Bart P Leroy

Publications (53)267.14 Total impact

• Article: HIGH-RESOLUTION OPTICAL COHERENCE TOMOGRAPHY, AUTOFLUORESCENCE, AND INFRARED REFLECTANCE IMAGING IN SJÖGREN RETICULAR DYSTROPHY.

  Pieter-Paul Schauwvlieghe, Kara Della Torre, Frauke Coppieters, Anneleen Van Hoey, Elfride De Baere, Julie De Zaeytijd, Bart P Leroy, Scott E Brodie
  [show abstract] [hide abstract]
  ABSTRACT: PURPOSE:: To describe the phenotype of three cases of Sjögren reticular dystrophy in detail, including high-resolution optical coherence tomography, autofluorescence imaging, and near-infrared reflectance imaging. METHODS:: Two unrelated teenagers were independently referred for ophthalmologic evaluation. Both underwent a full ophthalmologic workup, including electrophysiologic and extensive imaging with spectral-domain optical coherence tomography, autofluorescence imaging, and near-infrared reflectance imaging. In addition, mutation screening of ABCA4, PRPH2, and the mitochondrial tRNA gene was performed in Patient 1. Subsequently, the teenage sister of Patient 2 was examined. RESULTS:: Strikingly similar phenotypes were present in these three patients. Fundoscopy showed bilateral foveal pigment alterations, and a lobular network of deep retinal, pigmented deposits throughout the posterior pole, tapering toward the midperiphery, with relative sparing of the immediate perifoveal macula and peripapillary area. This network is mildly to moderately hyperautofluorescent on autofluorescence and bright on near-infrared reflectance imaging. Optical coherence tomography showed abnormalities of the retinal pigment epithelium-Bruch membrane complex, photoreceptor outer segments, and photoreceptor inner/outer segment interface. The results of retinal function test were entirely normal. No molecular cause was detected in Patient 1. CONCLUSION:: Imaging suggested that the lobular network of deep retinal deposits in Sjögren reticular dystrophy is the result of accumulation of both pigment and lipofuscin between photoreceptors and retinal pigment epithelium, as well as within the retinal pigment epithelium.
  Retina (Philadelphia, Pa.) 04/2013; · 2.93 Impact Factor
• Article: Maternal Uniparental Isodisomy of Chromosome 6 Reveals a TULP1 Mutation as a Novel Cause of Cone Dysfunction.

  Susanne Roosing, L Ingeborgh van den Born, Carel B Hoyng, Alberta A H J Thiadens, Elfride de Baere, Rob W J Collin, Robert K Koenekoop, Bart P Leroy, Norka van Moll-Ramirez, Hanka Venselaar, Frans C C Riemslag, Frans P M Cremers, Caroline C W Klaver, Anneke I den Hollander
  [show abstract] [hide abstract]
  ABSTRACT: PURPOSE: The majority of the genetic causes of autosomal recessive (ar) cone dystrophy (CD) and cone-rod dystrophy (CRD) are currently unknown. We used a high-resolution homozygosity mapping approach in a cohort of patients with CD or CRD to identify new genes for ar cone disorders. DESIGN: Case series. PARTICIPANTS: A cohort of 159 patients with ar CD and 91 patients with CRD. METHODS: The genomes of 83 patients with ar CD and 73 patients with CRD were analyzed for homozygous regions using single nucleotide polymorphism (SNP) microarrays. One patient showed homozygosity of SNPs across chromosome 6, and segregation analysis was performed using microsatellite markers. Direct sequencing of all retinal disease genes on chromosome 6 revealed a novel pathogenic TULP1 mutation in this patient. A cohort of 159 individuals with CD and 91 individuals with CRD was screened for this particular mutation using the restriction enzyme HhaI. The medical history of patients carrying the TULP1 mutation was reviewed and additional ophthalmic examinations were performed, including electroretinography (ERG), perimetry, optical coherence tomography (OCT), fundus autofluorescence (FAF), and fundus photography. MAIN OUTCOME MEASURES: TULP1 mutations, age at diagnosis, visual acuity, fundus appearance, color vision defects, visual field, ERG, FAF, and OCT findings. RESULTS: In 1 patient, homozygosity mapping and subsequent segregation analysis revealed maternal uniparental disomy (UPD) of chromosome 6. A novel homozygous missense mutation (p.Arg420Ser) was identified in TULP1, whereas no mutations were detected in other retinal disease genes on chromosome 6. The mutation affects a highly conserved amino acid residue in the Tubby domain and is predicted to be pathogenic. The same homozygous mutation was also identified in an additional, unrelated patient with CRD. Both patients carrying the p.Arg420Ser mutation presented with a bull's eye maculopathy. The first patient had progressive loss of visual acuity with a relatively preserved ERG, whereas the second patient developed loss of visual acuity, peripheral degeneration, and severely reduced ERG responses in a cone-rod pattern. CONCLUSIONS: Maternal UPD of chromosome 6 unmasked a mutation in the TULP1 gene as a novel cause of cone dysfunction. This expands the disease spectrum of TULP1 mutations from Leber congenital amaurosis and early-onset retinitis pigmentosa to cone-dominated disease. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
  Ophthalmology 03/2013; · 5.45 Impact Factor
• Source

