopathy following Alkali Burn
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Andreas Vanclooster, Julie De Zaeytijd, and Dimitri Roels
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alkali burn ,retinopathy ,cornea ,Ophthalmology ,RE1-994 - Abstract
Ocular alkali burns are known to cause profound damage to the anterior segment, especially the cornea and conjunctiva. However, rarely, additional adjacent chorioretinal complications may ensue. These chorioretinal complications appear primary by direct penetration of the alkali or secondary to an elevated intraocular pressure (IOP). In contrast to this, recent animal studies have suggested a causal link with upregulation of proinflammatory mediators. We present a patient with maculopathy following alkali ocular burn.
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- 2022
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4. Phenocopy of a heterozygous carrier of X-linked retinitis pigmentosa due to mosaicism for a RHO variant
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Ine Strubbe, Caroline Van Cauwenbergh, Julie De Zaeytijd, Sarah De Jaegere, Marieke De Bruyne, Toon Rosseel, Stijn Van de Sompele, Elfride De Baere, and Bart P. Leroy
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Medicine ,Science - Abstract
Abstract We describe both phenotype and pathogenesis in two male siblings with typical retinitis pigmentosa (RP) and the potentially X-linked RP (XLRP) carrier phenotype in their mother. Two affected sons, two unaffected daughters, and their mother underwent detailed ophthalmological assessments including Goldmann perimetry, color vision testing, multimodal imaging and ISCEV-standard electroretinography. Genetic testing consisted of targeted next-generation sequencing (NGS) of known XLRP genes and whole exome sequencing (WES) of known inherited retinal disease genes (RetNet-WES). Variant validation and segregation analysis were performed by Sanger sequencing. The mutational load of the RHO variant in the mother was assessed in DNA from leucocytes, buccal cells and hair follicles using targeted NGS. Both affected sons showed signs of classical RP, while the mother displayed patches of hyperautofluorescence on blue light autofluorescence imaging and regional, intraretinal, spicular pigmentation, reminiscent of a carrier phenotype of XLRP. XLRP testing was negative. RetNet-WES testing revealed RHO variant c.404G > C p.(Arg135Pro) in a mosaic state (21% of the reads) in the mother and in a heterozygous state in both sons. Targeted NGQSS of the RHO variant in different maternal tissues showed a mutation load between 25.06% and 41.72%. We report for the first time that somatic mosaicism of RHO variant c.404G > C p.(Arg135Pro) mimics the phenotype of a female carrier of XLRP, in combination with heterozygosity for the variant in the two affected sons.
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- 2021
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5. Long-Read Sequencing to Unravel Complex Structural Variants of CEP78 Leading to Cone-Rod Dystrophy and Hearing Loss
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Giulia Ascari, Nanna D. Rendtorff, Marieke De Bruyne, Julie De Zaeytijd, Michel Van Lint, Miriam Bauwens, Mattias Van Heetvelde, Gavin Arno, Julie Jacob, David Creytens, Jo Van Dorpe, Thalia Van Laethem, Toon Rosseel, Tim De Pooter, Peter De Rijk, Wouter De Coster, Björn Menten, Alfredo Dueñas Rey, Mojca Strazisar, Mette Bertelsen, Lisbeth Tranebjaerg, and Elfride De Baere
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CEP78 ,inherited retinal disease ,cone-rod dystrophy with hearing loss ,long-read sequencing ,structural variants ,single-cell gene expression analysis ,Biology (General) ,QH301-705.5 - Abstract
Inactivating variants as well as a missense variant in the centrosomal CEP78 gene have been identified in autosomal recessive cone-rod dystrophy with hearing loss (CRDHL), a rare syndromic inherited retinal disease distinct from Usher syndrome. Apart from this, a complex structural variant (SV) implicating CEP78 has been reported in CRDHL. Here we aimed to expand the genetic architecture of typical CRDHL by the identification of complex SVs of the CEP78 region and characterization of their underlying mechanisms. Approaches used for the identification of the SVs are shallow whole-genome sequencing (sWGS) combined with quantitative polymerase chain reaction (PCR) and long-range PCR, or ExomeDepth analysis on whole-exome sequencing (WES) data. Targeted or whole-genome nanopore long-read sequencing (LRS) was used to delineate breakpoint junctions at the nucleotide level. For all SVs cases, the effect of the SVs on CEP78 expression was assessed using quantitative PCR on patient-derived RNA. Apart from two novel canonical CEP78 splice variants and a frameshifting single-nucleotide variant (SNV), two SVs affecting CEP78 were identified in three unrelated individuals with CRDHL: a heterozygous total gene deletion of 235 kb and a partial gene deletion of 15 kb in a heterozygous and homozygous state, respectively. Assessment of the molecular consequences of the SVs on patient’s materials displayed a loss-of-function effect. Delineation and characterization of the 15-kb deletion using targeted LRS revealed the previously described complex CEP78 SV, suggestive of a recurrent genomic rearrangement. A founder haplotype was demonstrated for the latter SV in cases of Belgian and British origin, respectively. The novel 235-kb deletion was delineated using whole-genome LRS. Breakpoint analysis showed microhomology and pointed to a replication-based underlying mechanism. Moreover, data mining of bulk and single-cell human and mouse transcriptional datasets, together with CEP78 immunostaining on human retina, linked the CEP78 expression domain with its phenotypic manifestations. Overall, this study supports that the CEP78 locus is prone to distinct SVs and that SV analysis should be considered in a genetic workup of CRDHL. Finally, it demonstrated the power of sWGS and both targeted and whole-genome LRS in identifying and characterizing complex SVs in patients with ocular diseases.
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- 2021
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6. Serum Calcification Propensity T50 Associates with Disease Severity in Patients with Pseudoxanthoma Elasticum
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Lukas Nollet, Matthias Van Gils, Suzanne Fischer, Laurence Campens, Swapna Karthik, Andreas Pasch, Julie De Zaeytijd, Bart P. Leroy, Daniel Devos, Tine De Backer, Paul J. Coucke, and Olivier M. Vanakker
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pseudoxanthoma elasticum ,PXE ,ectopic calcification ,biomarker ,genetics ,rare diseases ,Medicine - Abstract
Pseudoxanthoma elasticum (PXE) is a currently intractable genetic disorder characterized by progressive ectopic calcification in the skin, eyes and arteries. Therapeutic trials in PXE are severely hampered by the lack of reliable biomarkers. Serum calcification propensity T50 is a blood test measuring the functional anticalcifying buffer capacity of serum. Here, we evaluated T50 in PXE patients aiming to investigate its determinants and suitability as a potential biomarker for disease severity. Fifty-seven PXE patients were included in this cross-sectional study, and demographic, clinical, imaging and biochemical data were collected from medical health records. PXE severity was assessed using Phenodex scores. T50 was measured using a validated, nephelometry-based assay. Multivariate models were then created to investigate T50 determinants and associations with disease severity. In short, the mean age of patients was 45.2 years, 68.4% was female and mean serum T50 was 347 min. Multivariate regression analysis identified serum fetuin-A (p < 0.001), phosphorus (p = 0.007) and magnesium levels (p = 0.034) as significant determinants of T50, while no correlations were identified with serum calcium, eGFR, plasma PPi levels or the ABCC6 genotype. After correction for covariates, T50 was found to be an independent determinant of ocular (p = 0.013), vascular (p = 0.013) and overall disease severity (p = 0.016) in PXE. To conclude, shorter serum T50—indicative of a higher calcification propensity—was associated with a more severe phenotype in PXE patients. This study indicates, for the first time, that serum T50 might be a clinically relevant biomarker in PXE and may thus be of importance to future therapeutic trials.
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- 2022
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7. Vitreous Hemorrhage as Presenting Sign of Retinal Arteriovenous Malformation
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Geraldine P. B. M. Accou, Fanny Nerinckx, Bart P. Leroy, and Julie De Zaeytijd
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Ophthalmology ,RE1-994 - Abstract
Objective. To describe a patient with vitreous hemorrhage and peripheral retinal ischemia, eventually diagnosed with an underlying retinal arteriovenous malformation. Methods. A 15-year-old girl presented with sudden-onset, painless visual loss in the right eye. She underwent a full ophthalmological work-up. Results. BCVA was less than 20/400 in the right eye and 20/20 in the left eye. Intraocular pressure and anterior segment examination were unremarkable. Fundoscopy was impossible due to an opaque vitreous hemorrhage in the right eye. The left eye was completely unremarkable. Examination during a 23-gauge pars plana vitrectomy showed dilated, tortuous arteriovenous vessels extending from the optic disc and silver wiring of the enlarged vessels. A clinical diagnosis of retinal arteriovenous malformation was made. During surgery, a peripheral retinal photocoagulation was executed to avoid rebleeding. Postoperatively, fluorescein angiography demonstrated additional macular microangiopathy and diffuse retinal nonperfusion in the periphery. The MRI brain revealed neither cerebral nor orbital vascular anomaly, confirming a group 2 retinal arteriovenous malformation. Conclusion. Retinal arteriovenous malformations are generally considered stable over time. However, complications due to retinal ischemia can occur. Hence, regular observation is warranted. In so doing, timely treatment can be offered to avoid complications.
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- 2020
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8. An atypical case of neurosarcoidosis presenting with neovascular glaucoma
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Melissa Vereecken, Karolien Hollanders, Deborah De Bruyn, Virginie Ninclaus, Julie De Zaeytijd, and Ilse De Schryver
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Neurosarcoidosis ,Neuro-ophthalmic sarcoidosis ,Compressive ischemic optic neuropathy ,Neovascular glaucoma ,Optic nerve mass granuloma ,Ophthalmology ,RE1-994 - Abstract
Abstract Background Sarcoidosis, a multisystem, granulomatous disorder, sometimes manifests with a neuro-ophthalmic subtype. The latter can pose a diagnostic challenge, especially when ocular symptoms appear before systemic involvement, as the clinical picture then can be non-specific and systemic laboratory and standard imaging investigations can be negative. Findings A 71-year-old woman presented with a 4-month history of sudden-onset visual loss in the left eye. Slit lamp examination revealed anterior chamber cells, iris, and angle neovascularization. Fundoscopy showed a pale edematous optic nerve head surrounded with intraretinal hemorrhages and yellow retinal infiltrates. The vasculature was very narrow to absent. Indeed, fluorescein angiography filling was limited to the (juxta-)papillary region. An extensive systemic work-up revealed a monoclonal gammopathy and absence of any inflammatory markers. On MRI, a mass infiltration of the intraorbital and the intracranial optic nerve was visible. Additional PET-CT scan revealed hilar lymph nodes. A transbronchial biopsy demonstrating a non-caseating granulomatous lesion led to the diagnosis of sarcoidosis and thus neurosarcoidosis. Treatment with high-dose prednisone and azathioprine was started to avoid progression and subsequent visual loss in the other eye. Conclusions A patient with neurosarcoidosis presenting with compressive ischemic optic disc edema and neovascular glaucoma is described, increasing the diversity of clinical presentations and confirming the diagnostic challenge of neurosarcoidosis.
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- 2018
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9. Mutations in Splicing Factor Genes Are a Major Cause of Autosomal Dominant Retinitis Pigmentosa in Belgian Families.
