582 results on '"MacDonald, Ian M."'
Search Results
202. Scheie's Syndrome
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Zabel, Ralph W., primary, MacDonald, Ian M., additional, Mintsioulis, George, additional, and Addison, David J., additional
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- 1989
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203. Growth and development in thanatophoric dysplasia
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MacDonald, Ian M., primary, Hunter, Alasdair G. W., additional, MacLeod, Patrick M., additional, and MacMurray, S. Brock, additional
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- 1989
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204. Corneal involvement in a case of autosomal dominant Stargardt-like macular dystrophy (STGD3) with ELOVL4 mutation.
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Zhai, Yi, Benson, Matthew D., and MacDonald, Ian M.
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DYSTROPHY , *CORNEA , *MEIBOMIAN glands , *ANTERIOR eye segment , *GENETIC mutation , *CYTOLOGY - Abstract
Stargardt-like macular dystrophy (STGD3) represents an early onset, autosomal dominant form of macular degeneration. (e) Pentacam corneal topography of both eyes at the initial visit revealed normal corneal thickness in the left eye and mild thinning temporally in the right eye. In order to verify the hypothesis of an association of STGD3 disease with dry eyes, future evaluation of the tear film stability of STGD3 patients, especially in older patients may be instructive. [Extracted from the article]
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- 2022
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205. Brothers with ocular motor apraxia, juvenile nephronophthisis, and mild cerebellar defects.
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Chan, Stephanie C., Rayat, Jaspreet, Sauvé, Yves, and MacDonald, Ian M.
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- 2016
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206. Genomics in the Era of Molecular Ophthalmology.
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Brooks, Brian P., MacDonald, Ian M., Tumminia, Santa J., Smaoui, Nizar, Blain, Delphine, Nezhuving, Ajaina A., and Sieving, Paul A.
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- 2008
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207. Genetics and ARMD.
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MacDonald, Ian M. and Lines, Matthew A.
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LETTERS to the editor , *RETINAL degeneration , *AGE distribution , *AGING , *CARRIER proteins , *MEMBRANE proteins , *GENETIC mutation , *PROTEINS , *PREVENTION - Abstract
Presents a letter to the editor about age-related macular degeneration.
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- 2004
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208. Electrophysiologic Testing in Disorders of the Retina, Optic Nerve, and Visual Pathway
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Hébert, Marc and MacDonald, Ian M.
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- 2001
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209. Complications in Ophthalmic SurgerySecond edition. Theodore Krupin, Allan E. Kolker and Lisa F. Rosenberg. Mosby, Inc., St. Louis. Available through Harcourt Canada Ltd., Toronto. 464 pages. $313.
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MacDonald, Ian M.
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- 2000
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210. Linking Genetic Duplications to Choroideremia Pathology.
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Chi, Jonathan Y., MacDonald, Ian M., and Hume, Stacey
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DEGENERATION (Pathology) , *VITAMIN A , *BIOCHEMICAL genetics , *PERIPHERAL vision , *BLINDNESS , *VISION disorders - Abstract
Introduction. Choroideremia is an X-linked progressive chorioretinal degenerative disease that affects 1 in 50,000 males. Clinically, patients with choroideremia present with nightblindness and progressive loss of peripheral vision; however, typically central vision and colour vision is maintained. Choroideremia arises from a dysfunctional Rab escort protein-1 (REP-1) which is encoded by the CHM gene. The absence of REP-1 in the eye, results in the gradual degeneration of the retina, retinal pigment epithelium, and choroid causing the ocular manifestations common in affected individuals. The exact pathogenesis, however, has yet to be determined. Through genetic studies, we have determined that choroideremia can arise from deletions in the CHM gene but deletions alone do not account for all cases of choroideremia. Our study delves into the biochemical genetics of the CHM gene to determine whether other genetic mutations such as copy number variants play a role in choroideremia pathogenesis. Methods. We designed a multiplex ligation-dependent probe amplification (MLPA) assay kit for the detection of copy number variants in the CHM gene. Using our MLPA assay kit, we tested the DNA of several choroideremia patients that screened negative for genetic deletions in their CHM gene. Results. A duplication of several consecutive exons of the CHM gene was determined in one particular patient DNA sample. Discussion. Prior to this study, only deletions in the CHM gene have been linked to choroideremia pathology. The duplication in the CHM gene observed in this study represents a novel pathological mutation and potentially a novel mechanism of pathogenesis. We hope that this discovery will help us further understand the pathogenesis of choroideremia. [ABSTRACT FROM AUTHOR]
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- 2011
211. Eyeing a New Network.
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MacDonald, Ian M., Brooks, Brian P., and Sieving, Paul A.
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LETTERS to the editor , *HEALTH care networks - Abstract
A letter to the editor is presented in response to the article "Reestablishing the researchers-patient compact," by I. S. Kohane and colleagues in the May 11, 2007 issue.
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- 2007
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212. Diplopia after Cataract Surgery
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MacDonald, Ian M., Wakeman, Bradley J., and Reed, George F.
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- 2006
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213. ErnestSmallCatlingPaul M.Canadian Medicinal Crops1999NRC Research PressOttawa240 pages. $29.95
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MacDonald, Ian M.
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- 2000
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214. Color Vision: From Genes to PerceptionEdited by Karl R. Gegenfurtner and Lindsay T. Sharpe. Cambridge University Press, Cambridge, UK. 492 pages. US$100.
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Hébert, Marc and MacDonald, Ian M.
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- 2000
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215. World Atlas Series of Ophthalmic SurgeryBoydBenjamin F.International editionHighlights of OphthalmologyVolume I1993Panama City, Panama. 285 pages. US$95. Four-volume set US$475
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MacDonald, Ian M.
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- 2000
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216. Zebrafish and inherited photoreceptor disease: Models and insights.
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Noel, Nicole C.L., Allison, W.Ted, MacDonald, Ian M., and Hocking, Jennifer C.
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RETINAL degeneration , *RETINA , *FISHES , *PHOTORECEPTORS , *VISUAL acuity , *ANIMALS - Abstract
Photoreceptor dysfunctions and degenerative diseases are significant causes of vision loss in patients, with few effective treatments available. Targeted interventions to prevent or reverse photoreceptor-related vision loss are not possible without a thorough understanding of the underlying mechanism leading to disease, which is exceedingly difficult to accomplish in the human system. Cone diseases are particularly challenging to model, as some popular genetically modifiable model animals are nocturnal with a rod-dominant visual system and cones that have dissimilarities to human cones. As a result, cone diseases, which affect visual acuity, colour perception, and central vision in patients, are generally poorly understood in terms of pathology and mechanism. Zebrafish (Danio rerio) provide the opportunity to model photoreceptor diseases in a diurnal vertebrate with a cone-rich retina which develops many macular degeneration-like pathologies. Zebrafish undergo external development, allowing early-onset retinal diseases to be detected and studied, and many ophthalmic tools are available for zebrafish visual assessment during development and adulthood. There are numerous zebrafish models of photoreceptor disease, spanning the various types of photoreceptor disease (developmental, rod, cone, and mixed photoreceptor diseases) and genetic/molecular cause. In this review, we explore the features of zebrafish that make them uniquely poised to model cone diseases, summarize the established zebrafish models of inherited photoreceptor disease, and discuss how disease in these models compares to the human presentation, where applicable. Further, we highlight the contributions of these zebrafish models to our understanding of photoreceptor biology and disease, and discuss future directions for utilising and investigating these diverse models. [ABSTRACT FROM AUTHOR]
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- 2022
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217. The [formula omitted] values of Canadian Shield brines and fracture minerals with applications to groundwater mixing, fracture history, and geochronology
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McNutt, Robert H, Frape, Shaun K, Fritz, Peter, Jones, Michael G, and MacDonald, Ian M
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- 1990
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218. PRIVATE HEALTH CARE SERVICES.
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MacDonald, Ian M.
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- 1995
219. Canadian Medicinal Crops, Ernest Small, Catling Paul M.. NRC Research Press (1999)
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MacDonald, Ian M.
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- 2000
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220. Communicating the Promise for Ocular Gene Therapies: Challenges and Recommendations.