  Available from: Ditta Zobor

  Dataset: KCNV2 Wissinger Zobor

  Bernd Wissinger, Simone Schaich, Britta Baumann, Michael Bonin, Herbert Jägle, Christoph Friedburg, Balázs Varsányi, Carel B Hoyng, Hélène Dollfus, John R Heckenlively, [......], Alexandra Sauer, Christiane Wolf, Ditta Zobor, Antje Bernd, Bart P Leroy, Péter Enyedi, Frans P M Cremers, Birgit Lorenz, Eberhart Zrenner, Susanne Kohl
• Source

  Available from: Balazs Varsányi

  Dataset: VB-BW-Humut-20111-KCNV2

  Bernd Wissinger, Simone Schaich, Britta Baumann, Michael Bonin, Herbert Jägle, Christoph Friedburg, Balázs Varsányi, Carel B Hoyng, Hélène Dollfus, John R Heckenlively, [......], Alexandra Sauer, Christiane Wolf, Ditta Zobor, Antje Bernd, Bart P Leroy, Péter Enyedi, Frans P M Cremers, Birgit Lorenz, Eberhart Zrenner, Susanne Kohl
• Source

  Available from: Enzo Maria Vingolo

  Article: BBS1 Mutations in a Wide Spectrum of Phenotypes Ranging From Nonsyndromic Retinitis Pigmentosa to Bardet-Biedl Syndrome.

  Alejandro Estrada-Cuzcano, Robert K Koenekoop, Audrey Senechal, Elfride B W De Baere, Thomy de Ravel, Sandro Banfi, Susanne Kohl, Carmen Ayuso, Dror Sharon, Carel B Hoyng, [......], Enzo M Vingolo, Sabrina Signorini, Eyal Banin, Liliana Mizrahi-Meissonnier, Eberhard Zrenner, Ulrich Kellner, Rob W J Collin, Anneke I den Hollander, Frans P M Cremers, B Jeroen Klevering
  [show abstract] [hide abstract]
  ABSTRACT: OBJECTIVE To investigate the involvement of the Bardet-Biedl syndrome (BBS) gene BBS1 p.M390R variant in nonsyndromic autosomal recessive retinitis pigmentosa (RP). METHODS Homozygosity mapping of a patient with isolated RP was followed by BBS1 sequence analysis. We performed restriction fragment length polymorphism analysis of the p.M390R allele in 2007 patients with isolated RP or autosomal recessive RP and in 1824 ethnically matched controls. Patients with 2 BBS1 variants underwent extensive clinical and ophthalmologic assessment. RESULTS In an RP proband who did not fulfill the clinical criteria for BBS, we identified a large homozygous region encompassing the BBS1 gene, which carried the p.M390R variant. In addition, this variant was detected homozygously in 10 RP patients and 1 control, compound heterozygously in 3 patients, and heterozygously in 5 patients and 6 controls. The 14 patients with 2 BBS1 variants showed the entire clinical spectrum, from nonsyndromic RP to full-blown BBS. In 8 of 14 patients, visual acuity was significantly reduced. In patients with electroretinographic responses, a rod-cone pattern of photoreceptor degeneration was observed. CONCLUSIONS Variants in BBS1 are significantly associated with nonsyndromic autosomal recessive RP and relatively mild forms of BBS. As exemplified in this study by the identification of a homozygous p.M390R variant in a control individual and in unaffected parents of BBS patients in other studies, cis - or trans -acting modifiers may influence the disease phenotype. CLINICAL RELEVANCE It is important to monitor patients with an early diagnosis of mild BBS phenotypes for possible life-threatening conditions.
  Archives of ophthalmology 11/2012; 130(11):1425-32. · 3.86 Impact Factor
• Article: Enhanced S-cone syndrome with preserved macular structure and severely depressed retinal function.