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Caroline Van Cauwenbergh, Frauke Coppieters, Dimitri Roels, Sarah De Jaegere, Helena Flipts, Julie De Zaeytijd, Sophie Walraedt, Charlotte Claes, Erik Fransen, Guy Van Camp, Fanny Depasse, Ingele Casteels, Thomy de Ravel, Bart P Leroy, and Elfride De Baere
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Medicine ,Science - Abstract
PURPOSE:Autosomal dominant retinitis pigmentosa (adRP) is characterized by an extensive genetic heterogeneity, implicating 27 genes, which account for 50 to 70% of cases. Here 86 Belgian probands with possible adRP underwent genetic testing to unravel the molecular basis and to assess the contribution of the genes underlying their condition. METHODS:Mutation detection methods evolved over the past ten years, including mutation specific methods (APEX chip analysis), linkage analysis, gene panel analysis (Sanger sequencing, targeted next-generation sequencing or whole exome sequencing), high-resolution copy number screening (customized microarray-based comparative genomic hybridization). Identified variants were classified following American College of Medical Genetics and Genomics (ACMG) recommendations. RESULTS:Molecular genetic screening revealed mutations in 48/86 cases (56%). In total, 17 novel pathogenic mutations were identified: four missense mutations in RHO, five frameshift mutations in RP1, six mutations in genes encoding spliceosome components (SNRNP200, PRPF8, and PRPF31), one frameshift mutation in PRPH2, and one frameshift mutation in TOPORS. The proportion of RHO mutations in our cohort (14%) is higher than reported in a French adRP population (10.3%), but lower than reported elsewhere (16.5-30%). The prevalence of RP1 mutations (10.5%) is comparable to other populations (3.5%-10%). The mutation frequency in genes encoding splicing factors is unexpectedly high (altogether 19.8%), with PRPF31 the second most prevalent mutated gene (10.5%). PRPH2 mutations were found in 4.7% of the Belgian cohort. Two families (2.3%) have the recurrent NR2E3 mutation p.(Gly56Arg). The prevalence of the recurrent PROM1 mutation p.(Arg373Cys) was higher than anticipated (3.5%). CONCLUSIONS:Overall, we identified mutations in 48 of 86 Belgian adRP cases (56%), with the highest prevalence in RHO (14%), RP1 (10.5%) and PRPF31 (10.5%). Finally, we expanded the molecular spectrum of PRPH2, PRPF8, RHO, RP1, SNRNP200, and TOPORS-associated adRP by the identification of 17 novel mutations.
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- 2017
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10. Randomized trial of bilateral gene therapy injection for m.11778G>A MT-ND4 Leber optic neuropathy
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Newman, Nancy J, Yu-Wai-Man, Patrick, Subramanian, Prem S, Moster, Mark L, Wang, An-Guor, Donahue, Sean P, Leroy, Bart P, Carelli, Valerio, Biousse, Valerie, Vignal-Clermont, Catherine, Sergott, Robert C, Sadun, Alfredo A, Rebolleda Fernández, Gema, Chwalisz, Bart K, Banik, Rudrani, Bazin, Fabienne, Roux, Michel, Cox, Eric D, Taiel, Magali, Sahel, José-Alain, Giulia, Amore, Shweta, Anand, Rudrani, Banik, Piero, Barboni, Valérie, Biousse, Hayley, Boston, Asma, Burale, Michele, Carbonelli, Valerio, Carelli, Celia, Chen, Hui-Chen, Cheng, Steve, Cho, Manuela, Contin, Pietro, D’Agati, DeBusk, Adam A, Julie, De Zaeytijd, Jannah, Dobbs, Lindreth, DuBois, Simona, Esposti, Alcides, Fernandes Filho, Elizabeth, Fortin, Sapna, Gangaputra, Deborah, Gibbs, François, Girmens Jean, Rabih, Hage, Haller, Julia A, Gad, Heilweil, George Baker, Hubbard III, Jeong-Min, Hwang, Laia, Jaumendreu Urquijo, Neringa, Jurkute, Rustum, Karanjia, Wahiba, Khemliche, La Chiara, Morgia, Maria, Massini, Marc, Mathias, Memon, Muhammad A, Susan, Mohamed, Muñoz Negrete, Francisco J, Ghazala, O’Keefe, Shriji, Patel, Paula, Pecen, Peragallo, Jason H, Lise, Plaine, Mary, Preston, Gema, Rebolleda Fernández, Martina, Romagnoli, José-Alain, Sahel, Melissa, SantaMaria, Chuanbin, Sun, Katy, Tai, Heather, Tollis, Irena, Tsui, Tucker, William R, Catherine, Vignal-Clermont, An-Guor, Wang, Saige, Wilkins, and Patrick, Yu-Wai-Man
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Biomedical and Clinical Sciences ,Ophthalmology and Optometry ,Clinical Research ,Genetics ,Neurosciences ,Clinical Trials and Supportive Activities ,Eye Disease and Disorders of Vision ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Eye ,Humans ,DNA ,Mitochondrial ,Genetic Therapy ,Inflammation ,Mutation ,Optic Atrophy ,Hereditary ,Leber ,LHON REFLECT Study Group ,NADH dehydrogenase 4 ,leber hereditary optic neuropathy ,lenadogene nolparvovec ,mitochondrial DNA ,recombinant adeno-associated virus vector 2 ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Neurology & Neurosurgery ,Biomedical and clinical sciences ,Health sciences ,Psychology - Abstract
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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- 2023
11. Optic nerve involvement in CACNA1F-related disease: observations from a multicentric case series
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Elisa Marziali, Filip Van Den Broeck, Sara Bargiacchi, Pina Fortunato, Roberto Caputo, Andrea Sodi, Julie De Zaeytijd, Vittoria Murro, Dario Pasquale Mucciolo, Dario Giorgio, Ilaria Passerini, Viviana Palazzo, Francesca Peluso, Elfride de Baere, Christina Zeitz, Bart P. Leroy, Jacopo Secci, and Giacomo M. Bacci
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Ophthalmology ,Pediatrics, Perinatology and Child Health ,Genetics (clinical) - Published
- 2022
12. The Natural History of Leber Congenital Amaurosis and Cone–Rod Dystrophy Associated with Variants in the GUCY2D Gene
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Leo C. Hahn, Michalis Georgiou, Hind Almushattat, Mary J. van Schooneveld, Emanuel R. de Carvalho, Nieneke L. Wesseling, Jacoline B. ten Brink, Ralph J. Florijn, Birgit I. Lissenberg-Witte, Ine Strubbe, Caroline van Cauwenbergh, Julie de Zaeytijd, Sophie Walraedt, Elfride de Baere, Rajarshi Mukherjee, Martin McKibbin, Magda A. Meester-Smoor, Alberta A.H.J. Thiadens, Saoud Al-Khuzaei, Engin Akyol, Andrew J. Lotery, Maria M. van Genderen, Jeannette Ossewaarde-van Norel, L. Ingeborgh van den Born, Carel B. Hoyng, Caroline C.W. Klaver, Susan M. Downes, Arthur A. Bergen, Bart P. Leroy, Michel Michaelides, Camiel J.F. Boon, Ophthalmology, Adult Psychiatry, Human Genetics, ANS - Complex Trait Genetics, ARD - Amsterdam Reproduction and Development, Epidemiology and Data Science, APH - Methodology, Human genetics, and Netherlands Institute for Neuroscience (NIN)
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genetic structures ,Cone-rod dystrophy ,Inherited retinal dystrophies ,Vision Disorders ,Visual Acuity ,BIOSTATISTICS ,PHENOTYPE ,EYE ,Leber congenital amaurosis ,eye diseases ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] ,Cone–rod dystrophy ,Ophthalmology ,VISION ,TRIALS ,Phenotype ,GUCY2D ,Medicine and Health Sciences ,Humans ,sense organs ,TUTORIAL ,MUTATION ,Cone-Rod Dystrophies ,Retrospective Studies - Abstract
Objective: To describe the spectrum of Leber congenital amaurosis (LCA) and cone-rod dystrophy (CORD) associated with the GUCY2D gene and to identify potential end points and optimal patient selection for future therapeutic trials.Design: International, multicenter, retrospective cohort study.Subjects: Eighty-two patients with GUCY2D-associated LCA or CORD from 54 families.Methods: Medical records were reviewed for medical history, best-corrected visual acuity (BCVA), ophthalmoscopy, visual fields, full-field electroretinography, and retinal imaging (fundus photography, spectral -domain OCT [SD-OCT], fundus autofluorescence).Main Outcomes Measures: Age of onset, evolution of BCVA, genotype-phenotype correlations, anatomic characteristics on funduscopy, and multimodal imaging.Results: Fourteen patients with autosomal recessive LCA and 68 with autosomal dominant CORD were included. The median follow-up times were 5.2 years (interquartile range [IQR] 2.6-8.8 years) for LCA and 7.2 years (IQR 2.2-14.2 years) for CORD. Generally, LCA presented in the first year of life. The BCVA in patients with LCA ranged from no light perception to 1.00 logarithm of the minimum angle of resolution (logMAR) and remained relatively stable during follow-up. Imaging for LCA was limited but showed little to no structural degeneration. In patients with CORD, progressive vision loss started around the second decade of life. The BCVA declined annually by 0.022 logMAR (P < 0.001) with no difference between patients with the c.2513G>A and the c.2512C>T GUCY2D variants (P = 0.798). At the age of 40 years, the probability of being blind or severely visually impaired was 32%. The integrity of the ellipsoid zone (EZ) and that of the external limiting membrane (ELM) on SD-OCT correlated signifi-cantly with BCVA (Spearman r = 0.744, P = 0.001, and r = 0.712, P < 0.001, respectively) in those with CORD.Conclusions: Leber congenital amaurosis associated with GUCY2D caused severe congenital visual impairment with relatively intact macular anatomy on funduscopy and available imaging, suggesting long pres-ervation of photoreceptors. Despite large variability, GUCY2D-associated CORD generally presented during adolescence, with a progressive loss of vision, and culminated in severe visual impairment during mid-to-late adulthood. The integrity of the ELM and EZ may be suitable structural end points for therapeutic studies of GUCY2D-associated CORD. Ophthalmology Retina 2022;6:711-722 (c) 2022 by the American Academy of Ophthalmology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).
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- 2022
13. X-Linked Retinoschisis
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Camiel J. F. Boon, Julie De Zaeytijd, Mary J. van Schooneveld, Maria M. van Genderen, Ralph J. Florijn, Bart P. Leroy, Carel B. Hoyng, Paul A. Sieving, Alberta A H J Thiadens, Sophie Walraedt, Jeannette Ossewaarde-van Norel, Magda A. Meester-Smoor, Leo C. Hahn, Birgit I. Lissenberg-Witte, Arthur A.B. Bergen, Jacoline B. ten Brink, Elfride De Baere, Nieneke L. Wesseling, Caroline Van Cauwenbergh, Caroline C W Klaver, Roselie M. Diederen, L. Ingeborgh van den Born, and Ine Strubbe
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Pediatrics ,medicine.medical_specialty ,Visual acuity ,genetic structures ,medicine.diagnostic_test ,business.industry ,Visual impairment ,Fundus photography ,Retinoschisis ,Retrospective cohort study ,medicine.disease ,Ophthalmoscopy ,Ophthalmology ,medicine ,Medical history ,medicine.symptom ,business ,Electroretinography - Abstract
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 XLRS patients for medical history, symptoms, visual acuity (VA), ophthalmoscopy, full-field electroretinography and retinal imaging (fundus photography, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence). Main Outcome Measures Age at onset, age of diagnosis, severity of visual impairment, annual visual decline, electroretinogram and imaging findings. Results In total, 340 patients were included with a mean follow-up time of 13.2 years (range, 0–50.1 years). The median age to reach mild visual impairment and low vision was 12 and 25 years, respectively. Severe visual impairment and blindness were predominantly observed in patients above 40 years old, with a predicted prevalence of 35% and 25% at the age of 60, respectively. The VA increased slightly in the first two decades of life, and subsequently transitioned in to an average annual decline of 0.44% (P A (p.(Glu72Lys) (101 subjects, 29.7%) and a deletion of exon 3 (38 subjects, 11.2%). Conclusion A large variability in phenotype and natural course of XLRS was 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 three 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 endpoints in future therapeutic studies. No clear genotype-phenotype correlation was found.
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- 2022
14. An eye-opening case report of constrictive pericarditis
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Sebastiaan Dhont, Yves Van Belleghem, Julie De Zaeytijd, and Els Vandecasteele
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Cardiology and Cardiovascular Medicine - Abstract
Background Constrictive pericarditis is characterized by the encasement of the heart by a stiff pericardium leading to impaired diastolic function, which ultimately leads to congestive heart failure. Case summary We report a case of a young woman, who first presented to the ophthalmologist with the sudden appearance of floaters and vision reduction. Eventually, invasive haemodynamic assessment led to the diagnosis of constrictive pericarditis leading to venous congestion. Conclusion Understanding the pathophysiology and integrating the results of invasive and non-invasive diagnostic work up is important in making this challenging diagnosis.