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Benjaminy, Shelly, Kowal, Stephanie P., MacDonald, Ian M., and Bubela, Tania
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Purpose: To identify challenges and pose solutions for communications about ocular gene therapy between patients and clinicians as clinical research progresses. Design: Literature review with recommendations. Methods: Literature review of science communication best practices to inform recommendations for patient-clinician discussions about ocular gene therapy. Results: Clinicians need to employ communications about ocular gene therapy that are both attentive to patient priorities and concerns and responsive to other sources of information, including overly positive news media and the Internet. Coverage often conflates research with therapy--clinical trials are experimental and are not risk free. If proven safe and efficacious, gene therapy may present a treatment but not a cure for patients who have already experienced vision loss. Clinicians can assist patients by providing realistic estimates for lengthy clinical development timelines and positioning current research within models of clinical translation. This enables patients to weigh future therapeutic options when making current disease management decisions. Conclusions: Ocular gene therapy clinical trials are raising hopes for treating a myriad of hereditary retinopathies, but most such therapies are many years in the future. Clinicians should be prepared to counter overly positive messaging, found in news media and on the Internet, with optimism tempered by evidence to support the ethical translation of gene therapy and other novel biotherapeutics. [ABSTRACT FROM AUTHOR]
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- 2015
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221. Choroideremia: Towards a Therapy.
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KALATZIS, VASILIKI, HAMEL, CHRISTIAN P., and MACDONALD, IAN M.
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RETINAL degeneration , *GENE therapy , *OPHTHALMOLOGICAL therapeutics , *PATHOLOGICAL physiology , *RETINAL diseases ,MEDICAL literature reviews - Abstract
PURPOSE: To review what progress has been made towards the application of ocular gene therapy to prevent progressive vision loss in patients affected by choroideremia. DESIGN: A Perspective based on the collective opinions of researchers and clinicians actively engaged in vision research on choroideremia and a review of current literature. METHODS: Researchers from Europe, Canada, Australia, and the United States were convened to the first International Choroideremia Research Symposium held in Sommie`res, France in September 2011. Attendees shared their collective understanding of the pathophysiology of choroideremia and current trends in the development of treatments, with an emphasis on the potential of gene therapy as an achievable approach. Supplemental perspectives are provided along with an update of progress made since the meeting. RESULTS: The complexity of treating a retinal disease such as choroideremia that affects multiple tissue layers has been brought to light. The genetic basis of choroideremia must be thoroughly deciphered and appropriate clinical tests selected to follow disease progression and evaluate the efficiency of treatments. CONCLUSIONS: Whereas the time frame for the development of therapies for some retinal dystrophies may be in the years hence, gene therapy trials for choroideremia have started in the United Kingdom and results are pending. These first trials may help resolve the remaining issues associated with the treatment of this disease. [ABSTRACT FROM AUTHOR]
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- 2013
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222. The use of lymphocytes to screen for oxidative phosphorylation disorders
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Marriage, Barbara J., Thomas Clandinin, M., MacDonald, Ian M., and Moira Glerum, D.
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PHOSPHORYLATION , *LYMPHOCYTES - Abstract
Biochemical analysis of oxidative phosphorylation (OXPHOS) disorders is traditionally carried out on muscle biopsies, cultured fibroblasts, and transformed lymphocytes. Here we present a new screening technique using lymphocytes to identify OXPHOS dysfunction and initially avoid an invasive diagnostic procedure. Lymphocytes represent an easily obtainable source of tissue that presents advantages over the use of fibroblasts or lymphoblast cell lines. The time delay in culturing skin fibroblasts and the interactions between cell transformation and mitochondrial activity are avoided in this methodology. The method requires a small amount of blood (
< 5 mL); can be completed in a few hours, and allows for repeated measurements. Our assay has been adapted from published methods utilizing cultured fibroblasts and transformed lymphocytes, and our data suggest that measurement of ATP synthesis in lymphocytes is an effective screening tool for diagnosing OXPHOS disorders. This method may also provide an objective tool for monitoring response to treatment and evaluating progression of disease. [Copyright &y& Elsevier]- Published
- 2003
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223. Severe retinal degeneration in a patient with Canavan disease.
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Benson, Matthew D., Plemel, David J.A., Freund, Paul R., Lewis, James R., Sass, Jörn Oliver, Bähr, Luzy, Gemperle-Britschgi, Corinne, Ferreira, Patrick, and MacDonald, Ian M.
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RETINAL degeneration , *RECESSIVE genes , *JUVENILE diseases , *RETINITIS pigmentosa , *CENTRAL nervous system , *ANIMAL disease models , *DYSTROPHY - Abstract
Background: Canavan disease is an autosomal recessive, neurodegenerative disorder caused by mutations in ASPA, a gene encoding the enzyme aspartoacylase. Patients present with macrocephaly, developmental delay, hypotonia, vision impairment and accumulation of N-acetylaspartic acid. Progressive white matter changes occur in the central nervous system. The disorder is often fatal in early childhood, but milder forms exist. Materials and methods: Case report. Results: We present the case of a 31-year-old male with mild/juvenile Canavan disease who had severe vision loss due to a retinal degeneration resembling retinitis pigmentosa. Prior to this case, vision loss in Canavan disease had been attributed to optic atrophy based on fundoscopic evidence of optic nerve pallor. Investigations for an alternative cause for our patient's retinal degeneration were non-revealing. Conclusion: We wonder if retinal degeneration may not have been previously recognized as a feature of Canavan disease. We highlight findings from animal models of Canavan disease to further support the association between Canavan disease and retinal degeneration. [ABSTRACT FROM AUTHOR]
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- 2021
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224. Combination Treatment with Rituximab and Bortezomib in a Patient with Non-Paraneoplastic Autoimmune Retinopathy.
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Benson, Matthew D., Plemel, David J. A., Yacyshyn, Elaine, Sandhu, Irwindeep, MacDonald, Ian M., and Baker, Chad F.
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BORTEZOMIB , *RITUXIMAB , *OPTICAL coherence tomography , *SERODIAGNOSIS , *RETINAL degeneration , *AUTOANTIBODIES , *RETINA , *PERIMETRY , *COMBINATION drug therapy , *PARANEOPLASTIC syndromes , *VISUAL fields , *AUTOIMMUNE diseases , *IMMUNOLOGICAL adjuvants , *RETINAL diseases , *ELECTRORETINOGRAPHY , *LONGITUDINAL method - Abstract
Purpose: To describe outcomes of combined rituximab and bortezomib treatment for non-paraneoplastic autoimmune retinopathy.Case: A 37-year-old female developed photopsias and reduced vision. Electroretinography, optical coherence tomography, and positive serum anti-retinal antibodies were consistent with autoimmune retinopathy. A negative malignancy work-up specified her non-paraneoplastic presentation. Given absence of response to periocular steroids, azathioprine, and methotrexate, a combination of rituximab and bortezomib was initiated as fifth-line therapy.Results: There was no significant improvement in the patient's symptoms or visual function following treatment. The full field electroretinogram amplitudes were reduced with progressive outer retinal degeneration evident on optical coherence tomography. Post-treatment anti-retinal antibody testing demonstrated the persistence of antibodies and revealed additional antibodies not previously detected.Conclusion: Combined rituximab and bortezomib treatment did not result in significant clinical improvement and there was evidence of disease progression. Further prospective studies are required to assess the efficacy of immunotherapy in patients with autoimmune retinopathy. [ABSTRACT FROM AUTHOR]- Published
- 2020
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225. A novel SVA retrotransposon insertion in the CHM gene results in loss of REP-1 causing choroideremia.
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Jones, Kaylie D., Radziwon, Alina, Birch, David G., and MacDonald, Ian M.
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LYMPHOBLASTOID cell lines , *RNA analysis , *GENETIC mutation , *RETINAL degeneration , *RHODOPSIN - Abstract
Choroideremia is an X-linked retinal disease characterized by progressive atrophy of the choroid and retinal pigment epithelium caused by mutations in the CHM gene. SVA (SINE-R/VNTR/Alu) elements are a type of non-autonomous retrotransposon that occasionally self-replicate, reinsert randomly into a gene, and cause disease. Intragenic SVA insertions have been reported as the mechanism underlying a number of diseases including a syndromic form of retinal dystrophy, but have never been found in CHM. Here we identified and characterized a novel hemizygous SVA insertion, c.97_98inSVA (p.Arg33insSVA), in exon 2 of CHM in a male choroideremia patient. The SVA insertion's impact was evaluated by establishing a patient-derived lymphoblastoid cell line as a source of RNA for mRNA analysis of the CHM transcript, and protein for immunoblot analysis of Rab Escort Protein 1 (REP-1). Immunoblot analysis revealed the absence of REP-1 protein, while a smaller than expected PCR product was amplified from cDNA. Sequencing of this PCR product showed skipping of exon 2, denoted r.50_116del. Ophthalmic examination including psychophysical tests, visual electrophysiology, and fundus imaging showed the patient's phenotype was consistent with severe early manifestations of choroideremia. This case is the first report of a SVA insertion in the CHM gene causing choroideremia. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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226. Severe retinal degeneration in a patient with Canavan disease
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David J.A. Plemel, Paul R. Freund, Corinne Gemperle-Britschgi, Matthew D. Benson, Jörn Oliver Sass, Luzy Bahr, Ian M. MacDonald, Patrick Ferreira, James R. Lewis, University of Zurich, and MacDonald, Ian M
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Retinal degeneration ,Adult ,Male ,Pathology ,medicine.medical_specialty ,N-Acetylaspartic acid ,2716 Genetics (clinical) ,Canavan Disease ,610 Medicine & health ,Pediatrics ,chemistry.chemical_compound ,medicine ,Humans ,Genetics(clinical) ,2735 Pediatrics, Perinatology and Child Health ,Gene ,Genetics (clinical) ,medicine.diagnostic_test ,business.industry ,Retinal Degeneration ,Macrocephaly ,medicine.disease ,Prognosis ,2731 Ophthalmology ,Perinatology ,Canavan disease ,Aspartoacylase ,and Child Health ,Ophthalmology ,chemistry ,10036 Medical Clinic ,Pediatrics, Perinatology and Child Health ,medicine.symptom ,business ,Electroretinography - Abstract
Background: Canavan disease is an autosomal recessive, neurodegenerative disorder caused by mutations in ASPA, a gene encoding the enzyme aspartoacylase. Patients present with macrocephaly, develop...