  Ivan Cima, Jelka Brecelj, Maja Sustar, Frauke Coppieters, Bart P Leroy, Elfride De Baere, Marko Hawlina
  [show abstract] [hide abstract]
  ABSTRACT: We present ophthalmic features and genetic analysis findings of a 44-year-old croatian patient with enhanced S-cone syndrome (ESCS). Complete ophthalmic examination, Ishihara colour vision test, dark adaptometry, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence imaging, Goldmann visual field and automated perimetry, full-field electroretinography (ERG), multifocal ERG, S-cone ERG and ON-OFF ERG were performed. Mutation screening of the NR2E3 gene, which encodes a photoreceptor-specific orphan nuclear receptor, was performed with polymerase chain reaction amplification and direct sequencing. The patient has good visual acuity and normal colour vision. Fundus examination showed normal posterior pole and nummular pigment depositions at the level of the retinal pigment epithelium in the mid-periphery of the retina. The SD-OCT images showed normal macular structure and thickness. The ERG showed characteristic findings: photopic and scotopic responses to the same stimulus had a similar waveform and were dominated by short-wavelength-sensitive mechanisms. Mutation analysis revealed the known NR2E3 mutation c.481delA (p.Thr161HisFsX18) and the novel NR2E3 variant c.1120C > T (p.Leu374Phe). To the best of our knowledge, this is the only ESCS patient older than 40 years who phenotypically has preserved macular structure, good central visual acuity and severely depressed full-field ERG as well as the first reported patient with NR2E3 mutation from Croatia.
  Documenta Ophthalmologica 06/2012; 125(2):161-8. · 2.11 Impact Factor
• Source

  Available from: Hoan Nguyen

  Article: Whole-exome sequencing identifies mutations in GPR179 leading to autosomal-recessive complete congenital stationary night blindness.

  Isabelle Audo, Kinga Bujakowska, Elise Orhan, Charlotte M Poloschek, Sabine Defoort-Dhellemmes, Isabelle Drumare, Susanne Kohl, Tien D Luu, Odile Lecompte, Eberhart Zrenner, [......], Thomy de Ravel, Ian Simmons, Hoan Nguyen, Hélène Dollfus, Olivier Poch, Thierry Léveillard, Kim Nguyen-Ba-Charvet, José-Alain Sahel, Shomi S Bhattacharya, Christina Zeitz
  [show abstract] [hide abstract]
  ABSTRACT: Congenital stationary night blindness (CSNB) is a heterogeneous retinal disorder characterized by visual impairment under low light conditions. This disorder is due to a signal transmission defect from rod photoreceptors to adjacent bipolar cells in the retina. Two forms can be distinguished clinically, complete CSNB (cCSNB) or incomplete CSNB; the two forms are distinguished on the basis of the affected signaling pathway. Mutations in NYX, GRM6, and TRPM1, expressed in the outer plexiform layer (OPL) lead to disruption of the ON-bipolar cell response and have been seen in patients with cCSNB. Whole-exome sequencing in cCSNB patients lacking mutations in the known genes led to the identification of a homozygous missense mutation (c.1807C>T [p.His603Tyr]) in one consanguineous autosomal-recessive cCSNB family and a homozygous frameshift mutation in GPR179 (c.278delC [p.Pro93Glnfs(∗)57]) in a simplex male cCSNB patient. Additional screening with Sanger sequencing of 40 patients identified three other cCSNB patients harboring additional allelic mutations in GPR179. Although, immunhistological studies revealed Gpr179 in the OPL in wild-type mouse retina, Gpr179 did not colocalize with specific ON-bipolar markers. Interestingly, Gpr179 was highly concentrated in horizontal cells and Müller cell endfeet. The involvement of these cells in cCSNB and the specific function of GPR179 remain to be elucidated.
  The American Journal of Human Genetics 02/2012; 90(2):321-30. · 10.60 Impact Factor
• Article: Massively parallel sequencing for early molecular diagnosis in Leber congenital amaurosis.