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- 2022
15. Longitudinal phenotypic study of late-onset retinal degeneration due to a founder variant c.562C>A p.(Pro188Thr) in the C1QTNF5 gene
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Caroline Van Cauwenbergh, Frauke Coppieters, Bart P. Leroy, Elfride De Baere, Julie De Zaeytijd, Jasper Van Royen, Dimitri Roels, Rani Six, and Marieke De Bruyne
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0301 basic medicine ,Retinal degeneration ,Pathology ,medicine.medical_specialty ,Retinal dystrophy ,Late-Onset Retinal Degeneration ,030105 genetics & heredity ,Biology ,medicine.disease ,Phenotype ,03 medical and health sciences ,Ophthalmology ,0302 clinical medicine ,Pediatrics, Perinatology and Child Health ,030221 ophthalmology & optometry ,medicine ,Gene ,Genetics (clinical) - Abstract
Background: Late-onset retinal degeneration (L-ORD) is a rare autosomal dominant retinal dystrophy related to C1QTNF5 gene variants.Materials and methods: Twenty-six patients (21–81 years) with L-O...
- Published
- 2021
16. Mild Leber hereditary optic neuropathy (LHON) in a Western European family due to the rare Asian m.14502T>C variant in the MT-ND6 gene
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Sara Seneca, Mattias Van Heetvelde, Justine Vandeputte, Elfride De Baere, Julie De Zaeytijd, Caroline Van Cauwenbergh, Bart P. Leroy, Clinical sciences, Medical Genetics, and Reproduction and Genetics
- Subjects
0301 basic medicine ,Proband ,Mitochondrial DNA ,Pathology ,medicine.medical_specialty ,genetic structures ,030105 genetics & heredity ,Temporal optic disc pallor ,MT-ND6 gene ,Optic neuropathy ,LHON ,03 medical and health sciences ,0302 clinical medicine ,Atrophy ,C%22">m.14502T>C ,Medicine ,Genetics(clinical) ,Genetics (clinical) ,business.industry ,Blind spot ,medicine.disease ,Penetrance ,eye diseases ,Ophthalmology ,Pediatrics, Perinatology and Child Health ,030221 ophthalmology & optometry ,alcohol and tobacco abuse ,MT-ND6 ,Leber hereditary optic neuropathy ,business ,reproductive medicine - Abstract
Background: Leber hereditary optic neuropathy (LHON) is a mitochondrial neurodegenerative disease. The majority (>90%) is related to three primary mitochondrial DNA (mtDNA) variants: ND1 m.3460G>A, ND4 m.11778G>A and ND6 m.14484T>C. The remaining 10% is associated with >40 secondary variants with variable penetrance and incidence between different ethnic backgrounds. Materials and methods: Five sisters underwent an extensive ophthalmic workup including psychophysical, electrophysiological, multimodal brain imaging, biochemical testing and molecular screening. MT-ND6 protein modelling was performed. Results: A 23-year-old woman presented with acute central visual loss to counting fingers in the right eye. She developed a central visual field scotoma, severe color vision deficiencies and impaired pattern visual evoked responses. Progressive optic atrophy ensued. The left eye was unremarkable, except for borderline thinning of the temporal retinal nerve fiber layer. Alcohol use and passive smoking were noted. MtDNA analysis revealed a rare variant, m.14502T>C in MT-ND6, exclusively known to cause optic neuropathy in an Asian population. Three sisters of the proband, two of whom reported tobacco and alcohol abuse, had bilateral temporal optic disc pallor without functional impact. A fourth non-smoker sister had a completely normal eye exam. Conclusions: The rare Asian m.14502T>C variant in the MT-ND6 gene was linked to a mild LHON phenotype in a Western European family. Penetrance in this family was likely triggered by alcohol and tobacco abuse. A full mtDNA sequencing is warranted in the case of high clinical suspicion of LHON when mutation analysis for the three common pathogenic variants is negative.
- Published
- 2021
17. Clinical and subclinical findings in heterozygous ABCC6 carriers: results from a Belgian cohort and clinical practice guidelines
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Julie De Zaeytijd, Paul Coucke, Lukas Nollet, Dimitri Hemelsoet, Laurence Campens, Bart P. Leroy, and Olivier Vanakker
- Subjects
0301 basic medicine ,medicine.medical_specialty ,education.field_of_study ,biology ,Vascular disease ,business.industry ,Population ,ABCC6 ,030204 cardiovascular system & hematology ,Pseudoxanthoma elasticum ,medicine.disease ,Loss of heterozygosity ,03 medical and health sciences ,Ectopic calcification ,030104 developmental biology ,0302 clinical medicine ,Internal medicine ,Genetics ,medicine ,biology.protein ,education ,business ,Genetics (clinical) ,Testicular microlithiasis ,Subclinical infection - Abstract
BackgroundBiallelic 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.MethodsThe 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.ResultsWe 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.ConclusionIn 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.
- Published
- 2021
18. Atypical clinical and novel radiological findings in Susac syndrome: Experience from a large monocentric cohort
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Cathérine Dekeyser, Alexander Vanhoorne, Dimitri Hemelsoet, Liesbeth Van Hijfte, Julie De Zaeytijd, Veroniek Van Driessche, Helen Van Hoecke, Marijke Miatton, Tineke Van Vrekhem, Leen Maes, and Guy Laureys
- Subjects
Neurology ,Immunology ,Immunology and Allergy ,Neurology (clinical) - Published
- 2023
19. Multi-omics profiling, in vitro and in vivo enhancer assays dissect the cis-regulatory mechanisms underlying North Carolina macular dystrophy, a retinal enhanceropathy
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Stijn Van de Sompele, Kent W. Small, Munevver Burcu Cicekdal, Víctor López Soriano, Eva D’haene, Fadi S. Shaya, Steven Agemy, Thijs Van der Snickt, Alfredo Dueñas Rey, Toon Rosseel, Mattias Van Heetvelde, Sarah Vergult, Irina Balikova, Arthur A. Bergen, Camiel J. F. Boon, Julie De Zaeytijd, Chris F. Inglehearn, Bohdan Kousal, Bart P. Leroy, Carlo Rivolta, Veronika Vaclavik, Jenneke van den Ende, Mary J. van Schooneveld, José Luis Gómez-Skarmeta, Juan J. Tena, Juan R. Martinez-Morales, Petra Liskova, Kris Vleminckx, and Elfride De Baere
- Abstract
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 gene 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 novel NCMD-associated non-coding SNVs that we identified. 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, putting forward this region as 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 gained insight into the cis-regulatory mechanisms of NCMD and supports that this condition is a retinal enhanceropathy.Graphical abstract
- Published
- 2022
20. Contributors
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Tomas S. Aleman, Patrizia Amati-Bonneau, Benoît Arveiler, Jane L. Ashworth, Isabelle Audo, Giacomo M. Bacci, Nicole Balducci, Irina Balikova, Miriam Bauwens, Piero Barboni, Johannes Birtel, Susmito Biswas, Graeme C.M. Black, Catherine Blanchet, Béatrice Bocquet, Camiel J.F. Boon, Antoine Brézin, Cyril Burin des Roziers, Emma Burkitt-Wright, Michele Callea, Michele Carbonelli, Valerio Carelli, Jasmina Cehajic-Kapetanovic, Kate E. Chandler, Aman Chandra, Jill Clayton-Smith, Johanna M. Colijn, Frauke Coppieters, Catherine A. Cukras, Avril Daly, Elfride De Baere, Julie De Zaeytijd, Arundhati Dev Borman, Hélène Dollfus, Sofia Douzgou Houge, Elizabeth C. Engle, Pascal Escher, D. Gareth Evans, Kristina Teär Fahnehjelm, Christina Fasser, Mathieu Fiore, Kaoru Fujinami, Yu Fujinami-Yokokawa, Brenda L. Gallie, Michalis Georgiou, Martin Gliem, Monika K. Grudzinska Pechhacker, Georgina Hall, Wolf M. Harmening, Robert H. Henderson, Elise Héon, Nashila Hirji, Frank G. Holz, Laryssa A. Huryn, Elizabeth A. Jones, Vasiliki Kalatzis, Arif O. Khan, Ungsoo S. Kim, Caroline C.W. Klaver, Neruban Kumaran, Chiara La Morgia, Fiona Lalloo, Eulalie Lasseaux, Helena Lee, Guy Lenaers, Eva Lenassi, Bart P. Leroy, Petra Liskova, I. Christopher Lloyd, Robert E. MacLaren, Omar A. Mahroo, Alvaro J. Mejia-Vergara, Isabelle Meunier, Michel Michaelides, Anthony T. Moore, Mariya Moosajee, Fanny Morice-Picard, Francis L. Munier, Magella M. Neveu, Erin C. O'Neil, Anna Nordenström, Neil R.A. Parry, Maria I. Patrício, Manoj V. Parulekar, Dipak Ram, Simon C. Ramsden, Johane Robitaille, Anthony G. Robson, Pierre-Raphaël Rothschild, Alfredo A. Sadun, Kaspar Schuerch, Miguel C. Seabra, Jay E. Self, Panagiotis I. Sergouniotis, Fadi Shaya, Paul A. Sieving, Ine Strubbe, Francesca Simonelli, Kent W. Small, Martin P. Snead, Karolina M. Stepien, Mays Talib, Rachel L. Taylor, Francesco Testa, Alberta A.H.J. Thiadens, Elias I. Traboulsi, Viet H. Tran, Veronika Vaclavik, Sophie Valleix, Caroline Van Cauwenbergh, Kristof Van Schil, Mary C. Whitman, Colin E. Willoughby, Kanmin Xue, Jingyan Yang, Patrick Yu-Wai-Man, Christina Zeitz, and Martin Zinkernagel
- Published
- 2022
21. Intravitreal antisense oligonucleotide sepofarsen in Leber congenital amaurosis type 10: a phase 1b/2 trial
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Stephen R. Russell, Arlene V. Drack, Artur V. Cideciyan, Samuel G. Jacobson, Bart P. Leroy, Caroline Van Cauwenbergh, Allen C. Ho, Alina V. Dumitrescu, Ian C. Han, Mitchell Martin, Wanda L. Pfeifer, Elliott H. Sohn, Jean Walshire, Alexandra V. Garafalo, Arun K. Krishnan, Christian A. Powers, Alexander Sumaroka, Alejandro J. Roman, Eva Vanhonsebrouck, Eltanara Jones, Fanny Nerinckx, Julie De Zaeytijd, Rob W. J. Collin, Carel Hoyng, Peter Adamson, Michael E. Cheetham, Michael R. Schwartz, Wilhelmina den Hollander, Friedrich Asmus, Gerard Platenburg, David Rodman, and Aniz Girach
- Subjects
Adult ,Leber Congenital Amaurosis ,Cell Cycle Proteins ,General Medicine ,Oligonucleotides, Antisense ,Blindness ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] ,General Biochemistry, Genetics and Molecular Biology ,Cytoskeletal Proteins ,Antigens, Neoplasm ,Medicine and Health Sciences ,Humans ,Child ,Vision, Ocular - Abstract
CEP290-associated Leber congenital amaurosis type 10 (LCA10) is a retinal disease resulting in childhood blindness. Sepofarsen is an RNA antisense oligonucleotide targeting the c.2991+1655A>G variant in the CEP290 gene to treat LCA10. In this open-label, phase 1b/2 (NCT03140969), 12-month, multicenter, multiple-dose, dose-escalation trial, six adult patients and five pediatric patients received ≤4 doses of intravitreal sepofarsen into the worse-seeing eye. The primary objective was to evaluate sepofarsen safety and tolerability via the frequency and severity of ocular adverse events (AEs); secondary objectives were to evaluate pharmacokinetics and efficacy via changes in functional outcomes. Six patients received sepofarsen 160 µg/80 µg, and five patients received sepofarsen 320 µg/160 µg. Ten of 11 (90.9%) patients developed ocular AEs in the treated eye (5/6 with 160 µg/80 µg; 5/5 with 320 µg/160 µg) versus one of 11 (9.1%) in the untreated eye; most were mild in severity and dose dependent. Eight patients developed cataracts, of which six (75.0%) were categorized as serious (2/3 with 160 µg/80 µg; 4/5 with 320 µg/160 µg), as lens replacement was required. As the 160-µg/80-µg group showed a better benefit–risk profile, higher doses were discontinued or not initiated. Statistically significant improvements in visual acuity and retinal sensitivity were reported (post hoc analysis). The manageable safety profile and improvements reported in this trial support the continuation of sepofarsen development.