- Published
- 2021
227. Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics
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Ymkje M. Hettinga, Karsten Hufendiek, Jacek P. Szaflik, Ian M. MacDonald, Isabelle Meunier, Marcela D. Mena, Kaoru Fujinami, Mubeen Khan, Eyal Banin, Elfride De Baere, G. Jane Farrar, Adrian Dockery, Rianne Miller, Tamar Ben-Yosef, Manar Salameh, L. Ingeborgh van den Born, Anna M Tracewska, Sandro Banfi, Caroline C W Klaver, John N. De Roach, Carmen Ayuso, Sabine Defoort, Damjan Glavač, Ulrich Kellner, Juliana Maria Ferraz Sallum, Claire-Marie Dhaenens, Stéphanie S. Cornelis, Bernhard H. F. Weber, Klaus Rüther, Jennifer A. Thompson, Bernard Puech, Raj Ramesar, Aurore Devos, Lisa Roberts, Herbert Jägle, Osvaldo L. Podhajcer, Hadas Newman, Bohdan Kousal, Femke Bults, Marta Del Pozo-Valero, Marc Pieterse, Laura Whelan, Xavier Zanlonghi, Alaa AlTalbishi, Francesca Simonelli, Marloes Steehouwer, Caroline Thuillier, Frans P.M. Cremers, Andrea L Vincent, Smaragda Kamakari, Ana Fakin, Anna Matynia, Dror Sharon, Ketan Mishra, Mariana Vallim Salles, Heidi Stöhr, Miriam Bauwens, Petra Liskova, Esmee H. Runhart, Buhle Ntozini, Georg Spital, Carel B. Hoyng, Takaaki Hayashi, Terri L. McLaren, Martine van Zweeden, Lubica Dudakova, Camiel J. F. Boon, Christian Gilissen, Jacquie Greenberg, Monika Ołdak, Tina M. Lamey, Yahya AlSwaiti, Alexander Hoischen, Marianthi Karali, Michael B. Gorin, Ophthalmology, ANS - Complex Trait Genetics, Khan, Mubeen, Cornelis, Stéphanie S, Pozo-Valero, Marta Del, Whelan, Laura, Runhart, Esmee H, Mishra, Ketan, Bults, Femke, Alswaiti, Yahya, Altalbishi, Alaa, De Baere, Elfride, Banfi, Sandro, Banin, Eyal, Bauwens, Miriam, Ben-Yosef, Tamar, Boon, Camiel J F, van den Born, L Ingeborgh, Defoort, Sabine, Devos, Aurore, Dockery, Adrian, Dudakova, Lubica, Fakin, Ana, Farrar, G Jane, Sallum, Juliana Maria Ferraz, Fujinami, Kaoru, Gilissen, Christian, Glavač, Damjan, Gorin, Michael B, Greenberg, Jacquie, Hayashi, Takaaki, Hettinga, Ymkje M, Hoischen, Alexander, Hoyng, Carel B, Hufendiek, Karsten, Jägle, Herbert, Kamakari, Smaragda, Karali, Marianthi, Kellner, Ulrich, Klaver, Caroline C W, Kousal, Bohdan, Lamey, Tina M, Macdonald, Ian M, Matynia, Anna, Mclaren, Terri L, Mena, Marcela D, Meunier, Isabelle, Miller, Rianne, Newman, Hada, Ntozini, Buhle, Oldak, Monika, Pieterse, Marc, Podhajcer, Osvaldo L, Puech, Bernard, Ramesar, Raj, Rüther, Klau, Salameh, Manar, Salles, Mariana Vallim, Sharon, Dror, Simonelli, Francesca, Spital, Georg, Steehouwer, Marloe, Szaflik, Jacek P, Thompson, Jennifer A, Thuillier, Caroline, Tracewska, Anna M, van Zweeden, Martine, Vincent, Andrea L, Zanlonghi, Xavier, Liskova, Petra, Stöhr, Heidi, Roach, John N De, Ayuso, Carmen, Roberts, Lisa, Weber, Bernhard H F, Dhaenens, Claire-Marie, and Cremers, Frans P M
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DEEP-INTRONIC VARIANTS ,Proband ,smMIP ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,ABCA4 ,RPE65 ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] ,Macular Degeneration ,Exon ,0302 clinical medicine ,Missing heritability problem ,purl.org/becyt/ford/3.2 [https] ,Medicine and Health Sciences ,smMIPs ,MUTATION ,Genetics (clinical) ,Genetics ,variants ,0303 health sciences ,structural ,biology ,Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] ,Genomics ,DYSTROPHY ,Pedigree ,3. Good health ,Stargardt disease ,MATERNAL UNIPARENTAL ISODISOMY ,purl.org/becyt/ford/3 [https] ,RETINAL ,CHROMOSOME-1 ,PATIENT ,STRUCTURAL VARIANTS ,Deep sequencing ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,deep-intronic variants ,REVEALS ,medicine ,Humans ,030304 developmental biology ,REPAIR ,deep-intronic variant ,structural variants ,medicine.disease ,GENE ,Introns ,Uniparental Isodisomy ,Mutation ,030221 ophthalmology & optometry ,biology.protein ,ATP-Binding Cassette Transporters ,Transcriptome - Abstract
Purpose: Missing heritability in human diseases represents a major challenge, and this is particularly true for ABCA4-associated Stargardt disease (STGD1). We aimed to elucidate the genomic and transcriptomic variation in 1054 unsolved STGD and STGD-like probands. Methods: Sequencing of the complete 128-kb ABCA4 gene was performed using single-molecule molecular inversion probes (smMIPs), based on a semiautomated and cost-effective method. Structural variants (SVs) were identified using relative read coverage analyses and putative splice defects were studied using in vitro assays. Results: In 448 biallelic probands 14 known and 13 novel deep-intronic variants were found, resulting in pseudoexon (PE) insertions or exon elongations in 105 alleles. Intriguingly, intron 13 variants c.1938-621G>A and c.1938-514G>A resulted in dual PE insertions consisting of the same upstream, but different downstream PEs. The intron 44 variant c.6148-84A>T resulted in two PE insertions and flanking exon deletions. Eleven distinct large deletions were found, two of which contained small inverted segments. Uniparental isodisomy of chromosome 1 was identified in one proband. Conclusion: Deep sequencing of ABCA4 and midigene-based splice assays allowed the identification of SVs and causal deep-intronic variants in 25% of biallelic STGD1 cases, which represents a model study that can be applied to other inherited diseases. Fil: Khan, Mubeen. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Cornelis, Stéphanie S.. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Del Pozo Valero, Marta. Hospital Universitario Fundación Jiménez Díaz; España. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Whelan, Laura. Trinity College; Estados Unidos Fil: Runhart, Esmee H.. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Mishra, Ketan. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Bults, Femke. Radboud University Nijmegen Medical Centre; Países Bajos Fil: AlSwaiti, Yahya. St John of Jerusalem Eye Hospital Group; Palestina (ANP) Fil: AlTalbishi, Alaa. St John of Jerusalem Eye Hospital Group; Palestina (ANP) Fil: De Baere, Elfride. University of Ghent; Bélgica Fil: Banfi, Sandro. Seconda Universita Degli Studi Di Napoli; Italia Fil: Banin, Eyal. The Hebrew University of Jerusalem; Israel Fil: Bauwens, Miriam. University of Ghent; Bélgica Fil: Ben Yosef, Tamar. The Ruth And Bruce Rappaport Faculty Of Medicine; Israel Fil: Boon, Camiel J. F.. Leiden University. Leiden University Medical Center; Países Bajos Fil: van den Born, L. Ingeborgh. Rotterdam Ophthalmic Institute; Países Bajos Fil: Defoort, Sabine. Universite Lille; Francia Fil: Devos, Aurore. Universite Lille; Francia Fil: Dockery, Adrian. Trinity College; Estados Unidos Fil: Dudakova, Lubica. Charles University and General University Hospital; República Checa Fil: Fakin, Ana. Charles University and General University Hospital; República Checa Fil: Farrar, G. Jane. Trinity College; Estados Unidos Fil: Ferraz Sallum, Juliana Maria. Universidade Federal de Sao Paulo; Brasil Fil: Fujinami, Kaoru. UCL Institute of Ophthalmology; Reino Unido Fil: Gilissen, Christian. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Glavac, Damjan. University of Ljubljana; Eslovenia Fil: Gorin, Michael B.. University of California at Los Angeles. School of Medicine; Estados Unidos Fil: Greenberg, Jacquie. University of Cape Town; Sudáfrica Fil: Hayashi, Takaaki. The Jikei University School of Medicine; Japón Fil: Hettinga, Ymkje M.. Bartiméus Diagnostic Center for Complex Visual Disorders; Países Bajos Fil: Hoischen, Alexander. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Hoyng, Carel B.. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Hufendiek, Karsten. University Eye Hospital Hannover Medical School; Alemania Fil: Jägle, Herbert. University Regensburg; Alemania Fil: Kamakari, Smaragda. OMMA Ophthalmological Institute of Athens; Grecia Fil: Karali, Marianthi. Seconda Universita Degli Studi Di Napoli; Italia Fil: Kellner, Ulrich. No especifíca; Fil: Klaver, Caroline C. W.. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Kousal, Bohdan. Charles University and General University Hospital; República Checa Fil: Lamey, Tina M.. University of Western Australia; Australia Fil: MacDonald, Ian M.. University of Alberta; Canadá Fil: Matynia, Anna. University of California at Los Angeles. School of Medicine; Estados Unidos Fil: McLaren, Terri L.. University of Western Australia; Australia Fil: Mena, Marcela D.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Meunier, Isabelle. Université Montpellier II; Francia Fil: Miller, Rianne. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Newman, Hadas. Universitat Tel Aviv; Israel Fil: Ntozini, Buhle. University of Cape Town; Sudáfrica Fil: Oldak, Monika. No especifíca; Fil: Pieterse, Marc. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Podhajcer, Osvaldo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Puech, Bernard. Universite Lille; Francia Fil: Ramesar, Raj. University of Cape Town; Sudáfrica Fil: Rüther, Klaus. No especifíca; Fil: Salameh, Manar. No especifíca; Fil: Salles, Mariana Vallim. Universidade de Sao Paulo; Brasil Fil: Sharon, Dror. The Hebrew University of Jerusalem; Israel Fil: Simonelli, Francesca. Seconda Universita Degli Studi Di Napoli; Italia Fil: Spital, Georg. No especifíca; Fil: Steehouwer, Marloes. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Szaflik, Jacek P.. No especifíca; Fil: Thompson, Jennifer A.. No especifíca; Fil: Thuillier, Caroline. Universite Lille; Francia Fil: Tracewska, Anna M.. No especifíca; Fil: van Zweeden, Martine. Radboud University Nijmegen Medical Centre; Países Bajos Fil: Vincent, Andrea L.. University of Auckland; Nueva Zelanda Fil: Zanlonghi, Xavier. No especifíca; Fil: Liskova, Petra. Charles University and General University Hospital; República Checa Fil: Stöhr, Heidi. Universitat Regensburg; Alemania Fil: De Roach, John N.. University of Western Australia; Australia Fil: Ayuso, Carmen. Hospital Universitario Fundación Jiménez Díaz; España Fil: Roberts, Lisa. University of Cape Town; Sudáfrica Fil: Weber, Bernhard H. F.. Universitat Regensburg; Alemania Fil: Dhaenens, Claire Marie. Universite Lille; Francia Fil: Cremers, Frans P. M.. Radboud University Nijmegen Medical Centre; Países Bajos
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- 2020
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228. An internet-based health survey on the co-morbidities of choroideremia patients.
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Zhou, Qi, Weis, Ekekiel, Ye, Ming, Benjaminy, Shelly, and MacDonald, Ian M
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- *
EYE diseases , *VISION disorders , *CHOROID , *DRY eye syndromes , *CATARACT , *HYPERCHOLESTEREMIA , *WOUNDS & injuries - Abstract
Purpose To examine the prevalence of systemic and ocular disease among choroideremia patients and carriers. Methods A cross-sectional analysis was performed on responses from affected males with choroideremia, female carriers, and unaffected brothers to an Internet-based survey made available from September 2009 to November 2010. Affected males were classified into two groups, those with or without functional vision. Carrier females were classified into those with and without symptoms. Comparisons were made between these groups. Results There was a higher prevalence of dry eye in our respondents than the North American population. The prevalence of dry eye, cataract, hypertension, diabetes, psychological problems and hypercholesterolemia were higher in choroideremia males without functional vision compared to those with functional vision. Likewise, statin intake was more prevalent among the affected males without functional vision than those with functional vision. After age adjustment, any differences between the two subgroups of male patients (with and without functional vision) were not significant. Conclusion Age plays an important role in determining the onset of severe visual impairment with loss of functional vision in male subjects affected by choroideremia. Although Internet surveys have limitations such as the use of self-reported diagnoses and the possibility that the responses may not be representative of the population as a whole, this study shows that such surveys can provide data quickly and easily, and for rare diseases such as choroideremia, with relatively large numbers of responses. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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229. A Mutation in SLC24A1 Implicated in Autosomal-Recessive Congenital Stationary Night Blindness
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Riazuddin, S. Amer, Shahzadi, Amber, Zeitz, Christina, Ahmed, Zubair M., Ayyagari, Radha, Chavali, Venkata R.M., Ponferrada, Virgilio G., Audo, Isabelle, Michiels, Christelle, Lancelot, Marie-Elise, Nasir, Idrees A., Zafar, Ahmad U., Khan, Shaheen N., Husnain, Tayyab, Jiao, Xiaodong, MacDonald, Ian M., Riazuddin, Sheikh, Sieving, Paul A., Katsanis, Nicholas, and Hejtmancik, J. Fielding
- Subjects
- *
GENETIC mutation , *NIGHT blindness , *RETINAL diseases , *RETINAL ganglion cells , *IMMUNOHISTOCHEMISTRY , *LABORATORY mice - Abstract
Congenital stationary night blindness (CSNB) is a nonprogressive retinal disorder that can be associated with impaired night vision. The last decade has witnessed huge progress in ophthalmic genetics, including the identification of three genes implicated in the pathogenicity of autosomal-recessive CSNB. However, not all patients studied could be associated with mutations in these genes and thus other genes certainly underlie this disorder. Here, we report a large multigeneration family with five affected individuals manifesting symptoms of night blindness. A genome-wide scan localized the disease interval to chromosome 15q, and recombination events in affected individuals refined the critical interval to a 10.41 cM (6.53 Mb) region that harbors SLC24A1, a member of the solute carrier protein superfamily. Sequencing of all the coding exons identified a 2 bp deletion in exon 2: c.1613_1614del, which is predicted to result in a frame shift that leads to premature termination of SLC24A1 (p.F538CfsX23) and segregates with the disorder under an autosomal-recessive model. Expression analysis using mouse ocular tissues shows that Slc24a1 is expressed in the retina around postnatal day 7. In situ and immunohistological studies localized both SLC24A1 and Slc24a1 to the inner segment, outer and inner nuclear layers, and ganglion cells of the retina, respectively. Our data expand the genetic basis of CSNB and highlight the indispensible function of SLC24A1 in retinal function and/or maintenance in humans. [ABSTRACT FROM AUTHOR]
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- 2010
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230. Electrophysiologic and phenotypic features of an autosomal cone-rod dystrophy caused by a novel CRX mutation.
- Author
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Lines, Matthew A., Hébert, Marc, McTaggart, Kerry E., Flynn, Sarah J., Tennant, Matthew T., and MacDonald, Ian M.