  Frauke Coppieters, Bram De Wilde, Steve Lefever, Ellen De Meester, Nina De Rocker, Caroline Van Cauwenbergh, Filip Pattyn, Françoise Meire, Bart P Leroy, Jan Hellemans, Jo Vandesompele, Elfride De Baere
  [show abstract] [hide abstract]
  ABSTRACT: Leber congenital amaurosis (LCA) is a rare congenital retinal dystrophy associated with 16 genes. Recent breakthroughs in LCA gene therapy offer the first prospect of treating inherited blindness, which requires an unequivocal and early molecular diagnosis. While present genetic tests do not address this due to a tremendous genetic heterogeneity, massively parallel sequencing (MPS) strategies might bring a solution. Here, we developed a comprehensive molecular test for LCA based on targeted MPS of all exons of 16 known LCA genes. We designed a unique and flexible workflow for targeted resequencing of all 236 exons from 16 LCA genes based on quantitative PCR (qPCR) amplicon ligation, shearing, and parallel sequencing of multiple patients on a single lane of a short-read sequencer. Twenty-two prescreened LCA patients were included, five of whom had a known molecular cause. Validation of 107 variations was performed as proof of concept. In addition, the causal genetic defect and a single heterozygous mutation were identified in 3 and 5, respectively, of 17 patients without previously identified mutations. We propose a novel targeted MPS-based approach that is suitable for accurate, fast, and cost-effective early molecular testing in LCA, and easily applicable in other genetic disorders.
  Genetics in medicine: official journal of the American College of Medical Genetics 01/2012; 14(6):576-85. · 3.92 Impact Factor
• Article: Clinical course, genetic etiology, and visual outcome in cone and cone-rod dystrophy.

  Alberta A H J Thiadens, T My Lan Phan, Renate C Zekveld-Vroon, Bart P Leroy, L Ingeborgh van den Born, Carel B Hoyng, Caroline C W Klaver, Susanne Roosing, Jan-Willem R Pott, Mary J van Schooneveld, Norka van Moll-Ramirez, Maria M van Genderen, Camiel J F Boon, Anneke I den Hollander, Arthur A B Bergen, Elfride De Baere, Frans P M Cremers, Andrew J Lotery
  [show abstract] [hide abstract]
  ABSTRACT: To evaluate the clinical course, genetic etiology, and visual prognosis in patients with cone dystrophy (CD) and cone-rod dystrophy (CRD). Clinic-based, longitudinal, multicenter study. Consecutive probands with CD (N = 98), CRD (N = 83), and affected relatives (N = 41 and N = 17, respectively) from various ophthalmogenetic clinics in The Netherlands, Belgium, and the United Kingdom. Data on best-corrected Snellen visual acuity, color vision, ophthalmoscopy, fundus photography, Goldmann perimetry, and full-field standard electroretinogram (ERG) from all patients were registered from medical charts over a mean follow-up of 19 years. The ABCA4, CNGB3, KCNV2, PDE6C, and RPGR genes were analyzed by direct sequencing in autosomal recessive (AR) and X-linked (XL), respectively. Genotyping was not undertaken for autosomal-dominant cases. The 10-year progression of all clinical parameters and cumulative lifetime risk of low vision and legal blindness were assessed. The mean age onset for CD was 16 years (standard deviation, 11), and of CRD 12 years (standard deviation, 11; P = 0.02). The pattern of inheritance was AR in 92% of CD and 90% of CRD. Ten years after diagnosis, 35% of CD and 51% of CRD had a bull's eye maculopathy; 70% of CRD showed absolute peripheral visual field defects and 37% of CD developed rod involvement on ERG. The mean age of legal blindness was 48 (standard error [SE], 3.1) years in CD, and 35 (SE, 1.1; P<0.001) years in CRD. ABCA4 mutations were found in 8 of 90 (9%) of AR-CD, and in 17 of 65 (26%) of AR-CRD. Other mutations were detected in CNGB3 (3/90; 3%), KCNV2 (4/90; 4%), and in PDE6C (1/90; 1%). The RPGR gene was mutated in the 2 XL-CD and in 4 of 5 (80%) of XL-CRD. ABCA4 mutations as well as age of onset <20 years were significantly associated with a faster progression to legal blindness (P<0.001). Although CD had a slightly more favorable clinical course than CRD, both disorders progressed to legal blindness in the majority of patients. Mutations in the ABCA4 gene and early onset of disease were independent prognostic parameters for visual loss. Our data may serve as an aid in counseling patients with progressive cone disorders.
  Ophthalmology 01/2012; 119(4):819-26. · 5.45 Impact Factor
• Article: Clinical utility gene card for: BEST1-related dystrophies (Bestrophinopathies).