- Published
- 2021
22. Longitudinal phenotypic study of late-onset retinal degeneration due to a founder variant c.562CA p.(Pro188Thr) in the
- Author
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Julie, De Zaeytijd, Frauke, Coppieters, Marieke, De Bruyne, Jasper, Van Royen, Dimitri, Roels, Rani, Six, Caroline, Van Cauwenbergh, Elfride, De Baere, and Bart P, Leroy
- Subjects
Adult ,Aged, 80 and over ,Male ,Retinal Degeneration ,Visual Acuity ,Middle Aged ,Polymorphism, Single Nucleotide ,Founder Effect ,Pedigree ,Young Adult ,Phenotype ,Electroretinography ,Humans ,Female ,Collagen ,Longitudinal Studies ,Fluorescein Angiography ,Visual Fields ,Tomography, Optical Coherence ,Aged - Published
- 2021
23. Mild Leber hereditary optic neuropathy (LHON) in a Western European family due to the rare Asian m.14502TC variant in the
- Author
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Justine, Vandeputte, Mattias, Van Heetvelde, Caroline, Van Cauwenbergh, Sara, Seneca, Elfride, De Baere, Bart P, Leroy, and Julie, De Zaeytijd
- Subjects
Adult ,Siblings ,DNA Mutational Analysis ,Visual Acuity ,NADH Dehydrogenase ,Optic Atrophy, Hereditary, Leber ,Heteroplasmy ,Slit Lamp Microscopy ,DNA, Mitochondrial ,Ophthalmoscopy ,Young Adult ,Asian People ,Electroretinography ,Evoked Potentials, Visual ,Humans ,Point Mutation ,Female ,Scotoma ,Tomography, Optical Coherence - Abstract
Leber hereditary optic neuropathy (LHON) is a mitochondrial neurodegenerative disease. The majority (90%) is related to three primary mitochondrial DNA (mtDNA) variants:Five sisters underwent an extensive ophthalmic workup including psychophysical, electrophysiological, multimodal brain imaging, biochemical testing and molecular screening. MT-ND6 protein modelling was performed.A 23-year-old woman presented with acute central visual loss to counting fingers in the right eye. She developed a central visual field scotoma, severe color vision deficiencies and impaired pattern visual evoked responses. Progressive optic atrophy ensued. The left eye was unremarkable, except for borderline thinning of the temporal retinal nerve fiber layer. Alcohol use and passive smoking were noted. MtDNA analysis revealed a rare variant, m.14502TC inThe rare Asian m.14502TC variant in the
- Published
- 2021
24. ABCA4-associated disease as a model for missing heritability in autosomal recessive disorders: novel noncoding splice, cis-regulatory, structural, and recurrent hypomorphic variants
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Bernd Wissinger, Thomy de Ravel de l'Argentière, Frans P.M. Cremers, Jim Bauwens, Bart P. Leroy, Riccardo Sangermano, Caroline Van Cauwenbergh, Julie De Zaeytijd, Ana Fakin, Sarah De Jaegere, Toon Rosseel, Mubeen Khan, Gavin Arno, Susanne Kohl, Andrew R. Webster, Meindert De Vries, Elfride De Baere, Rob W.J. Collin, Alejandro Garanto, Irina Balikova, Keren J. Carss, Thalia Van Laethem, Miriam Bauwens, Kim De Leeneer, Marnik Vuylsteke, Sarah Naessens, Yves Sznajer, Timothy J. Cherry, Françoise Sadler, Nicole Weisschuh, Software Languages Lab, Informatics and Applied Informatics, Faculty of Sciences and Bioengineering Sciences, UCL - (SLuc) Centre de génétique médicale UCL, and UCL - SSS/IREC/SLUC - Pôle St.-Luc
- Subjects
DEEP-INTRONIC VARIANTS ,Male ,ABCA4 ,PHENOTYPE ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] ,Cohort Studies ,0302 clinical medicine ,Gene Frequency ,Missing heritability problem ,STARGARDT-DISEASE ,Medicine and Health Sciences ,Genetics(clinical) ,Genetics (clinical) ,Genetics ,0303 health sciences ,biology ,noncoding ,deep-intronic ,Exons ,DYSTROPHY ,Middle Aged ,Phenotype ,3. Good health ,Pedigree ,Female ,Adult ,Genes, Recessive ,ANTISENSE OLIGONUCLEOTIDES ,Article ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,AON ,Retinitis pigmentosa ,RETINITIS-PIGMENTOSA ,REVEALS ,Retinal Dystrophies ,medicine ,non-coding ,Humans ,splice ,Allele ,Gene ,Alleles ,030304 developmental biology ,SPECTRUM ,TRANSPORTER GENE ABCR ,MUTATIONS ,Biology and Life Sciences ,ABCA4-associated disease ,Oligonucleotides, Antisense ,medicine.disease ,Introns ,Stargardt disease ,HEK293 Cells ,missing heritability ,Mutation ,030221 ophthalmology & optometry ,biology.protein ,ATP-Binding Cassette Transporters - Abstract
PURPOSE: ABCA4-associated disease, a recessive retinal dystrophy, is hallmarked by a large proportion of patients with only one pathogenic ABCA4 variant, suggestive for missing heritability. METHODS: By locus-specific analysis of ABCA4, combined with extensive functional studies, we aimed to unravel the missing alleles in a cohort of 67 patients (p), with one (p = 64) or no (p = 3) identified coding pathogenic variants of ABCA4. RESULTS: We identified eight pathogenic (deep-)intronic ABCA4 splice variants, of which five are novel and six structural variants, four of which are novel, including two duplications. Together, these variants account for the missing alleles in 40.3% of patients. Furthermore, two novel variants with a putative cis-regulatory effect were identified. The common hypomorphic variant c.5603A>T p.(Asn1868Ile) was found as a candidate second allele in 43.3% of patients. Overall, we have elucidated the missing heritability in 83.6% of our cohort. In addition, we successfully rescued three deep-intronic variants using antisense oligonucleotide (AON)-mediated treatment in HEK 293-T cells and in patient-derived fibroblast cells. CONCLUSION: Noncoding pathogenic variants, novel structural variants, and a common hypomorphic allele of the ABCA4 gene explain the majority of unsolved cases with ABCA4-associated disease, rendering this retinopathy a model for missing heritability in autosomal recessive disorders. ispartof: GENETICS IN MEDICINE vol:21 issue:8 pages:1761-1771 ispartof: location:United States status: published
- Published
- 2019
25. Effect of an intravitreal antisense oligonucleotide on vision in Leber congenital amaurosis due to a photoreceptor cilium defect
- Author
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Patricia Biasutto, Alejandro J. Roman, Magali Taiel, Michael E. Cheetham, Julie De Zaeytijd, Artur V. Cideciyan, Ian C. Han, Michael R. Schwartz, Alexandra V. Garafalo, David M. Rodman, Maria D. Tome, Alexander Sumaroka, Arlene V. Drack, Wilma de Wit, Irina Balikova, Allen C. Ho, Stephen R. Russell, Fanny Nerinckx, Peter Adamson, Caroline Van Cauwenbergh, Wanda L. Pfeifer, Maria D. Hochstedler, Bart P. Leroy, Samuel G. Jacobson, Elliott H. Sohn, Gerard Platenburg, and Jason Charng
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Visual acuity ,genetic structures ,Oligonucleotide ,business.industry ,Childhood blindness ,General Medicine ,medicine.disease ,Ciliopathies ,eye diseases ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Ciliopathy ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Ophthalmology ,RNA splicing ,medicine ,medicine.symptom ,Allele ,business ,Gene - Abstract
Photoreceptor ciliopathies constitute the most common molecular mechanism of the childhood blindness Leber congenital amaurosis. Ten patients with Leber congenital amaurosis carrying the c.2991+1655A>G allele in the ciliopathy gene centrosomal protein 290 (CEP290) were treated (ClinicalTrials.gov no. NCT03140969 ) with intravitreal injections of an antisense oligonucleotide to restore correct splicing. There were no serious adverse events, and vision improved at 3 months. The visual acuity of one exceptional responder improved from light perception to 20/400. RNA antisense oligonucleotide therapy to restore normal splicing of a ciliopathy gene shows promising safety and efficacy results in a clinical trial to treat a form of childhood blindness.
- Published
- 2018
26. Pathogenic variants in the ABCC6 gene are associated with an increased risk for ischemic stroke
- Author
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Olivier Le Saux, Dimitri Hemelsoet, Paul Coucke, Anne De Paepe, Olivier Vanakker, Julie De Zaeytijd, Mohammad Jakir Hosen, Jacques De Reuck, Bart P. Leroy, Eva De Vilder, and Stefanie Cardoen
- Subjects
0301 basic medicine ,medicine.medical_specialty ,biology ,Angiogenesis ,business.industry ,General Neuroscience ,Case-control study ,Ischemia ,ABCC6 ,Disease ,medicine.disease ,Pseudoxanthoma elasticum ,Pathology and Forensic Medicine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Internal medicine ,medicine ,biology.protein ,Cardiology ,Neurology (clinical) ,Risk factor ,business ,Stroke ,030217 neurology & neurosurgery - Abstract
Ischemic stroke causes a high mortality and morbidity worldwide. It results from a complex interplay of incompletely known environmental and genetic risk factors. We investigated the ABCC6 gene as a candidate risk factor for ischemic stroke because of the increased ischemic stroke incidence in the autosomal recessive disorder pseudoxanthoma elasticum, caused by biallelic pathogenic ABCC6 variants, the higher cardiovascular risk in heterozygous carriers and the established role of ABCC6 dysfunction in myocardial ischemia. We established segregation of a known pathogenic ABCC6 variant (p.[Arg1314Gln]) in 11/19 family members of an ischemic stroke patient in a large multigenerational family suffering from ischemic stroke and/or cardiovascular disease at a relatively young age. In an independent case-control study in 424 ischemic stroke patients and 250 healthy controls, pathogenic ABCC6 variants were 4.9 times more frequent (P = 0.036; 95% CI 1.11-21.33) in the ischemic stroke patient cohort. To study cellular consequences of ABCC6 deficiency in the brain, immunostaining of brain sections in Abcc6-deficient mice and wild-type controls were performed. An upregulation of Bmp4 and Eng and a downregulation of Alk2 was identified in Abcc6-/- mice, suggesting an increase in apoptosis and angiogenesis. As both of these processes are induced in ischemia, we propose that a pro-ischemic state may explain the higher risk to suffer from ischemic stroke in patients carrying a pathogenic ABCC6 variant, as this may lower the threshold to develop acute ischemic events in these patients. In conclusion, this study identified heterozygous ABCC6 variants as a risk factor for ischemic stroke. Further, dysregulation of Bmp (Bmp4, Alk2) and Tgf beta (Eng) signaling in the brain of Abcc6-/- mice could lead to a pro-ischemic state, lowering the threshold to develop acute ischemic events. These data demonstrate the importance of a molecular analysis of the ABCC6 gene in patients diagnosed with cryp togenic ischemic stroke.
- Published
- 2018
27. CRB1-associated retinal dystrophies in a Belgian cohort: genetic characteristics and long-term clinical follow-up
- Author
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Caroline Van Cauwenbergh, David Van Wynsberghe, Julie De Zaeytijd, Mays Talib, Camiel J. F. Boon, Elfride De Baere, Bart P. Leroy, Ophthalmology, and ANS - Complex Trait Genetics
- Subjects
0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,retina ,Retinal Disorder ,Visual acuity ,genetic structures ,030105 genetics & heredity ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Retinitis pigmentosa ,Medicine ,Medical history ,genetics ,CRB1 ,business.industry ,Retrospective cohort study ,Macular dystrophy ,medicine.disease ,Sensory Systems ,eye diseases ,Ophthalmology ,dystrophy ,030221 ophthalmology & optometry ,sense organs ,medicine.symptom ,business ,Retinal Dystrophies - Abstract
AimTo investigate the natural history in a Belgian cohort of CRB1-associated retinal dystrophies.MethodsAn in-depth retrospective study focusing on visual function and retinal structure.ResultsForty patients from 35 families were included (ages: 2.5–80.1 years). In patients with a follow-up of >1 year (63%), the mean follow-up time was 12.0 years (range: 2.3–29.2 years). Based on the patient history, symptoms and/or electroretinography, 22 patients (55%) were diagnosed with retinitis pigmentosa (RP), 15 (38%) with Leber congenital amaurosis (LCA) and 3 (8%) with macular dystrophy (MD), the latter being associated with the p.(Ile167_Gly169del) mutation (in compound heterozygosity). MD later developed into a rod-cone dystrophy in one patient. Blindness at initial presentation was seen in the first decade of life in LCA, and in the fifth decade of life in RP. Eventually, 28 patients (70%) reached visual acuity-based blindness (ConclusionBi-allelic CRB1 mutations result in a range of progressive retinal disorders, most of which are generalised, with characteristically early macular involvement. Visual function and retinal structure analysis indicates a window for potential intervention with gene therapy before the fourth decade of life in RP and the first decade in LCA.