- Subjects
- *
EYE abnormalities , *ELECTRORETINOGRAPHY , *MOLECULAR genetics , *DYSTROPHY - Abstract
: PurposeTo reexamine a large Albertan family previously reported with a progressive cone dystrophy with variable phenotype and to map the disorder using molecular genetic techniques.: DesignObservational case series.: ParticipantsTwenty-nine subjects (10 affected) from four generations of a large kindred were clinically examined. Twenty-three of these individuals, as well as two unaffected spouses, were included in the molecular genetic study. Subject ages ranged from 17 to 91 years of age.: MethodsDisease status and associated ocular abnormalities were assessed primarily by measurement of visual acuity, color vision, fundus photography, and both full-field and multifocal electroretinography (ERG and mfERG). Linkage of the disorder to the rhodopsin gene was studied using microsatellites. A mutational screen of the CRX gene was performed to identify coding sequence changes.: Main outcome measuresVisual acuity and color discrimination were reduced in clinically affected individuals; full-field flash ERG was used to measure function of both cones and rods. mfERG and fundus photography allowed documentation of the observed macular changes.: ResultsWe noted a variable, adult-onset macular dystrophy, progressing in some cases to a retinitis pigmentosa-like phenotype. Both photopic and scotopic full-field ERG amplitudes were reduced by approximately 50%, demonstrating involvement of both photoreceptor systems. A reduced b-wave amplitude with a relatively preserved a-wave was observed at both cone and rod levels. Macular involvement was confirmed by mfERG. The rhodopsin locus was excluded by haplotype analysis. A novel frameshift mutation was detected in exon III of the CRX retinal homeobox gene. ERG and molecular genetic findings were consistent with the reclassification of this disease as an autosomal dominant cone-rod dystrophy (CRD): ConclusionsWe report a novel CRX mutation causing autosomal dominant CRD. Observed ERG changes suggest that this mutation primarily impairs inner retinal function. Because retinal expression of CRX is limited to photoreceptors, this dysfunction may be the result of faulty photoreceptor communication with second-order retinal neurons. We propose misexpression of gated cation channels caused by altered CRX activity as one putative mechanism by which a sole photoreceptor defect may selectively impair neurotransmission without disrupting the upstream events of phototransduction. [Copyright &y& Elsevier]
- Published
- 2002
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231. Macular Pigment and Lutein Supplementation in Choroideremia
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Duncan, Jacque L., Aleman, Tomas S., Gardner, Leigh M., De Castro, Elaine, Marks, Daniel A., Emmons, Jessica M., Bieber, Michelle L., Steinberg, Janet D., Bennett, Jean, Stone, Edwin M., MacDonald, Ian M., Cideciyan, Artur V., Maguire, Maureen G., and Jacobson, Samuel G.
- Subjects
- *
RETINAL degeneration , *CAROTENOIDS , *BIOLOGICAL pigments - Abstract
Choroideremia is an incurable X-linked retinal degeneration caused by mutations in the gene encoding Rab escort protein-1. A group of clinically defined and genotyped patients were studied to determine: (1) the degree of rod and cone dysfunction and structural abnormality in the central retina and the level of macular pigment; and (2) the response of macular pigment and foveal vision to a 6month trial of supplementation with oral lutein (at 20 mg per day). Rod and cone-mediated function was measured with dark-adapted static perimetry; in vivo retinal structure was determined with optical coherence tomography; and macular pigment optical density was measured with heterochromatic flicker photometry. In this cohort of patients (ages 15–65 years), both rod- and cone-mediated central function declined with age as did central retinal thickness. Macular pigment levels did not differ between patients and male control subjects. Supplementation of oral lutein in a subset of patients led to an increase in serum lutein and macular pigment levels; absolute foveal sensitivity did not change. It is concluded that macular pigment density can be augmented by oral intake of lutein in patients with choroideremia. There was no short-term change in the central vision of the patients on the supplement, but long-term influences of lutein supplementation on disease natural history warrant further study. [ABSTRACT FROM AUTHOR]
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- 2002
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232. Breaking bad news in ophthalmology: a pilot skills workshop for residents.
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Papp KM and MacDonald IM
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- Humans, Pilot Projects, Education, Medical, Graduate methods, Male, Communication, Female, Education methods, Alberta, Ophthalmology education, Internship and Residency, Truth Disclosure, Clinical Competence, Physician-Patient Relations
- Abstract
Objective: To design and implement a formal skills workshop for ophthalmology residents to practice breaking bad news., Methods: A 2-session workshop was developed for 7 ophthalmology residents at the University of Alberta based on a workshop published by Ohio State University. Residents discussed the SPIKES protocol for breaking bad news, practiced mock cases with standardized patients, and listened to shared experiences from patients who had received ocular diagnoses., Results: All the residents (n = 6; p = 0.03) at the University of Alberta reported an increase in confidence in 3 measures of an encounter in which they had to break bad news, one of which shared the significant improvement reported by the Ohio State group (n = 9; p = 0.01): setting realistic expectations without destroying hope. Standardized patients discussed their satisfaction with their case training and suggested the provision of eye models or printouts to enhance the realism in the examination rooms. The University of Alberta workshop results replicated those from Ohio State in that the SPIKES lecture and standardized patient session were ranked highly in efficacy (median, 4 of 5). The University of Alberta panel discussion was ranked lower than at Ohio State University, which may have resulted from 1 of 2 patient guest speakers being unexpectedly unable to attend., Conclusion: The pilot Breaking Bad News Workshop was well received overall and may serve to inform future incorporation of soft skills development in a formal residency curriculum., (Copyright © 2023 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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233. Pleiotropy in FOXC1-attributable phenotypes involves altered ciliation and cilia-dependent signaling.
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Havrylov S, Chrystal P, van Baarle S, French CR, MacDonald IM, Avasarala J, Rogers RC, Berry FB, Kume T, Waskiewicz AJ, and Lehmann OJ
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- Humans, Animals, Mice, Hedgehog Proteins metabolism, Hedgehog Proteins genetics, Anterior Eye Segment abnormalities, Anterior Eye Segment metabolism, Anterior Eye Segment pathology, Receptor, Platelet-Derived Growth Factor alpha metabolism, Receptor, Platelet-Derived Growth Factor alpha genetics, Ciliopathies genetics, Ciliopathies metabolism, Ciliopathies pathology, Female, Male, Zinc Finger Protein Gli2 metabolism, Zinc Finger Protein Gli2 genetics, Mutation, Cilia metabolism, Cilia pathology, Forkhead Transcription Factors metabolism, Forkhead Transcription Factors genetics, Signal Transduction, Phenotype, Eye Abnormalities genetics, Eye Abnormalities pathology, Eye Abnormalities metabolism, Eye Diseases, Hereditary genetics, Eye Diseases, Hereditary metabolism, Eye Diseases, Hereditary pathology
- Abstract
Alterations to cilia are responsible for a wide range of severe disease; however, understanding of the transcriptional control of ciliogenesis remains incomplete. In this study we investigated whether altered cilia-mediated signaling contributes to the pleiotropic phenotypes caused by the Forkhead transcription factor FOXC1. Here, we show that patients with FOXC1-attributable Axenfeld-Rieger Syndrome (ARS) have a prevalence of ciliopathy-associated phenotypes comparable to syndromic ciliopathies. We demonstrate that altering the level of Foxc1 protein, via shRNA mediated inhibition, CRISPR/Cas9 mutagenesis and overexpression, modifies cilia length in vitro. These structural changes were associated with substantially perturbed cilia-dependent signaling [Hedgehog (Hh) and PDGFRα], and altered ciliary compartmentalization of the Hh pathway transcription factor, Gli2. Consistent with these data, in primary cultures of murine embryonic meninges, cilia length was significantly reduced in heterozygous and homozygous Foxc1 mutants compared to controls. Meningeal expression of the core Hh signaling components Gli1, Gli3 and Sufu was dysregulated, with comparable dysregulation of Pdgfrα signaling evident from significantly altered Pdgfrα and phosphorylated Pdgfrα expression. On the basis of these clinical and experimental findings, we propose a model that altered cilia-mediated signaling contributes to some FOXC1-induced phenotypes., (© 2024. The Author(s).)
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- 2024
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234. Pseudoxanthoma elasticum and retinitis pigmentosa in a patient with a novel mutation in the ABCC6 gene.
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Mishra AV, Martens R, and MacDonald IM
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- Female, Humans, Adult, Mutation, Fundus Oculi, Multidrug Resistance-Associated Proteins genetics, Pseudoxanthoma Elasticum complications, Pseudoxanthoma Elasticum diagnosis, Pseudoxanthoma Elasticum genetics, Angioid Streaks diagnosis, Angioid Streaks genetics, Retinitis Pigmentosa diagnosis, Retinitis Pigmentosa genetics
- Abstract
Background: Pseudoxanthoma elasticum (PXE) is an autosomal recessive condition caused by mutations in the ABCC6 gene. Ocular features include angioid streaks, peau d'orange fundus, and drusen. We report a novel ABCC6 mutation causing PXE in a patient with a mixed phenotype of PXE and retinitis pigmentosa (RP)., Case: A 37-year-old female presented with decreased peripheral vision and nyctalopia. Ocular imaging revealed angioid streaks emanating from the optic nerve as well as peripheral pigmentary changes and bone spicules. Genetic testing revealed two mutations in ABCC6 in trans. No other mutation was identified., Conclusion: We present a rare case with ocular findings of PXE and RP in a patient with a novel ABCC6 mutation. The patient presented both with peripheral pigmentary changes and angioid streaks. Further investigation into this novel mutation would be beneficial to determine if the mutation is involved in the RP phenotype.