  Simon C Ramsden, Alice E Davidson, Bart P Leroy, Anthony T Moore, Andrew R Webster, Graeme C M Black, Forbes D C Manson
  European journal of human genetics: EJHG 01/2012; 20(5). · 3.56 Impact Factor
• Article: Insights into levator muscle dysfunction in a cohort of patients with molecularly confirmed blepharophimosis-ptosis-epicanthus inversus syndrome using high-resolution imaging, anatomic examination, and histopathologic examination.

  Christian E Decock, Elfride E De Baere, Wouter Bauters, Akash D Shah, Christophe Delaey, Ramese Forsyth, Bart P Leroy, Philippe Kestelyn, Ilse Claerhout
  [show abstract] [hide abstract]
  ABSTRACT: To study the basis of defective levator palpebrae superioris (LPS) function in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), an autosomal dominant eyelid malformation sometimes associated with ovarian dysfunction. Eight patients with molecularly proved BPES underwent high-resolution surface-coil 3-T magnetic resonance imaging before surgical intervention. The features of LPS muscle and adjoining connective tissue were compared with an age-matched control subject. During LPS resection for ptosis repair, detailed anatomic examination of the LPS was performed. Histopathologic characteristics were compared with normal control samples from a cadaver and a patient with simple severe congenital ptosis. The most striking feature shown on magnetic resonance imaging was the thin, long anterior part of the LPS. During the operation, this consisted of a disorganized, thin, long aponeurosis. However, in the posterior part of the LPS, there was an organized thick structure suggestive of a muscle belly. Histopathologic examination revealed posteriorly well-formed striated muscle fibers in all patients with BPES but not in the control sample from the patient with simple severe congenital ptosis. These striated muscle fibers were comparable to those of the normal control tissue but were more intermixed with collagenous tissue and little fatty degeneration. The presence of striated muscle fibers in LPS of patients with BPES contrasts with the fatty degeneration in patients with simple severe congenital ptosis. To our knowledge, this is the first study providing novel insights into the pathogenesis of the eyelid malformation in BPES through extensive imaging, anatomic study, and histopathologic testing in a unique cohort of patients with molecularly proved BPES.
  Archives of ophthalmology 12/2011; 129(12):1564-9. · 3.86 Impact Factor
• Source

  Available from: Leon J Schurgers

  Article: Atypical presentation of pseudoxanthoma elasticum with abdominal cutis laxa: evidence for a spectrum of ectopic calcification disorders?

  Olivier M Vanakker, Bart P Leroy, Leon J Schurgers, Cees Vermeer, Paul J Coucke, Anne De Paepe
  [show abstract] [hide abstract]
  ABSTRACT: A patient is presented with severe cutis laxa of the abdomen. Molecular investigations, including sequencing of the fibulin-5 and elastin gene, failed to endorse the diagnosis of inherited cutis laxa. Ultrasonographical discovery of renal calcifications during his general work-up suggested a possible diagnosis of pseudo-xanthoma elasticum (PXE). A discrete yellowish reticular pattern in the anterior neck region was detected upon careful clinical examination. Clinically, the patient presented characteristics of both classic PXE (retinopathy, renal calcifications) and the PXE-like syndrome (cutis laxa beyond the flexural areas). Skin biopsy and ophthalmological examination confirmed the diagnosis of PXE. In addition, ultrastructural evaluation revealed calcium deposits in the periphery of elastic fibers, a typical observation in the PXE-like syndrome. Immunohistochemical experiments and ELISA tests for various inhibitors of calcification displayed results which were partly reminiscent of both PXE and the PXE-like syndrome. Molecular analysis revealed not only two ABCC6 mutations (related to PXE), but also a gain of function SNP in the GGCX gene, in which loss-of-function mutations cause the PXE-like syndrome. We conclude that the patients phenotype and--to a further extent--the PXE-like syndrome, are part of a spectrum of ectopic calcification disorders which are clinically and/or pathogenetically related to PXE. The molecular findings in this patient are however insufficient to explain the entire phenotype and suggest a role for multiple genetic factors in soft tissue mineralization.
  American Journal of Medical Genetics Part A 09/2011; 155A(11):2855-9. · 2.39 Impact Factor
• Article: Large deletions of the KCNV2 gene are common in patients with cone dystrophy with supernormal rod response.