- Published
- 2021
28. Scheimpflug-based analysis of the reflectivity of the cornea in Marfan syndrome
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Elke O. Kreps, Julie De Zaeytijd, Alejandra Consejo, and Michèle Tack
- Subjects
Marfan syndrome ,medicine.medical_specialty ,Biometry ,genetic structures ,Ocular surgery ,Arbitrary unit ,Scheimpflug principle ,Biomedical Engineering ,Article ,corneal transparency ,Ectopia Lentis ,Cornea ,Ophthalmology ,Medicine and Health Sciences ,medicine ,Humans ,Ectopia lentis ,scheimpflug imaging ,Retrospective Studies ,business.industry ,medicine.disease ,Reflectivity ,eye diseases ,THICKNESS MEASUREMENTS ,ELASTIC FIBERS ,Light intensity ,medicine.anatomical_structure ,corneal reflectivity ,BIOMECHANICAL PROPERTIES ,VIVO CONFOCAL MICROSCOPY ,sense organs ,Human medicine ,marfan syndrome ,business - Abstract
Purpose:We sought to investigate corneal reflectivity inMarfan syndrome (MFS) on the basis of Scheimpflug light intensity distribution. Methods: In a retrospective case-control analysis, the left eyes of 40 MFS patients and 40 age- and refraction-matched healthy controls were investigated. Patients with MFS meeting the Ghent II diagnostic criteria and with genetic confirmation of disease were included. Exclusion criteria were the following: Coexisting corneal, conjunctival, or scleral pathology, use of medication known to affect corneal transparency, history of ocular surgery, and insufficient data. Scheimpflug tomography images were exported to analyze corneal transparency in different corneal layers and regions. Each corneal image was automatically segmented, after which the corresponding pixel intensities in the defined regions of interest were statistically modeled using a Weibull probability density function from which parameters a (transparency) and ß (homogeneity) were derived. Results: The cornea in MFS showed significantly higher light reflectivity (overall cornea, a = 71 ± 17 arbitrary units (a.u.)) than in the control group (overall cornea, a = 59 ± 15 a.u.) (t test, P = 0.003). The a parameter was significantly higher in MFS eyes in all examined layers and regions (P < 0.05), whereas the ß parameter showed no statistical difference between MFS and controls (P > 0.05). The difference in a did not correlate with ocular biometric properties (corneal thickness and curvature) or ectopia lentis (P> 0.05). Conclusions: The cornea in MFS shows significantly higher reflectivity than healthy controls with similar levels of homogeneity. Translational Relevance: The proposed methodology detects corneal reflectivity changes in MFS not available from regular slit-lamp examination.
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- 2021
29. Clinical characteristics and natural history of RHO-associated retinitis pigmentosa
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Gislin Dagnelie, Ralph J. Florijn, Caroline Van Cauwenbergh, Maria M. van Genderen, Alberta A H J Thiadens, Mays Talib, Nicoline E. Schalij-Delfos, Jan Wijnholds, Julie De Zaeytijd, Camiel J. F. Boon, Mary J. van Schooneveld, Caroline C W Klaver, Irina Balikova, Elfride De Baere, Marta Fiocco, Carel B. Hoyng, Magda A. Meester-Smoor, Xuan Thanh An Nguyen, Arthur A.B. Bergen, L. Ingeborgh van den Born, Jacoline B. ten Brink, Bart P. Leroy, Ophthalmology, Epidemiology, Human Genetics, ANS - Complex Trait Genetics, ARD - Amsterdam Reproduction and Development, and Netherlands Institute for Neuroscience (NIN)
- Subjects
0301 basic medicine ,Male ,Visual acuity ,genetic structures ,Visual Acuity ,Retinal Pigment Epithelium ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] ,chemistry.chemical_compound ,0302 clinical medicine ,Medicine and Health Sciences ,sector retinitis pigmentosa ,General Medicine ,Middle Aged ,Natural history ,Phenotype ,natural history ,Female ,medicine.symptom ,Tomography, Optical Coherence ,medicine.medical_specialty ,Long term follow up ,inherited retinal dystrophies ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,Ophthalmology ,retinitis pigmentosa ,Retinitis pigmentosa ,medicine ,Electroretinography ,Humans ,In patient ,Aged ,Retrospective Studies ,Surrogate endpoint ,business.industry ,Retinal ,medicine.disease ,eye diseases ,Low vision ,030104 developmental biology ,chemistry ,rhodopsin ,030221 ophthalmology & optometry ,sense organs ,Visual Fields ,business ,Acute-Phase Proteins ,Follow-Up Studies ,Forecasting - Abstract
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
- Published
- 2021
30. New variants and in silico analyses in GRK1 associated Oguchi disease
- Author
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James A. Poulter, Elfride De Baere, Kaoru Fujinami, Andrew R. Webster, Atta Ur Rehman, Gavin Arno, Abdur Rehman, Rachel L. Taylor, Sarah A. Harris, Graeme C.M. Black, James Bellingham, Julie De Zaeytijd, Martin McKibbin, Chris F. Inglehearn, Molly S. C. Gravett, Kamron N. Khan, Muhammad Ansar, Takaaki Hayashi, Robert H. Henderson, Manir Ali, Nigel P. Davies, Dan Donnelly, Mineo Kondo, Omar A. Mahroo, Carmel Toomes, Bart P. Leroy, Carlo Rivolta, and UK Inherited Retinal Disease Consortium, Genomics England Research Consortium
- Subjects
MECHANISM ,G-Protein-Coupled Receptor Kinase 1 ,In silico ,PROTEIN ,GRK1 ,PHOTOTRANSDUCTION ,Disease ,Biology ,Genome ,ACTIVATION ,03 medical and health sciences ,Night Blindness ,Medicine and Health Sciences ,Genetics ,medicine ,Missense mutation ,Humans ,Genetics(clinical) ,CSNB ,MUTATION ,Exome ,Genetics (clinical) ,Exome sequencing ,Research Articles ,030304 developmental biology ,0303 health sciences ,DELETION ,Oguchi disease ,030305 genetics & heredity ,Eye Diseases, Hereditary ,DEFECTS ,Eye Diseases, Hereditary/genetics ,G-Protein-Coupled Receptor Kinase 1/genetics ,Night Blindness/genetics ,rhodopsin ,medicine.disease ,genomic DNA ,RHODOPSIN KINASE GENE ,FORM ,PATHOGENICITY ,Research Article - Abstract
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., In this study, Poulter et al. expand the number of mutations in Rhodopsin Kinase (GRK1), associated with Oguchi disease, from 13 to 21. The authors compare disease associated mutations with likely nonpathogenic variants in a range of bioinformatic prediction software. In silico analyses of the mutations, using a homology model, suggest mutations result in one of three potential mechanisms of disease: loss of protein, loss of kinase function or a failure of prenylation leading to mislocalisation of the protein.
- Published
- 2020
31. Isolated Maculopathy and Moderate Rod-Cone Dystrophy Represent the Milder End of the RDH12-related Retinal Dystrophy Spectrum
- Author
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Mattias Van Heetvelde, Bart P. Leroy, Elfride De Baere, Julie De Zaeytijd, Caroline Van Cauwenbergh, Frauke Coppieters, and Marieke De Bruyne
- Subjects
Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Visual acuity ,Adolescent ,genetic structures ,DNA Mutational Analysis ,Visual Acuity ,030105 genetics & heredity ,Macular Degeneration ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Optical coherence tomography ,Foveal ,Ophthalmology ,Electroretinography ,medicine ,Rod-cone dystrophy ,Humans ,medicine.diagnostic_test ,business.industry ,Genetic heterogeneity ,Dystrophy ,General Medicine ,medicine.disease ,eye diseases ,Pedigree ,Alcohol Oxidoreductases ,Phenotype ,Mutation ,030221 ophthalmology & optometry ,Maculopathy ,Female ,sense organs ,Visual Fields ,medicine.symptom ,business ,Cone-Rod Dystrophies ,Tomography, Optical Coherence ,Photoreceptor Cells, Vertebrate ,Retinopathy - Abstract
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.
- Published
- 2020
32. Clinical and subclinical findings in heterozygous
- Author
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Lukas, Nollet, Laurence, Campens, Julie, De Zaeytijd, Bart, Leroy, Dimitri, Hemelsoet, Paul J, Coucke, and Olivier M, Vanakker
- Subjects
Cohort Studies ,Heterozygote ,Phenotype ,Belgium ,Humans ,Multidrug Resistance-Associated Proteins ,Pseudoxanthoma Elasticum - Abstract
Biallelic pathogenic variants in theThe phenotype of 56 individuals carrying heterozygous pathogenicWe found thatIn this study, we delineated the multisystemic
- Published
- 2020
33. Phenocopy of a heterozygous carrier of X-linked retinitis pigmentosa due to mosaicism for a RHO variant
- Author
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Bart P. Leroy, Toon Rosseel, Julie De Zaeytijd, Sarah De Jaegere, Elfride De Baere, Caroline Van Cauwenbergh, Ine Strubbe, Marieke De Bruyne, and Stijn Van de Sompele
- Subjects
0301 basic medicine ,Adult ,Male ,Heterozygote ,Rhodopsin ,Science ,Buccal swab ,Gene Dosage ,030105 genetics & heredity ,Biology ,Article ,Loss of heterozygosity ,03 medical and health sciences ,symbols.namesake ,Young Adult ,Retinitis pigmentosa ,Genetics research ,Medicine and Health Sciences ,medicine ,Humans ,Point Mutation ,Clinical genetics ,Exome sequencing ,Genetic testing ,Genetics ,Phenocopy ,Sanger sequencing ,Multidisciplinary ,medicine.diagnostic_test ,Base Sequence ,Mosaicism ,Medical genetics ,Middle Aged ,medicine.disease ,Phenotype ,eye diseases ,030104 developmental biology ,symbols ,Medicine ,Female ,Gene expression ,Retinitis Pigmentosa - Abstract
We describe both phenotype and pathogenesis in two male siblings with typical retinitis pigmentosa (RP) and the potentially X-linked RP (XLRP) carrier phenotype in their mother. Two affected sons, two unaffected daughters, and their mother underwent detailed ophthalmological assessments including Goldmann perimetry, color vision testing, multimodal imaging and ISCEV-standard electroretinography. Genetic testing consisted of targeted next-generation sequencing (NGS) of known XLRP genes and whole exome sequencing (WES) of known inherited retinal disease genes (RetNet-WES). Variant validation and segregation analysis were performed by Sanger sequencing. The mutational load of the RHO variant in the mother was assessed in DNA from leucocytes, buccal cells and hair follicles using targeted NGS. Both affected sons showed signs of classical RP, while the mother displayed patches of hyperautofluorescence on blue light autofluorescence imaging and regional, intraretinal, spicular pigmentation, reminiscent of a carrier phenotype of XLRP. XLRP testing was negative. RetNet-WES testing revealed RHO variant c.404G > C p.(Arg135Pro) in a mosaic state (21% of the reads) in the mother and in a heterozygous state in both sons. Targeted NGQSS of the RHO variant in different maternal tissues showed a mutation load between 25.06% and 41.72%. We report for the first time that somatic mosaicism of RHO variant c.404G > C p.(Arg135Pro) mimics the phenotype of a female carrier of XLRP, in combination with heterozygosity for the variant in the two affected sons.