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- 2024
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235. Overcoming the Challenges to Clinical Development of X-Linked Retinitis Pigmentosa Therapies: Proceedings of an Expert Panel.
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Birch DG, Cheetham JK, Daiger SP, Hoyng C, Kay C, MacDonald IM, Pennesi ME, and Sullivan LS
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- Humans, Mutation, Retina, Vision, Ocular, Eye Proteins genetics, Retinitis Pigmentosa diagnosis, Retinitis Pigmentosa genetics, Retinitis Pigmentosa therapy
- Abstract
X-linked retinitis pigmentosa (XLRP) is a rare inherited retinal disease manifesting as impaired night vision and peripheral vision loss that progresses to legal blindness. Although several trials of ocular gene therapy for XLRP have been conducted or are in progress, there is currently no approved treatment. In July 2022, the Foundation Fighting Blindness convened an expert panel to examine relevant research and make recommendations for overcoming the challenges and capitalizing on the opportunities in conducting clinical trials of RPGR-targeted therapy for XLRP. Data presented concerned RPGR structure and mutation types known to cause XLRP, RPGR mutation-associated retinal phenotype diversity, patterns in genotype/phenotype relationships, disease onset and progression from natural history studies, and the various functional and structural tests used to monitor disease progression. Panel recommendations include considerations, such as genetic screening and other factors that can impact clinical trial inclusion criteria, the influence of age on defining and stratifying participant cohorts, the importance of conducting natural history studies early in clinical development programs, and the merits and drawbacks of available tests for measuring treatment outcomes. We recognize the need to work with regulators to adopt clinically meaningful end points that would best determine the efficacy of a trial. Given the promise of RPGR-targeted gene therapy for XLRP and the difficulties encountered in phase III clinical trials to date, we hope these recommendations will help speed progress to finding a cure., Translational Relevance: Examination of relevant data and recommendations for the successful clinical development of gene therapies for RPGR-associated XLRP.
- Published
- 2023
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236. AAV2-Mediated Gene Therapy for Choroideremia: 5-Year Results and Alternate Anti-sense Oligonucleotide Therapy.
- Author
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Zhai Y, Xu M, Radziwon A, Dimopoulos IS, Crichton P, Mah R, MacLaren RE, Somani R, Tennant MT, and MacDonald IM
- Subjects
- Humans, Oligonucleotides, Antisense therapeutic use, Prospective Studies, Genetic Therapy methods, Retina, Retinal Pigment Epithelium metabolism, Tomography, Optical Coherence methods, Choroideremia diagnosis, Choroideremia genetics, Choroideremia therapy
- Abstract
Purpose: To assess the long-term safety and efficacy of AAV2-REP1 in choroideremia (CHM) patients, and to test a potential antisense oligonucleotide therapy for CHM., Design: Extended, prospective phase 1/2 clinical trial and laboratory investigation., Methods: Five patients who received a single subfoveal injection of AAV2-REP1 were studied. The long-term safety was evaluated by ophthalmic examination, spectral domain optical coherence tomography, and fundus autofluorescence (FAF) for up to 5 years. Functional and structural changes were determined by different test modalities. Four antisense oligonucleotides (ASOs) were designed to treat the CHM c.1245-521A>G mutation, which was present in 2 patients within this trial., Results: Subject P3 experienced a localized intraretinal immune response that resulted in a significant loss of preserved retinal pigment epithelium (RPE). P4 experienced an exacerbation of peripheral retinoschisis. P2 had a constant ≥15-letter best-corrected visual acuity (BCVA) gain in the treated eye, whereas P5 had ≥15-letter BCVA improvement once in the untreated eye. The preserved FAF areas declined more rapidly in the treated eyes compared to the untreated eyes (P = .043). A customized 25-mer ASO recovered 83.2% to 95.0% of the normal RNA and 57.5% of the normal protein in fibroblasts from 2 trial patients., Conclusions: Intraretinal inflammation triggered by AAV2-REP1 subretinal injection stabilized after 2 years but resulted in permanent damage to the retinal structure. Long-term progression of the disease was seen in both treated and untreated eyes, casting doubt as to the effectiveness of this approach in late-stage CHM. Alternative approaches such as ASO may have a therapeutic effect in a subgroup of CHM patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)
- Published
- 2023
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237. Upward saccadic intrusions as the presenting feature for incomplete congenital stationary night blindness.
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Aghazadeh H, MacDonald IM, and Jivraj I
- Subjects
- Male, Humans, Infant, Mutation, Electroretinography, Night Blindness congenital, Eye Diseases, Hereditary diagnosis, Myopia diagnosis, Genetic Diseases, X-Linked genetics, Ocular Motility Disorders, Retinal Dystrophies
- Abstract
We describe the case of a 9-month-old boy presenting with isolated intermittent vertical eye movements most in keeping with upward saccadic pulses, a form of saccadic intrusions. Full-field electroretinogram was consistent with a generalized retinal dystrophy, and genetic testing revealed a hemizygous pathogenic mutation in the CACNA1F gene, confirming the diagnosis of incomplete congenital stationary night blindness (iCSNB). This case describes vertical saccadic pulses as the sole presenting sign of a retinal dystrophy., (Copyright © 2022 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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238. The inner junction protein CFAP20 functions in motile and non-motile cilia and is critical for vision.
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Chrystal PW, Lambacher NJ, Doucette LP, Bellingham J, Schiff ER, Noel NCL, Li C, Tsiropoulou S, Casey GA, Zhai Y, Nadolski NJ, Majumder MH, Tagoe J, D'Esposito F, Cordeiro MF, Downes S, Clayton-Smith J, Ellingford J, Mahroo OA, Hocking JC, Cheetham ME, Webster AR, Jansen G, Blacque OE, Allison WT, Au PYB, MacDonald IM, Arno G, and Leroux MR
- Subjects
- Male, Animals, Humans, Cilia metabolism, Zebrafish genetics, Caenorhabditis elegans metabolism, Semen metabolism, Proteins metabolism, Ciliopathies genetics, Ciliopathies metabolism, Retinal Dystrophies
- Abstract
Motile and non-motile cilia are associated with mutually-exclusive genetic disorders. Motile cilia propel sperm or extracellular fluids, and their dysfunction causes primary ciliary dyskinesia. Non-motile cilia serve as sensory/signalling antennae on most cell types, and their disruption causes single-organ ciliopathies such as retinopathies or multi-system syndromes. CFAP20 is a ciliopathy candidate known to modulate motile cilia in unicellular eukaryotes. We demonstrate that in zebrafish, cfap20 is required for motile cilia function, and in C. elegans, CFAP-20 maintains the structural integrity of non-motile cilia inner junctions, influencing sensory-dependent signalling and development. Human patients and zebrafish with CFAP20 mutations both exhibit retinal dystrophy. Hence, CFAP20 functions within a structural/functional hub centered on the inner junction that is shared between motile and non-motile cilia, and is distinct from other ciliopathy-associated domains or macromolecular complexes. Our findings suggest an uncharacterised pathomechanism for retinal dystrophy, and potentially for motile and non-motile ciliopathies in general., (© 2022. The Author(s).)
- Published
- 2022
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239. Breaking Bad News in Eye Care.
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Papp KM, Gracie SK, and Macdonald IM
- Subjects
- Communication, Humans, Physician-Patient Relations, Truth Disclosure
- Published
- 2022
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240. Lessons learned from research on choroideremia.
- Author
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MacDonald IM
- Abstract
Having devoted over 35 years of my professional life to various projects on choroideremia (CHM), I began to reflect on the many lessons that I learned along the way. One of the most important is: we should pay careful attention to possible, unintended psychological harm in clinical research. This lesson was learned early and then reinforced when I engaged CHM patients in an investigator-sponsored Phase IB clinical trial of ocular gene therapy for choroideremia. My second lesson came from the trial itself in that preliminary data may not be sufficient to predict the risks to patients in a clinical trial. In the significant push to begin a gene therapy trial for CHM patients, writing grants, recruiting personnel, interacting with regulatory authorities, acquiring research equipment to test outcome measures, I missed a third lesson. There is significant bias when the principal investigator of an investigator-sponsored clinical trial is also the treating physician in the trial. Ideally, those two roles should be kept separate. Finally, having completed the clinical trial, I learned that gene replacement with an AAV vector may not be the only genetic therapy for CHM; an antisense oligonucleotide therapy may be possible in select cases.