  Bernd Wissinger, Simone Schaich, Britta Baumann, Michael Bonin, Herbert Jägle, Christoph Friedburg, Balázs Varsányi, Carel B Hoyng, Hélène Dollfus, John R Heckenlively, [......], Alexandra Sauer, Christiane Wolf, Ditta Zobor, Antje Bernd, Bart P Leroy, Péter Enyedi, Frans P M Cremers, Birgit Lorenz, Eberhart Zrenner, Susanne Kohl
  [show abstract] [hide abstract]
  ABSTRACT: Cone dystrophy with supernormal rod response (CDSRR) is considered to be a very rare autosomal recessive retinal disorder. CDSRR is associated with mutations in KCNV2, a gene that encodes a modulatory subunit (Kv8.2) of a voltage-gated potassium channel. In this study, we found that KCNV2 mutations are present in a substantial fraction (2.2-4.3%) of a sample of 367 independent patients with a variety of initial clinical diagnoses of cone malfunction, indicating that CDSRR is underdiagnosed and more common than previously thought. In total, we identified 20 different KCNV2 mutations; 15 of them are novel. A new finding of this study is the substantial proportion of large deletions at the KCNV2 locus that accounts for 15.5% of the mutant alleles in our sample. We determined the breakpoints and size of all five different deletions, which ranged between 10.9 and 236.8 kb. Two deletions encompass the entire KCNV2 gene and one also includes the adjacent VLDLR gene. Furthermore, we investigated N-terminal amino acid substitution mutations for its effect on interaction with Kv2.1 using yeast two-hybrid technology. We found that these mutations dramatically reduce or abolish this interaction suggesting a lack of assembly of heteromeric Kv channels as one underlying pathomechanism of CDSRR.
  Human Mutation 08/2011; 32(12):1398-406. · 5.69 Impact Factor
• Article: Childhood-onset autosomal recessive bestrophinopathy.

  Arundhati Dev Borman, Alice E Davidson, James O'Sullivan, Dorothy A Thompson, Anthony G Robson, Elfride De Baere, Graeme C M Black, Andrew R Webster, Graham E Holder, Bart P Leroy, Forbes D C Manson, Anthony T Moore
  Archives of ophthalmology 08/2011; 129(8):1088-93. · 3.86 Impact Factor
• Article: Age-dependent ocular phenotype in hereditary hyperferritinaemia cataract syndrome (HHCS).

  Elise Platteau, Kristien Hoornaert, Koen Moens, Bart P Leroy
  Acta ophthalmologica 06/2011; 90(3):e239-40. · 2.44 Impact Factor
• Article: The human visual cortex responds to gene therapy-mediated recovery of retinal function.

  Manzar Ashtari, Laura L Cyckowski, Justin F Monroe, Kathleen A Marshall, Daniel C Chung, Alberto Auricchio, Francesca Simonelli, Bart P Leroy, Albert M Maguire, Kenneth S Shindler, Jean Bennett
  [show abstract] [hide abstract]
  ABSTRACT: Leber congenital amaurosis (LCA) is a rare degenerative eye disease, linked to mutations in at least 14 genes. A recent gene therapy trial in patients with LCA2, who have mutations in RPE65, demonstrated that subretinal injection of an adeno-associated virus (AAV) carrying the normal cDNA of that gene (AAV2-hRPE65v2) could markedly improve vision. However, it remains unclear how the visual cortex responds to recovery of retinal function after prolonged sensory deprivation. Here, 3 of the gene therapy trial subjects, treated at ages 8, 9, and 35 years, underwent functional MRI within 2 years of unilateral injection of AAV2-hRPE65v2. All subjects showed increased cortical activation in response to high- and medium-contrast stimuli after exposure to the treated compared with the untreated eye. Furthermore, we observed a correlation between the visual field maps and the distribution of cortical activations for the treated eyes. These data suggest that despite severe and long-term visual impairment, treated LCA2 patients have intact and responsive visual pathways. In addition, these data suggest that gene therapy resulted in not only sustained and improved visual ability, but also enhanced contrast sensitivity.
  The Journal of clinical investigation 06/2011; 121(6):2160-8. · 15.39 Impact Factor
• Article: Correction of the lower eyelid malpositioning in the blepharophimosis-ptosis-epicanthus inversus syndrome.