- Published
- 2020
34. Author response for 'VEGFA variants as prognostic markers for the retinopathy in Pseudoxanthoma elasticum'
- Author
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null Eva Y.G. De Vilder, null Mohammad J. Hosen, null Ludovic Martin, null Julie De Zaeytijd, null Bart P. Leroy, null Jean-Marc Ebran, null Paul J. Coucke, null Anne De Paepe, and null Olivier M. Vanakker
- Published
- 2020
35. Author response for 'VEGFA variants as prognostic markers for the retinopathy in Pseudoxanthoma elasticum'
- Author
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Jean-Marc Ebran, Mohammad Jakir Hosen, Eva De Vilder, Paul Coucke, Olivier Vanakker, Ludovic Martin, Julie De Zaeytijd, Anne De Paepe, and Bart Leroy
- Subjects
medicine.medical_specialty ,Vascular endothelial growth factor A ,business.industry ,Ophthalmology ,medicine ,Pseudoxanthoma elasticum ,medicine.disease ,business ,Retinopathy - Published
- 2020
36. New pathogenic variants and insights into pathogenic mechanisms in GRK1-related Oguchi disease
- Author
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Chris F. Inglehearn, Nigel P. Davies, Gavin Arno, Robert H. Henderson, Kamron N. Khan, Rachel L. Taylor, Omar A. Mahroo, James Bellingham, Manir Ali, James A. Poulter, Molly S. C. Gravett, Elfride De Baere, Dan Donnelly, Atta Ur Rehman, Abdur Rehman, Carlo Rivolta, Kaoru Fujinami, Graeme C.M. Black, Julie De Zaeytijd, Mineo Kondo, Sarah A. Harris, Martin McKibbin, Andrew R. Webster, Takaaki Hayashi, Muhammad Ansar, Bart P. Leroy, and Carmel Toomes
- Subjects
Genetics ,0303 health sciences ,Oguchi disease ,Biology ,medicine.disease ,Genome ,3. Good health ,03 medical and health sciences ,genomic DNA ,0302 clinical medicine ,030221 ophthalmology & optometry ,medicine ,Missense mutation ,Leiden Open Variation Database ,Exome ,Gene ,Exome sequencing ,030304 developmental biology - Abstract
PurposeBiallelic 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 pathogenic GRK1 variants and use in-depth bioinformatic analyses to evaluate how their impact on protein structure could lead to pathogenicity.MethodsPatients’ genomic DNA was sequenced by whole genome, whole exome or focused exome sequencing. Pathogenic 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.ResultsWe identified eleven previously unpublished cases with biallelic pathogenic GRK1 variants, including seven novel variants, and reviewed all GRK1 pathogenic variants. Further structure-based scoring revealed a hotspot for missense variants in the kinase domain. Additionally, to aid future clinical interpretation, we identified the bioinformatics tools best able to differentiate pathogenic from non-pathogenic variants.ConclusionWe identified new GRK1 pathogenic variants in Oguchi disease patients and investigated how disease-causing variants may impede protein function, giving new insights into the mechanisms of pathogenicity. All pathogenic GRK1 variants described to date have been collated into a Leiden Open Variation Database (http://dna2.leeds.ac.uk/GRK1_LOVD/genes/GRK1).
- Published
- 2020
37. Vitreous hemorrhage as presenting sign of retinal arteriovenous malformation
- Author
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Fanny Nerinckx, Geraldine P. B. M. Accou, Bart P. Leroy, and Julie De Zaeytijd
- Subjects
Pars plana ,medicine.medical_specialty ,Intraocular pressure ,genetic structures ,medicine.medical_treatment ,Case Report ,Vitrectomy ,01 natural sciences ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Ophthalmology ,medicine ,Medicine and Health Sciences ,0101 mathematics ,medicine.diagnostic_test ,business.industry ,010102 general mathematics ,Retinal ,General Medicine ,COMPLICATION ,RE1-994 ,Fluorescein angiography ,medicine.disease ,eye diseases ,ISCHEMIA ,medicine.anatomical_structure ,Retinal Arteriovenous Malformation ,chemistry ,WYBURN-MASON-SYNDROME ,Vitreous hemorrhage ,030221 ophthalmology & optometry ,sense organs ,business ,Optic disc - Abstract
Objective. To describe a patient with vitreous hemorrhage and peripheral retinal ischemia, eventually diagnosed with an underlying retinal arteriovenous malformation. Methods. A 15-year-old girl presented with sudden-onset, painless visual loss in the right eye. She underwent a full ophthalmological work-up. Results. BCVA was less than 20/400 in the right eye and 20/20 in the left eye. Intraocular pressure and anterior segment examination were unremarkable. Fundoscopy was impossible due to an opaque vitreous hemorrhage in the right eye. The left eye was completely unremarkable. Examination during a 23-gauge pars plana vitrectomy showed dilated, tortuous arteriovenous vessels extending from the optic disc and silver wiring of the enlarged vessels. A clinical diagnosis of retinal arteriovenous malformation was made. During surgery, a peripheral retinal photocoagulation was executed to avoid rebleeding. Postoperatively, fluorescein angiography demonstrated additional macular microangiopathy and diffuse retinal nonperfusion in the periphery. The MRI brain revealed neither cerebral nor orbital vascular anomaly, confirming a group 2 retinal arteriovenous malformation. Conclusion. Retinal arteriovenous malformations are generally considered stable over time. However, complications due to retinal ischemia can occur. Hence, regular observation is warranted. In so doing, timely treatment can be offered to avoid complications.
- Published
- 2020
38. Intravitreal Sepofarsen for Leber Congenital Amaurosis Type 10 (LCA10)
- Author
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Alexandra V. Garafalo, Allen C. Ho, Alina V. Dumitrescu, David M. Rodman, Rob W.J. Collin, Carel B. Hoyng, Wanda L. Pfeifer, Mitchell Martin, Arun kumar Krishnan, Julie De Zaeytijd, Bart P. Leroy, Eva Vanhonsebrouck, Aniz Girach, Alejandro J. Roman, Stephen R. Russell, Wilhelmina den Hollander, Gerard Platenburg, Ian C. Han, Fanny Nerinckx, Arlene V. Drack, Christian A. Powers, Friedrich Asmus, Jean Walshire, Samuel G. Jacobson, Caroline Van Cauwenbergh, Elliott H. Sohn, Artur V. Cideciyan, Eltanara A Jones, Michael R. Schwartz, Michael E. Cheetham, Peter Adamson, and Alexander Sumaroka
- Subjects
medicine.medical_specialty ,Visual acuity ,business.industry ,Institutional review board ,Leber congenital amaurosis ,medicine.disease ,Informed consent ,Internal medicine ,Good clinical practice ,Clinical endpoint ,Medicine ,In patient ,medicine.symptom ,business ,Macular edema - Abstract
Background: Sepofarsen is an RNA antisense oligonucleotide (AON) targeting the common c.2991+1655A>G mutation in the CEP290 gene to treat Leber congenital amaurosis type 10 (LCA10), a condition with severe childhood-onset vision loss or blindness. Methods: In this 12-month, multicenter, open-label, multiple-dose, dose-escalation, phase 1b/2 trial, patients with LCA10 received up to four doses of intravitreal sepofarsen in the worse-seeing eye. Primary end point was safety; secondary end points included vision outcome measures. Findings: Of 11 patients enrolled (8–44 years of age), six received loading/maintenance doses of sepofarsen of 160 µg/80 µg and five received 320 µg/160 µg. Reported cases of cataracts, mild cystoid macular edema, and retinal thinning were 3, 0, and 0, respectively, in the 160-µg/80-µg group and 5, 2, and 2 in the 320-µg/160-µg group. Pooled data (n=11) showed improvements from baseline to Month 12 in treated eyes vs untreated eyes in mean ± standard error of the mean best-corrected visual acuity (BCVA: −0·55 ± 0·26 vs −0·12 ± 0·07 logarithm of the minimum angle of resolution [logMAR], p
- Published
- 2020
39. VEGFA variants as prognostic markers for the retinopathy in pseudoxanthoma elasticum
- Author
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Bart P. Leroy, Ludovic Martin, Anne De Paepe, Eva De Vilder, Julie De Zaeytijd, Olivier Vanakker, Paul Coucke, Jean-Marc Ebran, and Mohammad Jakir Hosen
- Subjects
0301 basic medicine ,Oncology ,Adult ,Genetic Markers ,Male ,Vascular Endothelial Growth Factor A ,medicine.medical_specialty ,Visual acuity ,Adolescent ,030105 genetics & heredity ,Polymorphism, Single Nucleotide ,Cohort Studies ,03 medical and health sciences ,chemistry.chemical_compound ,symbols.namesake ,Young Adult ,Retinal Diseases ,Internal medicine ,Genetics ,medicine ,Humans ,Pseudoxanthoma Elasticum ,Genetics (clinical) ,Genetic Association Studies ,Aged ,Skin ,Sanger sequencing ,Aged, 80 and over ,business.industry ,Middle Aged ,Pseudoxanthoma elasticum ,medicine.disease ,Prognosis ,eye diseases ,Choroidal Neovascularization ,Vascular endothelial growth factor ,Vascular endothelial growth factor A ,030104 developmental biology ,Choroidal neovascularization ,chemistry ,Cohort ,symbols ,Female ,medicine.symptom ,business ,Retinopathy - Abstract
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
- Published
- 2019
40. Uveitis and immune checkpoint inhibition: when a blockage isn’t just a blockage
- Author
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Sylvie Rottey, Ilse De Schryver, Kurt Geldhof, Ingel Demedts, Julie De Zaeytijd, and Arnaud Potvin
- Subjects
Ophthalmology ,business.industry ,Immunology ,medicine ,General Medicine ,medicine.disease ,business ,Immune checkpoint ,Uveitis - Published
- 2019
41. Antisense oligonucleotide treatment in CEP290‐related leber congenital amaurosis
- Author
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David Rodham, Samuel G. Jacobson, Julie De Zaeytijd, Caroline Van Cauwenbergh, Patricia Biasutto, Aniz Girach, Peter Adamson, Arlene V. Drack, Artur V. Cideciyan, Alejandro J. Roman, Alexandra V. Garafalo, Bart P. Leroy, Stephen R. Russell, Wilma de Wit, Michael E. Cheetham, Allen C. Ho, and Michael D. Schwartz
- Subjects
Ophthalmology ,business.industry ,Antisense oligonucleotides ,Medicine ,General Medicine ,Leber congenital amaurosis ,business ,Molecular biology - Published
- 2019
42. The Spectrum of Structural and Functional Abnormalities in Female Carriers of Pathogenic Variants in the RPGR Gene
- Author
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Arthur A.B. Bergen, Nicoline E. Schalij-Delfos, Camiel J. F. Boon, L. Ingeborgh van den Born, Carel B. Hoyng, Jan Wijnholds, Magda A. Meester-Smoor, Gislin Dagnelie, Elfride De Baere, Bart P. Leroy, Julie De Zaeytijd, Ralph J. Florijn, Jacoline B. ten Brink, Frans P.M. Cremers, Caroline C W Klaver, Caroline Van Cauwenbergh, Mays Talib, Mary J. van Schooneveld, Maria M. van Genderen, Alberta A H J Thiadens, Netherlands Institute for Neuroscience (NIN), Ophthalmology, Epidemiology, Human Genetics, ANS - Cellular & Molecular Mechanisms, and ARD - Amsterdam Reproduction and Development
- Subjects
0301 basic medicine ,Visual acuity ,genetic structures ,Visual Acuity ,Pedigree chart ,Retinal Pigment Epithelium ,Fundus (eye) ,PHENOTYPE ,Gastroenterology ,FAMILIES ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] ,0302 clinical medicine ,Myopia ,Medicine and Health Sciences ,Child ,Aged, 80 and over ,EXON ORF15 ,Retinitis pigmentosa GTPase regulator ,Middle Aged ,gene therapy ,Phenotype ,VISUAL FUNCTION ,DOMINANT ,PROGRESSIVE CONE ,Child, Preschool ,Female ,medicine.symptom ,retinitis pigmentosa GTPase regulator ,Adult ,Heterozygote ,medicine.medical_specialty ,Adolescent ,Young Adult ,03 medical and health sciences ,disease progression ,All institutes and research themes of the Radboud University Medical Center ,X-CHROMOSOME INACTIVATION ,retinitis pigmentosa ,Internal medicine ,LINKED RETINITIS-PIGMENTOSA ,Retinitis pigmentosa ,Journal Article ,medicine ,Humans ,Eye Proteins ,Aged ,Retrospective Studies ,RETINAL DYSTROPHIES ,MUTATIONS ,business.industry ,Dystrophy ,Heterozygote advantage ,Retrospective cohort study ,medicine.disease ,eye diseases ,030104 developmental biology ,030221 ophthalmology & optometry ,sense organs ,business - Abstract
PURPOSE. The purpose of this study was to investigate the phenotype and long-term clinical course of female carriers of RPGR mutations. METHODS. This was a retrospective cohort study of 125 heterozygous RPGR mutation carriers from 49 families. RESULTS. Eighty-three heterozygotes were from retinitis pigmentosa (RP) pedigrees, 37 were from cone-/cone-rod dystrophy (COD/CORD) pedigrees, and 5 heterozygotes were from pedigrees with mixed RP/CORD or unknown diagnosis. Mutations were located in exon 1-14 and in ORF15 in 42 of 125 (34%) and 83 of 125 (66%) subjects, respectively. The mean age at the first examination was 34.4 years (range, 2.1 to 86.0 years). The median follow-up time in heterozygotes with longitudinal data (n = 62) was 12.2 years (range, 1.1 to 52.2 years). Retinal pigmentary changes were present in 73 (58%) individuals. Visual symptoms were reported in 51 (40%) cases. Subjects with both symptoms and pigmentary fundus changes were older than the other heterozygotes (P = 0.01) and had thinner foveal outer retinas (P = 0.006). Complete expression of the RP or CORD phenotype was observed in 29 (23%) heterozygotes, although usually in milder forms than in affected male relatives. Best-corrected visual acuity (BCVA) was < 20/40 and < 20/400 in at least one eye in 45 of 116 (39%) and 11 of 116 (9%) heterozygotes, respectively. Myopia was observed in 74 of 101 (73%) subjects and was associated with lower BCVA (P = 0.006). Increasing age was associated with lower BCVA (P = 0.002) and decreasing visual field size (P = 0.012; I4e isopter). CONCLUSIONS. RPGR mutations lead to a phenotypic spectrum in female carriers, with myopia as a significantly aggravating factor. Complete disease expression is observed in some individuals, who may benefit from future (gene) therapeutic options.