- Published
- 2022
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241. Iris Flocculi Investigated for Familial Thoracic Aortic Aneurysms and Dissections.
- Author
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MacDonald IM, Modeste D, and MacPherson MJ
- Subjects
- Actins metabolism, Adult, Aortic Dissection diagnosis, Aortic Dissection metabolism, Aortic Aneurysm, Thoracic diagnosis, Aortic Aneurysm, Thoracic metabolism, Humans, Iris diagnostic imaging, Iris Diseases diagnosis, Iris Diseases metabolism, Tomography, X-Ray Computed, Abnormalities, Multiple, Actins genetics, Aortic Dissection genetics, Aortic Aneurysm, Thoracic genetics, Iris abnormalities, Iris Diseases genetics
- Published
- 2021
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242. Whole exome sequencing reveals putatively novel associations in retinopathies and drusen formation.
- Author
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Doucette LP, Noel NCL, Zhai Y, Xu M, Caluseriu O, Hoang SC, Radziwon AJ, and MacDonald IM
- Subjects
- Adolescent, Adult, Aged, Child, Developmental Disabilities pathology, Female, Humans, Male, Middle Aged, Mutation, Pedigree, Retinal Drusen pathology, Retinoschisis pathology, Syndrome, Exome Sequencing, Developmental Disabilities genetics, Low Density Lipoprotein Receptor-Related Protein-1 genetics, Retinal Drusen genetics, Retinoschisis genetics
- Abstract
Inherited retinal dystrophies (IRDs) affect 1 in 3000 individuals worldwide and are genetically heterogeneous, with over 270 identified genes and loci; however, there are still many identified disorders with no current genetic etiology. Whole exome sequencing (WES) provides a hypothesis-free first examination of IRD patients in either a clinical or research setting to identify the genetic cause of disease. We present a study of IRD in ten families from Alberta, Canada, through the lens of novel gene discovery. We identify the genetic etiology of IRDs in three of the families to be variants in known disease-associated genes, previously missed by clinical investigations. In addition, we identify two potentially novel associations: LRP1 in early-onset drusen formation and UBE2U in a multi-system condition presenting with retinoschisis, cataracts, learning disabilities, and developmental delay. We also describe interesting results in our unsolved cases to provide further information to other investigators of these blinding conditions., (© 2021. The Author(s), under exclusive licence to European Society of Human Genetics.)
- Published
- 2021
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243. PEX6 Mutations in Peroxisomal Biogenesis Disorders: An Usher Syndrome Mimic.
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Benson MD, Papp KM, Casey GA, Radziwon A, St Laurent CD, Doucette LP, and MacDonald IM
- Abstract
Purpose: Peroxisomal biogenesis disorders (PBDs) represent a spectrum of conditions that result in vision loss, sensorineural hearing loss, neurologic dysfunction, and other abnormalities resulting from aberrant peroxisomal function caused by mutations in PEX genes. With no treatments currently available, we sought to investigate the disease mechanism in a patient with a PBD caused by defects in PEX6 and to probe whether overexpression of PEX6 could restore peroxisome function and potentially offer therapeutic benefit., Design: Laboratory-based study., Participants: A 12-year-old boy sought treatment with hearing loss and retinopathy. After negative results in an Usher syndrome panel, targeted genetic testing revealed compound heterozygous mutations in PEX6 . These included a 14-nucleotide deletion (c.802_815del: p.(Asp268Cysfs∗8)) and a milder missense variant (c.35T→C:(p.Phe12Ser))., Methods: Patient-derived skin fibroblasts were cultured, and a PEX6 knockout cell line was developed using clustered regularly interspaced short palindromic repeats and Cas9 technology in HEK293T cells to emulate a more severe disease phenotype. Immunoblot analysis of whole cell lysates was performed to assess peroxisome number. Immunofluorescence studies used antibodies against components of the peroxisomal protein import pathway to interrogate the effects of mutations in PEX6 on protein trafficking., Main Outcome Measures: Primary outcome measures were peroxisome abundance and matrix protein import., Results: Peroxisome number was not significantly different between control fibroblasts and patient fibroblasts; however, fewer peroxisomes were observed in PEX6 knockout cells compared with wild-type cells ( P = 0.04). Analysis by immunofluorescent microscopy showed significantly impaired peroxisomal targeting signal 1- and peroxisomal targeting signal 2-mediated matrix protein import in both patient fibroblasts and PEX6 knockout cells. Overexpressing PEX6 resulted in improved matrix protein import in PEX6 knockout cells., Conclusions: Mutations in PEX6 were responsible for combined hearing loss and retinopathy in our patient. The primary peroxisomal defect in our patient's skin fibroblasts was impaired peroxisomal protein import as opposed to reduction in the number of peroxisomes. Genetic strategies that introduce wild-type PEX6 into cells deficient in PEX6 protein show promise in restoring peroxisome function. Future studies of patient-specific induced pluripotent stem cell-derived retinal pigment epithelium cells may clarify the role of PEX6 in the retina and the potential for gene therapy in these patients., (© 2021 by the American Academy of Ophthalmology.)
- Published
- 2021
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244. Validating Ellipsoid Zone Area Measurement With Multimodal Imaging in Choroideremia.
- Author
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Zhai Y, Oke S, and MacDonald IM
- Subjects
- Humans, Multimodal Imaging, Reproducibility of Results, Retrospective Studies, Visual Acuity, Choroideremia diagnostic imaging
- Abstract
Purpose: To assess en face ellipsoid zone (EZ) maps of remaining retinal structure as outcome measures for the future clinical research in patients with choroideremia., Methods: Twenty eyes from 12 patients with a confirmed genetic diagnosis of choroideremia were included retrospectively from a single site. From spectral domain-optical coherence tomography volume scans, slabs including the EZ were manually segmented to create the en face EZ maps. The preserved EZ area was measured by two graders. Lengths of the EZ were recorded at 0°, 45°, 90°, and 135°. The intraclass correlation coefficients and Bland-Altman plots were used to show intergrader agreement. The Pearson correlation coefficient evaluated the correlation between length and area. A Bland-Altman plot compared en face EZ and the preserved fundus autofluorescence area., Results: Measurements of EZ area by two graders showed excellent agreement with an intraclass correlation coefficient of 0.992 (95% confidence interval, 0.980-0.997). A Pearson correlation analysis showed that the existing marker for preserved photoreceptor (horizontal EZ length) was correlated with the area (r = 0.722). The average EZ length in four meridians showed a much better correlation with the EZ area (r = 0.929). The fundus autofluorescence area was found to be a mean of 0.45 ± 0.99 mm2 greater than the EZ area., Conclusions: EZ area measurement provides excellent intergrader reliability, although the process is time consuming. We propose a less time-consuming alternative to estimate the EZ by using the average EZ band length in meridians. Our data also suggest that the loss of photoreceptor inner segments is an early change in choroideremia and may happen before the loss of the retinal pigment epithelium., Translational Relevance: En face EZ mapping is a potential tool for future clinical trials to quantify preserved photoreceptor structure in choroideremia.
- Published
- 2021
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245. Zebrafish Models of Photoreceptor Dysfunction and Degeneration.
- Author
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Noel NCL, MacDonald IM, and Allison WT
- Subjects
- Animals, Animals, Genetically Modified, Disease Models, Animal, Models, Biological, Mutation genetics, Retinal Degeneration genetics, Retinal Degeneration therapy, Zebrafish, Photoreceptor Cells, Vertebrate pathology, Retinal Degeneration pathology, Retinal Degeneration physiopathology
- Abstract
Zebrafish are an instrumental system for the generation of photoreceptor degeneration models, which can be utilized to determine underlying causes of photoreceptor dysfunction and death, and for the analysis of potential therapeutic compounds, as well as the characterization of regenerative responses. We review the wealth of information from existing zebrafish models of photoreceptor disease, specifically as they relate to currently accepted taxonomic classes of human rod and cone disease. We also highlight that rich, detailed information can be derived from studying photoreceptor development, structure, and function, including behavioural assessments and in vivo imaging of zebrafish. Zebrafish models are available for a diversity of photoreceptor diseases, including cone dystrophies, which are challenging to recapitulate in nocturnal mammalian systems. Newly discovered models of photoreceptor disease and drusenoid deposit formation may not only provide important insights into pathogenesis of disease, but also potential therapeutic approaches. Zebrafish have already shown their use in providing pre-clinical data prior to testing genetic therapies in clinical trials, such as antisense oligonucleotide therapy for Usher syndrome., Competing Interests: The authors declare no conflict of interest.