  Christian E Decock, Ilse Claerhout, Bart P Leroy, Philippe Kesteleyn, Akash D Shah, Elfride De Baere
  [show abstract] [hide abstract]
  ABSTRACT: Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is an autosomal dominant complex eyelid malformation. The authors aim to offer an explanation for the lower eyelid malformation and propose a novel surgical approach to correct it. An observational and interventional case series of 10 consecutive, molecularly proven BPES patients who underwent surgical repair of the lower eyelid malformation. During surgery detailed anatomical examination and surgical repositioning of the medial canthal tendon was performed. All the patients were followed up regularly after the surgery and assessed for epiphora. All patients exhibited a marked asymmetry in the attachment of the lower and upper eyelid to the medial canthal tendon, with the lower eyelid being much less attached. This resulted in an abnormal downward concavity with a temporal ectropion and a temporally displaced lower eyelid. Consequently, the inferior punctum was displaced temporally. All patients underwent a novel surgical technique to remediate this, namely, inserting a 4.0 nylon suture between the tarsal plate of the lower eyelid and the medial canthal tendon during telecanthus surgery. This simple additional surgical step corrected not only the position of the lower eyelid but also its abnormal downward concavity, the temporal ectropion and the lateral displacement of the inferior punctum. None of the authors' patients had lasting epiphora. Lateral displacement of the inferior punctum is an important hallmark in the diagnosis of BPES. The authors demonstrate an anatomical explanation for the complex lower eyelid malformation and also propose a novel surgical technique to correct this. During surgical repair of the telecanthus and blepharophimosis, specific attention should be paid to reattachment of the lower eyelid to the medial canthal tendon. This understanding improves clinical diagnosis and surgical treatment of BPES patients.
  Ophthalmic plastic and reconstructive surgery 05/2011; 27(5):368-70. · 0.69 Impact Factor
• Article: The clinical and molecular genetic features of idiopathic infantile periodic alternating nystagmus.

  Mervyn G Thomas, Moira Crosier, Susan Lindsay, Anil Kumar, Shery Thomas, Masasuke Araki, Chris J Talbot, Rebecca J McLean, Mylvaganam Surendran, Katie Taylor, Bart P Leroy, Anthony T Moore, David G Hunter, Richard W Hertle, Patrick Tarpey, Andrea Langmann, Susanne Lindner, Martina Brandner, Irene Gottlob
  [show abstract] [hide abstract]
  ABSTRACT: Periodic alternating nystagmus consists of involuntary oscillations of the eyes with cyclical changes of nystagmus direction. It can occur during infancy (e.g. idiopathic infantile periodic alternating nystagmus) or later in life. Acquired forms are often associated with cerebellar dysfunction arising due to instability of the optokinetic-vestibular systems. Idiopathic infantile periodic alternating nystagmus can be familial or occur in isolation; however, very little is known about the clinical characteristics, genetic aetiology and neural substrates involved. Five loci (NYS1-5) have been identified for idiopathic infantile nystagmus; three are autosomal (NYS2, NYS3 and NYS4) and two are X-chromosomal (NYS1 and NYS5). We previously identified the FRMD7 gene on chromosome Xq26 (NYS1 locus); mutations of FRMD7 are causative of idiopathic infantile nystagmus influencing neuronal outgrowth and development. It is unclear whether the periodic alternating nystagmus phenotype is linked to NYS1, NYS5 (Xp11.4-p11.3) or a separate locus. From a cohort of 31 X-linked families and 14 singletons (70 patients) with idiopathic infantile nystagmus we identified 10 families and one singleton (21 patients) with periodic alternating nystagmus of which we describe clinical phenotype, genetic aetiology and neural substrates involved. Periodic alternating nystagmus was not detected clinically but only on eye movement recordings. The cycle duration varied from 90 to 280 s. Optokinetic reflex was not detectable horizontally. Mutations of the FRMD7 gene were found in all 10 families and the singleton (including three novel mutations). Periodic alternating nystagmus was predominantly associated with missense mutations within the FERM domain. There was significant sibship clustering of the phenotype although in some families not all affected members had periodic alternating nystagmus. In situ hybridization studies during mid-late human embryonic stages in normal tissue showed restricted FRMD7 expression in neuronal tissue with strong hybridization signals within the afferent arms of the vestibulo-ocular reflex consisting of the otic vesicle, cranial nerve VIII and vestibular ganglia. Similarly within the afferent arm of the optokinetic reflex we showed expression in the developing neural retina and ventricular zone of the optic stalk. Strong FRMD7 expression was seen in rhombomeres 1 to 4, which give rise to the cerebellum and the common integrator site for both these reflexes (vestibular nuclei). Based on the expression and phenotypic data, we hypothesize that periodic alternating nystagmus arises from instability of the optokinetic-vestibular systems. This study shows for the first time that mutations in FRMD7 can cause idiopathic infantile periodic alternating nystagmus and may affect neuronal circuits that have been implicated in acquired forms.
  Brain 02/2011; 134(Pt 3):892-902. · 9.46 Impact Factor
• Article: Discordance for retinitis pigmentosa in two monozygotic twin pairs.