- Published
- 2018
43. Thrombomodulin and Endothelial Dysfunction: A Disease-Modifier Shared between Malignant Hypertension and Atypical Hemolytic Uremic Syndrome
- Author
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Wim Van Biesen, Steven Van Laecke, Marieke Demeulenaere, Johan Vande Walle, Julie De Zaeytijd, Hilde Vanbelleghem, and Katrien Devreese
- Subjects
Adult ,0301 basic medicine ,Thrombotic microangiopathy ,Thrombomodulin ,030204 cardiovascular system & hematology ,Kidney ,Preeclampsia ,Hypertension, Malignant ,03 medical and health sciences ,0302 clinical medicine ,Atypical hemolytic uremic syndrome ,Humans ,Medicine ,Endothelial dysfunction ,Child ,Atypical Hemolytic Uremic Syndrome ,Thrombotic Microangiopathies ,business.industry ,medicine.disease ,Thrombosis ,Transplantation ,030104 developmental biology ,Child, Preschool ,Immunology ,Female ,Endothelium, Vascular ,business ,Protein C ,medicine.drug - Abstract
Thrombomodulin (TM) is an endothelial glycoprotein that is present in all blood vessels. Five percent of all patients with atypical hemolytic uremic syndrome (aHUS) have mutations in the gene coding for TM, with a peak presentation in young children. Mutations often translate into quantitative and qualitative abnormalities of this endothelial glycoprotein. Outcome of the TM-associated aHUS is relatively poor with frequent relapses after transplantation despite its membrane-bound character. We observed a woman presenting with malignant hypertension (MHT) and associated kidney, brain, cardiac, and hematological involvement with thrombotic microangiopathy on kidney biopsy. She had a documented mutation of the gene coding for TM, which was associated with both aHUS and an increased risk for venous and arterial thrombosis. As TM has anti-coagulant, anti-inflammatory, and cytoprotective properties and also attenuates alternative complement activation, this glycoprotein could play an active role in other diseases with endothelial involvement apart from aHUS. We discuss the potential role of TM in the pathophysiology of various endotheliopathies including MHT. We also provide a framework for future therapeutic options.
- Published
- 2018
44. Clinical characterization of 66 patients with congenital retinal disease due to the deep-intronic c.2991+1655A>G mutation in CEP290
- Author
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Birgit Lorenz, Markus N. Preising, Caroline Van Cauwenbergh, Alberta A H J Thiadens, Jan Willem R. Pott, Frauke Coppieters, Rob W.J. Collin, L. Ingeborgh van den Born, Julie De Zaeytijd, Dyon Valkenburg, Carel B. Hoyng, Caroline C W Klaver, Mary J. van Schooneveld, Hester Y. Kroes, Mies M. van Genderen, Bart P. Leroy, Mette Bertelsen, and Ophthalmology
- Subjects
Male ,0301 basic medicine ,retina ,Visual acuity ,genetic structures ,FEATURES ,Leber Congenital Amaurosis ,Visual Acuity ,Cell Cycle Proteins ,Compound heterozygosity ,PHENOTYPE ,Polymerase Chain Reaction ,THERAPY ,chemistry.chemical_compound ,0302 clinical medicine ,Foveal ,Medicine and Health Sciences ,Medicine ,Child ,Low vision ,AMAUROSIS ,medicine.diagnostic_test ,Retinal dystrophy ,High-Throughput Nucleotide Sequencing ,Middle Aged ,DYSTROPHY ,DEGENERATION ,RPE65 MUTATIONS ,Sensory Systems ,Neoplasm Proteins ,medicine.anatomical_structure ,Child, Preschool ,visual development ,Female ,medicine.symptom ,Tomography, Optical Coherence ,Genetic diseases ,Adult ,medicine.medical_specialty ,Adolescent ,low vision ,Retina ,MECHANISMS ,Young Adult ,03 medical and health sciences ,Amaurosis ,Visual development ,Cellular and Molecular Neuroscience ,genetic diseases ,Antigens, Neoplasm ,Ophthalmology ,Electroretinography ,Humans ,retinal dystrophy ,Retrospective Studies ,IDENTIFICATION ,business.industry ,Gene Amplification ,Infant ,Retinal ,medicine.disease ,GENE ,Introns ,eye diseases ,Cytoskeletal Proteins ,030104 developmental biology ,chemistry ,Mutation ,030221 ophthalmology & optometry ,sense organs ,Age of onset ,business ,Follow-Up Studies - Abstract
Purpose: To describe the phenotypic spectrum of retinal disease caused by the c.2991+1655A>G mutation in CEP290 and to compare disease severity between homozygous and compound heterozygous patients. Methods: Medical records were reviewed for best-corrected visual acuity (BCVA), age of onset, fundoscopy descriptions. Foveal outer nuclear layer (ONL) and ellipsoid zone (EZ) presence was assessed using spectral-domain optical coherence tomography (SD-OCT). Differences between compound heterozygous and homozygous patients were analyzed based on visual performance and visual development. Results: A total of 66 patients were included. The majority of patients had either light perception or no light perception. In the remaining group of 14 patients, median BCVA was 20/195 Snellen (0.99 LogMAR; range 0.12-1.90) for the right eye, and 20/148 Snellen (0.87 LogMAR; range 0.22-1.90) for the left. Homozygous patients tended to be more likely to develop light perception compared to more severely affected compound heterozygous patients (P = 0.080) and are more likely to improve from no light perception to light perception (P = 0.022) before the age of 6 years. OCT data were available in 12 patients, 11 of whom had retained foveal ONL and EZ integrity up to 48 years (median 23 years) of age. Conclusions: Homozygous patients seem less severely affected compared to their compound-heterozygous peers. Improvement of visual function may occur in the early years of life, suggesting a time window for therapeutic intervention up to the approximate age of 17 years. This period may be extended by an intact foveal ONL and EZ on OCT.
- Published
- 2018
45. A different type of genetic therapy: correcting a defective gene using antisense oligonucleotide treatment in CEP290 p.Cys998X LCA
- Author
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Julie De Zaeytijd, Bart P. Leroy, Artur V. Cideciyan, Stephen R. Russell, Wil den Hollander, Aniz Girach, Allen C. Ho, Alexandra V. Garafolo, Caroline Van Cauwenbergh, Arlene V. Drack, Samuel G. Jacobson, Fredrich Asmus, Alina V. Dumitrescu, Wanda L. Pfeifer, and Michael R. Schwartz
- Subjects
Ophthalmology ,business.industry ,Pediatrics, Perinatology and Child Health ,Antisense oligonucleotides ,Medicine ,business ,Gene ,Molecular biology ,Genetic therapy - Published
- 2021
46. DETAILED CLINICAL PHENOTYPING OF OXALATE MACULOPATHY IN PRIMARY HYPEROXALURIA TYPE 1 AND REVIEW OF THE LITERATURE
- Author
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Steven Van Laecke, Sophie Walraedt, Julie De Zaeytijd, Patricia Delbeke, Ann Raes, Thierry Derveaux, and Bart P. Leroy
- Subjects
Adult ,Male ,Pathology ,medicine.medical_specialty ,Visual Acuity ,030232 urology & nephrology ,Retinal Pigment Epithelium ,Fundus (eye) ,Multimodal Imaging ,Polymerase Chain Reaction ,Primary hyperoxaluria ,Young Adult ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Retinal Diseases ,Electroretinography ,Humans ,Medicine ,Color perception test ,Child ,Transaminases ,Color Perception Tests ,Retinal pigment epithelium ,medicine.diagnostic_test ,business.industry ,Infant ,Retinal ,General Medicine ,medicine.disease ,Fibrosis ,Transplantation ,Ophthalmology ,Phenotype ,medicine.anatomical_structure ,chemistry ,Hyperoxaluria, Primary ,030221 ophthalmology & optometry ,Kidney Failure, Chronic ,Visual Field Tests ,Maculopathy ,Female ,business ,Tomography, Optical Coherence ,Retinopathy - Abstract
Purpose To describe the structural and functional characteristics of oxalate retinopathy. Methods Five patients with molecularly confirmed primary hyperoxaluria (PH) Type 1 underwent multimodal retinal imaging (spectral-domain optical coherence tomography, white light, and HRA multispectral imaging) and functional testing, including color vision testing, Goldmann perimetry, and International Society for Clinical Electrophysiology of Vision standard electrophysiological testing. Results Four distinct retinal phenotypes are presented. One patient with a c.[33dupC]; c.[731T>C] mutation showed bilateral perifoveal retinal pigment epithelium hyperplasia. The fundus in the four other patients, all of whom share an identical homozygous c.[33dupC] mutation, ranged from normal to bilateral widespread distribution of retinal crystals and confluent macular retinal pigment epithelium hyperplasia with subfoveal fibrosis. All patients who had developed end-stage renal disease showed some sign of retinopathy, more severe with earlier onset. Conclusion Retinopathy in PH Type 1 shows considerable interindividual variation. No correlation between genotype and retinal phenotype was detected. Oxalate crystals at the level of the retinal pigment epithelium seem to be irreversible. A proposed clinical grading system of oxalate maculopathy, based on a literature review, may provide clinicians with a tool to better predict visual function and prognosis.