- Published
- 2021
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246. RP1L1 and inherited photoreceptor disease: A review.
- Author
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Noel NCL and MacDonald IM
- Subjects
- DNA Mutational Analysis, Electroretinography, Eye Proteins metabolism, Humans, Phenotype, Retinal Cone Photoreceptor Cells pathology, Retinal Diseases metabolism, DNA genetics, Eye Proteins genetics, Mutation, Retinal Cone Photoreceptor Cells metabolism, Retinal Diseases genetics
- Abstract
Retinitis pigmentosa 1-like 1 (RP1L1) is a component of the photoreceptor cilium. Pathogenic variants in RP1L1 lead to photoreceptor disease, suggesting an important role for RP1L1 in photoreceptor biology, though its exact function is unknown. To date, RP1L1 variants have been associated with occult macular dystrophy (a cone degeneration) and retinitis pigmentosa (a rod disease). Here, we summarize reported RP1L1-associated photoreceptor conditions and disease-causing RP1L1 variants. We also discuss novel associations between RP1L1 and additional photoreceptor conditions-besides occult macular dystrophy and retinitis pigmentosa-and fit RP1L1 into the broader scope of photoreceptor disease. RP1L1 appears to have a complex relationship with other photoreceptor proteins and may modify disease phenotype. Ultimately, further exploration of the relationship between RP1L1, other cilium components, and their impact on photoreceptor health is needed., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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247. A diagnostic approach to syndromic retinal dystrophies with intellectual disability.
- Author
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Yang XR, Benson MD, MacDonald IM, and Innes AM
- Subjects
- Adult, Child, Female, Genotype, Humans, Intellectual Disability complications, Intellectual Disability genetics, Intellectual Disability pathology, Male, Mutation, Retinal Dystrophies complications, Retinal Dystrophies genetics, Retinal Dystrophies pathology, Diagnosis, Differential, Eye Proteins genetics, Intellectual Disability diagnosis, Retinal Dystrophies diagnosis
- Abstract
Inherited retinal dystrophies are a group of monogenic disorders that, as a whole, contribute significantly to the burden of ocular disease in both pediatric and adult patients. In their syndromic forms, retinal dystrophies can be observed in association with intellectual disability, frequently alongside other systemic manifestations. There are now over 80 genes implicated in syndromic retinal dystrophies with intellectual disability. Identifying and accurately characterizing these disorders allows the clinician to narrow the differential diagnosis, evaluate for relevant associated features, arrive at a timely and accurate diagnosis, and address both sight-threatening ocular manifestations and morbidity-causing systemic manifestations. The co-occurrence of retinal dystrophy and intellectual disability in an individual can be challenging to investigate, diagnose, and counsel given the considerable phenotypic and genotypic heterogeneity that exists within this broad group of disorders. We performed a review of the current literature and propose an algorithm to facilitate the evaluation, and clinical and mechanistic classification, of these individuals., (© 2020 Wiley Periodicals LLC.)
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- 2020
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248. Ocular Gene Therapy with Adeno-associated Virus Vectors: Current Outlook for Patients and Researchers.
- Author
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Casey GA, Papp KM, and MacDonald IM
- Abstract
In this "Perspective", we discuss ocular gene therapy - the patient's perspective, the various strategies of gene replacement and gene editing, the place of adeno-associated virus vectors, routes of delivery to the eye and the remaining question - "why does immunity continue to limit efficacy?" Through the coordinated efforts of patients, researchers, granting agencies and industry, and after many years of pre-clinical studies, biochemical, cellular, and animal models, we are seeing clinical trials emerge for many previously untreatable heritable ocular disorders. The pathway to therapies has been led by the successful treatment of the RPE65 form of Leber congenital amaurosis with LUXTURNA TM . In some cases, immune reactions to the vectors continue to occur, limiting efficacy. The underlying mechanisms of inflammation require further study, and new vectors need to be designed that limit the triggers of immunity. Researchers studying ocular gene therapies and clinicians enrolling patients in clinical trials must recognize the current limitations of these therapies to properly manage expectations and avoid disappointment, but we believe that gene therapies are well on their way to successful, widespread utilization to treat heritable ocular disorders., Competing Interests: There are no conflicts of interest., (Copyright © 2020 Casey et al.)
- Published
- 2020
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249. Improved electroretinographic responses following dietary intervention in a patient with Refsum disease.
- Author
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Benson MD, MacDonald IM, Sheehan M, and Jain S
- Abstract
Refsum disease is a rare inherited metabolic disorder arising from a defect in peroxisomal metabolism. Patients lack the functional enzyme phytanoyl-CoA hydroxylase, resulting in perturbed alpha oxidation of fatty acids. Phytanic acid accumulates in nervous and adipose tissue and leads to several disease phenotypes including early-onset retinal degeneration, hearing loss, peripheral neuropathy, anosmia, and cerebellar ataxia, among others. Currently, restricting dietary phytanic acid is the only means of altering the chronic sequelae and the disease course. While dietary intervention has been demonstrated to improve peripheral neuropathy, ichthyosis, and ataxia, there have been no reports of improved retinal function in patients with Refsum disease. We describe the case of a 51-year-old patient with molecularly and biochemically confirmed Refsum disease who underwent electroretinography before and after beginning a phytanic acid-restricted diet. His post-intervention 30 Hz flicker electroretinogram demonstrated significantly improved waveform amplitudes and implicit times, suggesting improved retinal function. Thus, we propose that the possibility exists for some visual recovery in these patients and we highlight the utility of performing standardized electroretinography to assess treatment response in Refsum disease., Competing Interests: The authors declare that they have no conflict of interest., (© 2020 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)
- Published
- 2020
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250. Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics.
- Author
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Khan M, Cornelis SS, Pozo-Valero MD, Whelan L, Runhart EH, Mishra K, Bults F, AlSwaiti Y, AlTalbishi A, De Baere E, Banfi S, Banin E, Bauwens M, Ben-Yosef T, Boon CJF, van den Born LI, Defoort S, Devos A, Dockery A, Dudakova L, Fakin A, Farrar GJ, Sallum JMF, Fujinami K, Gilissen C, Glavač D, Gorin MB, Greenberg J, Hayashi T, Hettinga YM, Hoischen A, Hoyng CB, Hufendiek K, Jägle H, Kamakari S, Karali M, Kellner U, Klaver CCW, Kousal B, Lamey TM, MacDonald IM, Matynia A, McLaren TL, Mena MD, Meunier I, Miller R, Newman H, Ntozini B, Oldak M, Pieterse M, Podhajcer OL, Puech B, Ramesar R, Rüther K, Salameh M, Salles MV, Sharon D, Simonelli F, Spital G, Steehouwer M, Szaflik JP, Thompson JA, Thuillier C, Tracewska AM, van Zweeden M, Vincent AL, Zanlonghi X, Liskova P, Stöhr H, Roach JN, Ayuso C, Roberts L, Weber BHF, Dhaenens CM, and Cremers FPM
- Subjects
- ATP-Binding Cassette Transporters genetics, Genomics, Humans, Introns, Mutation, Pedigree, Stargardt Disease, Macular Degeneration genetics, Transcriptome
- Abstract
Purpose: Missing heritability in human diseases represents a major challenge, and this is particularly true for ABCA4-associated Stargardt disease (STGD1). We aimed to elucidate the genomic and transcriptomic variation in 1054 unsolved STGD and STGD-like probands., Methods: Sequencing of the complete 128-kb ABCA4 gene was performed using single-molecule molecular inversion probes (smMIPs), based on a semiautomated and cost-effective method. Structural variants (SVs) were identified using relative read coverage analyses and putative splice defects were studied using in vitro assays., Results: In 448 biallelic probands 14 known and 13 novel deep-intronic variants were found, resulting in pseudoexon (PE) insertions or exon elongations in 105 alleles. Intriguingly, intron 13 variants c.1938-621G>A and c.1938-514G>A resulted in dual PE insertions consisting of the same upstream, but different downstream PEs. The intron 44 variant c.6148-84A>T resulted in two PE insertions and flanking exon deletions. Eleven distinct large deletions were found, two of which contained small inverted segments. Uniparental isodisomy of chromosome 1 was identified in one proband., Conclusion: Deep sequencing of ABCA4 and midigene-based splice assays allowed the identification of SVs and causal deep-intronic variants in 25% of biallelic STGD1 cases, which represents a model study that can be applied to other inherited diseases.
- Published
- 2020
- Full Text
- View/download PDF
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