  Lieve V Berghmans, Regina Halfeld Furtado de Mendonça, Frauke Coppieters, Otacílio de Oliveira Maia, Walter Yukihiko Takahashi, Willy Lissens, Elfride de Baere, Bart P Leroy
  [show abstract] [hide abstract]
  ABSTRACT: Retinitis pigmentosa (RP) is a group of genetically heterogeneous diseases with progressive degeneration of the retina. The condition can be inherited as an autosomal dominant, autosomal recessive, and X-linked trait. We report on two female twin pairs. One twin of each pair is affected with RP, the other twin is unaffected, both clinically and functionally.Molecular analysis in both twins included zygosity determination, arrayed primer extension chip analysis for autosomal recessive and dominant RP, sequencing of the entire RPGR gene, and analysis of X-chromosome inactivation status. Both unrelated twin pairs were genetically identical. Of the potential pathogenetic mechanisms, skewed X-inactivation was excluded on leukocytes. Autosomal recessive RP and autosomal dominant RP arrayed primer extension chip analysis result was completely normal, excluding known mutations in known genes as the cause of disease in the affected twins. Sequencing excluded mutations in RPGR. A postzygotic recessive or dominant genetic mutation of an RP gene is not impossible. A postfertilization error as a potential cause of uniparental isodisomy is unlikely albeit not entirely impossible. The authors report on the second and third unrelated identical twin pair discordant for RP. The exact cause of the condition and the explanation of the clinical discordance remain elusive.
  Retina (Philadelphia, Pa.) 01/2011; 31(6):1164-9. · 2.93 Impact Factor
• Article: Ptosis as an associated finding in maternally inherited diabetes and deafness.

  Kirsten Robberecht, Christian Decock, Annemie Stevens, Sara Seneca, Jan De Bleecker, Bart P Leroy
  [show abstract] [hide abstract]
  ABSTRACT: To report ptosis as an associated finding in 2 patients with maternally inherited diabetes and deafness (MIDD). Two unrelated female patients with genetically proven MIDD are described. A complete ophthalmological examination included evaluation of levator muscle function, vertical fissure height and upper lid crease position measurements, the ice pack test and extensive imaging. In addition, pathology of the levator muscle was performed in 1 patient. The first patient had an asymmetric ptosis at presentation. Levator muscle function was initially normal and decreased 3 years after, suggestive of a myogenic ptosis. Fundus examination revealed a macular pattern dystrophy. The second MIDD patient was referred for bilateral pigment alterations at the posterior pole. Gradually bilateral ptosis developed over a 3-year period. In both patients, ocular motility testing revealed a reduced upgaze. Myogenic ptosis has been described in association with several of the phenotypes caused by the m.3243A>G mutation, but up to now it had not been described as a finding in MIDD. MIDD has pleomorphic manifestations, and myogenic ptosis should be added to the list of associated clinical features. The additional symmetric elevation deficit in both patients may be an early sign of chronic progressive external ophthalmoplegia (CPEO). The results provide further evidence to suggest that MIDD represents only a part of a continuous spectrum of disease related to the m.3243A>G point mutation in the tRNA(Leu) gene.
  Ophthalmic Genetics 12/2010; 31(4):240-3. · 0.93 Impact Factor