- Published
- 2016
47. The majority of autosomal recessive nanophthalmos and posterior microphthalmia can be attributed to biallelic sequence and structural variants in MFRP and PRSS56
- Author
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Basamat Almoallem, Gavin Arno, Anne Destree, Elfride De Baere, Denise Williams, Anthony T. Moore, Thomy de Ravel, Ingele Casteels, Andrew R. Webster, Sarah Hull, Irina Balikova, Bart P. Leroy, Martina Suzani, Julie De Zaeytijd, John R. Ainsworth, Hannah Verdin, Michelle Y. Peng, and Medical Genetics
- Subjects
0301 basic medicine ,Male ,lcsh:Medicine ,Gene mutation ,PHENOTYPE ,Compound heterozygosity ,Microphthalmia ,Cohort Studies ,Exon ,0302 clinical medicine ,Genotype ,Medicine and Health Sciences ,2.1 Biological and endogenous factors ,Microphthalmos ,Aetiology ,lcsh:Science ,Child ,Genetics ,Multidisciplinary ,Molecular medicine ,ASSOCIATION ,Middle Aged ,Disease gene identification ,Microphthalmos/genetics ,Child, Preschool ,Female ,FRIZZLED-RELATED PROTEIN ,Adult ,Serine Proteases/genetics ,Heterozygote ,Adolescent ,DNA Copy Number Variations ,Biology ,Article ,03 medical and health sciences ,Clinical Research ,RETINITIS-PIGMENTOSA ,GENE MUTATION ,Retinitis pigmentosa ,medicine ,Humans ,Family ,Allele ,Membrane Proteins/genetics ,Preschool ,Alleles ,Aged ,IDENTIFICATION ,Whole Genome Sequencing ,HIGH HYPEROPIA ,lcsh:R ,Membrane Proteins ,Hereditary eye disease ,medicine.disease ,Brain Disorders ,030104 developmental biology ,Mutation ,030221 ophthalmology & optometry ,FOVEOSCHISIS ,lcsh:Q ,Serine Proteases - Abstract
This study aimed to genetically and clinically characterize a unique cohort of 25 individuals from 21 unrelated families with autosomal recessive nanophthalmos (NNO) and posterior microphthalmia (MCOP) from different ethnicities. An ophthalmological assessment in all families was followed by targeted MFRP and PRSS56 testing in 20 families and whole-genome sequencing in one family. Three families underwent homozygosity mapping using SNP arrays. Eight distinct MFRP mutations were found in 10/21 families (47.6%), five of which are novel including a deletion spanning the 5′ untranslated region and the first coding part of exon 1. Most cases harbored homozygous mutations (8/10), while a compound heterozygous and a monoallelic genotype were identified in the remaining ones (2/10). Six distinct PRSS56 mutations were found in 9/21 (42.9%) families, three of which are novel. Similarly, homozygous mutations were found in all but one, leaving 2/21 families (9.5%) without a molecular diagnosis. Clinically, all patients had reduced visual acuity, hyperopia, short axial length and crowded optic discs. Retinitis pigmentosa was observed in 5/10 (50%) of the MFRP group, papillomacular folds in 12/19 (63.2%) of MCOP and in 3/6 (50%) of NNO cases. A considerable phenotypic variability was observed, with no clear genotype-phenotype correlations. Overall, our study represents the largest NNO and MCOP cohort reported to date and provides a genetic diagnosis in 19/21 families (90.5%), including the first MFRP genomic rearrangement, offering opportunities for gene-based therapies in MFRP-associated disease. Finally, our study underscores the importance of sequence and copy number analysis of the MFRP and PRSS56 genes in MCOP and NNO.
- Published
- 2019
48. Correction: Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease
- Author
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Stijn Van de Sompele, Claire Smith, Marianthi Karali, Marta Corton, Kristof Van Schil, Frank Peelman, Timothy Cherry, Toon Rosseel, Hannah Verdin, Julien Derolez, Thalia Van Laethem, Kamron N. Khan, Martin McKibbin, Carmel Toomes, Manir Ali, Annalaura Torella, Francesco Testa, Belen Jimenez, Francesca Simonelli, Julie De Zaeytijd, Jenneke Van den Ende, Bart P. Leroy, Frauke Coppieters, Carmen Ayuso, Chris F. Inglehearn, Sandro Banfi, and Elfride De Baere
- Subjects
Adult ,Male ,Genotype ,DNA Mutational Analysis ,Mutation, Missense ,Genes, Recessive ,Retina ,White People ,Article ,Retinal Diseases ,retinitis pigmentosa ,Humans ,Eye Proteins ,Genetic Association Studies ,Genetics (clinical) ,Homeodomain Proteins ,novel ARRP gene ,Correction ,RAX2 ,Middle Aged ,Pedigree ,Phenotype ,Haplotypes ,loss of function ,Mutation ,Female ,homeobox-containing transcription factor ,Transcription Factors - Abstract
Purpose RAX2 encodes a homeobox-containing transcription factor, in which four monoallelic pathogenic variants have been described in autosomal dominant cone-dominated retinal disease. Methods Exome sequencing in a European cohort with inherited retinal disease (IRD) (n = 2086) was combined with protein structure modeling of RAX2 missense variants, bioinformatics analysis of deletion breakpoints, haplotyping of RAX2 variant c.335dup, and clinical assessment of biallelic RAX2-positive cases and carrier family members. Results Biallelic RAX2 sequence and structural variants were found in five unrelated European index cases, displaying nonsyndromic autosomal recessive retinitis pigmentosa (ARRP) with an age of onset ranging from childhood to the mid-40s (average mid-30s). Protein structure modeling points to loss of function of the novel recessive missense variants and to a dominant-negative effect of the reported dominant RAX2 alleles. Structural variants were fine-mapped to disentangle their underlying mechanisms. Haplotyping of c.335dup in two cases suggests a common ancestry. Conclusion This study supports a role for RAX2 as a novel disease gene for recessive IRD, broadening the mutation spectrum from sequence to structural variants and revealing a founder effect. The identification of biallelic RAX2 pathogenic variants in five unrelated families shows that RAX2 loss of function may be a nonnegligible cause of IRD in unsolved ARRP cases.
- Published
- 2019
49. The N‐terminal p.(Ser38Cys) TIMP3 mutation underlying Sorsby fundus dystrophy is a founder mutation disrupting an intramolecular disulfide bond
- Author
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Julie De Zaeytijd, Delfien Syx, Frauke Coppieters, Frank Peelman, Roosmarijn E. Vandenbroucke, Sarah Naessens, Bart P. Leroy, Frédéric Smeets, and Caroline Van Cauwenbergh
- Subjects
Male ,TIMP3 ,Protein Conformation ,MATRIX METALLOPROTEINASES ,Mutant ,medicine.disease_cause ,PHENOTYPE ,Macular Degeneration ,Protein structure ,Medicine and Health Sciences ,Disulfides ,Genetics (clinical) ,Research Articles ,Genetics ,0303 health sciences ,Mutation ,dimerization ,030305 genetics & heredity ,Phenotype ,Founder Effect ,Pedigree ,Matrix Metalloproteinase 2 ,Female ,Research Article ,EXPRESSION ,glycosylation ,Biology ,03 medical and health sciences ,Structure-Activity Relationship ,TISSUE INHIBITOR ,aberrant disulfide bonding ,medicine ,Humans ,Protein Interaction Domains and Motifs ,030304 developmental biology ,Aged ,Tissue Inhibitor of Metalloproteinase-3 ,STABILITY ,Haplotype ,Wild type ,Biology and Life Sciences ,METALLOPROTEINASES-3 TIMP3 ,Fibroblasts ,GENE ,Molecular Weight ,Gene Expression Regulation ,Haplotypes ,founder mutation ,Sorsby fundus dystrophy ,Founder effect ,Cysteine - Abstract
Sorsby fundus dystrophy (SFD) is a macular degeneration caused by mutations in TIMP3, the majority of which introduce a novel cysteine. However, the exact molecular mechanisms underlying SFD remain unknown. We aimed to provide novel insights into the functional consequences of a distinct N‐terminal mutation. Haplotype reconstruction in three SFD families revealed that the identified c.113C>G, p.(Ser38Cys) mutation is a founder in Belgian and northern French families with a late‐onset SFD phenotype. Functional consequences of the p.(Ser38Cys) mutation were investigated by high‐resolution Western blot analysis of wild type and mutant TIMP3 using patient fibroblasts and in vitro generated proteins, and by molecular modeling of TIMP3 and its interaction partners. We could not confirm a previous hypothesis on dimerization of mutant TIMP3 proteins. However, we identified aberrant intramolecular disulfide bonding. Our data provide evidence for disruption of the established Cys36‐Cys143 disulfide bond and formation of a novel Cys36‐Cys38 bond, possibly associated with increased glycosylation of the protein. In conclusion, we propose a novel pathogenetic mechanism underlying the p.(Ser38Cys) TIMP3 founder mutation involving intramolecular disulfide bonding. These results provide new insights into the pathogenesis of SFD and other retinopathies linked to mutations in TIMP3, such as age‐related macular degeneration.
- Published
- 2019
50. Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease
- Author
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Julien Derolez, Hannah Verdin, Carmen Ayuso, Frauke Coppieters, Marta Corton, Frank Peelman, Marianthi Karali, Francesca Simonelli, Thalia Van Laethem, Kamron N. Khan, Julie De Zaeytijd, Jenneke van den Ende, Belen Jimenez, Sandro Banfi, Manir Ali, Francesco Testa, Elfride De Baere, Claire E. L. Smith, Martin McKibbin, Annalaura Torella, Timothy J. Cherry, Bart P. Leroy, Carmel Toomes, Chris F. Inglehearn, Toon Rosseel, Kristof Van Schil, Stijn Van De Sompele, Van de Sompele, Stijn, Smith, Claire, Karali, Marianthi, Corton, Marta, Van Schil, Kristof, Peelman, Frank, Cherry, Timothy, Rosseel, Toon, Verdin, Hannah, Derolez, Julien, Van Laethem, Thalia, Khan, Kamron N., Mckibbin, Martin, Toomes, Carmel, Ali, Manir, Torella, Annalaura, Testa, Francesco, Jimenez, Belen, Simonelli, Francesca, De Zaeytijd, Julie, Van den Ende, Jenneke, Leroy, Bart P., Coppieters, Frauke, Ayuso, Carmen, Inglehearn, Chris F., Banfi, Sandro, and De Baere, Elfride
- Subjects
0301 basic medicine ,EXPRESSION ,CRX ,PROTEIN ,Disease ,030105 genetics & heredity ,Biology ,03 medical and health sciences ,chemistry.chemical_compound ,retinitis pigmentosa ,Retinitis pigmentosa ,medicine ,Medicine and Health Sciences ,Genetics (clinical) ,Loss function ,Sequence (medicine) ,HOMEOBOX GENE [novel ARRP gene KeyWords Plus] ,Genetics ,MUTATIONS ,novel ARRP gene ,Biology and Life Sciences ,Retinal ,RAX2 ,medicine.disease ,030104 developmental biology ,chemistry ,loss of function ,homeobox-containing transcription factor ,Human medicine ,NRL - Abstract
Purpose: RAX2 encodes a homeobox-containing transcription factor, in which four monoallelic pathogenic variants have been described in autosomal dominant cone-dominated retinal disease. Methods: Exome sequencing in a European cohort with inherited retinal disease (IRD) (n = 2086) was combined with protein structure modeling of RAX2 missense variants, bioinformatics analysis of deletion breakpoints, haplotyping of RAX2 variant c.335dup, and clinical assessment of biallelic RAX2-positive cases and carrier family members. Results: Biallelic RAX2 sequence and structural variants were found in five unrelated European index cases, displaying nonsyndromic autosomal recessive retinitis pigmentosa (ARRP) with an age of onset ranging from childhood to the mid-40s (average mid-30s). Protein structure modeling points to loss of function of the novel recessive missense variants and to a dominant-negative effect of the reported dominant RAX2 alleles. Structural variants were fine-mapped to disentangle their underlying mechanisms. Haplotyping of c.335dup in two cases suggests a common ancestry. Conclusion: This study supports a role for RAX2 as a novel disease gene for recessive IRD, broadening the mutation spectrum from sequence to structural variants and revealing a founder effect. The identification of biallelic RAX2 pathogenic variants in five unrelated families shows that RAX2 loss of function may be a nonnegligible cause of IRD in unsolved ARRP cases. Purpose: RAX2 encodes a homeobox-containing transcription factor, in which four monoallelic pathogenic variants have been described in autosomal dominant cone-dominated retinal disease. Methods: Exome sequencing in a European cohort with inherited retinal disease (IRD) (n = 2086) was combined with protein structure modeling of RAX2 missense variants, bioinformatics analysis of deletion breakpoints, haplotyping of RAX2 variant c.335dup, and clinical assessment of biallelic RAX2-positive cases and carrier family members. Results: Biallelic RAX2 sequence and structural variants were found in five unrelated European index cases, displaying nonsyndromic autosomal recessive retinitis pigmentosa (ARRP) with an age of onset ranging from childhood to the mid-40s (average mid-30s). Protein structure modeling points to loss of function of the novel recessive missense variants and to a dominant-negative effect of the reported dominant RAX2 alleles. Structural variants were fine-mapped to disentangle their underlying mechanisms. Haplotyping of c.335dup in two cases suggests a common ancestry. Conclusion: This study supports a role for RAX2 as a novel disease gene for recessive IRD, broadening the mutation spectrum from sequence to structural variants and revealing a founder effect. The identification of biallelic RAX2 pathogenic variants in five unrelated families shows that RAX2 loss of function may be a nonnegligible cause of IRD in unsolved ARRP cases.
- Published
- 2019
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