Alice Yang Zhang1, Naveen Mysore1, Hojatollah Vali2, Jamie Koenekoop3, Sang Ni Cao3, Shen Li3, Huanan Ren3, Vafa Keser3, Irma Lopez-Solache3, Sorath Noorani Siddiqui1, Ayesha Khan1, Jeannie Mui4, Kelly Sears4, Jim Dixon5, Jeremy Schwartzentruber6, Jacek Majewski6, Nancy Braverman7, Robert K Koenekoop1. 1. Department of Paediatric Surgery, Human Genetics and Ophthalmology, McGill University, Montreal, Quebec, Canada 2McGill Ocular Genetics Laboratory, Montreal, Quebec, Canada. 2. Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada 4Facility for Electron Microscopy Research, McGill University, Montreal, Quebec, Canada. 3. McGill Ocular Genetics Laboratory, Montreal, Quebec, Canada. 4. Facility for Electron Microscopy Research, McGill University, Montreal, Quebec, Canada. 5. Department of Pathology, Montreal Children's Hospital, McGill University, Montreal, Quebec, Canada. 6. Faculty of Medicine, Human Genetics, McGill University, Montreal, Quebec, Canada 7Quebec Genome Centre, Montreal, Quebec, Canada. 7. Faculty of Medicine, Human Genetics, McGill University, Montreal, Quebec, Canada 8Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada.
Abstract
PURPOSE: Photoreceptor neuronal degenerations are common, incurable causes of human blindness affecting 1 in 2000 patients worldwide. Only half of all patients are associated with known mutations in over 250 disease genes, prompting our research program to identify the remaining new genes. Most retinal degenerations are restricted to the retina, but photoreceptor degenerations can also be found in a wide variety of systemic diseases. We identified an X-linked family from Sri Lanka with a severe choroidal degeneration and postulated a new disease entity. Because of phenotypic overlaps with Bietti's crystalline dystrophy, which was recently found to have systemic features, we hypothesized that a systemic disease may be present in this new disease as well. METHODS: For phenotyping, we performed detailed eye exams with in vivo retinal imaging by optical coherence tomography. For genotyping, we performed whole exome sequencing, followed by Sanger sequencing confirmations and cosegregation. Systemic investigations included electron microscopy studies of peripheral blood cells in patients and in normal controls and detailed fatty acid profiles (both plasma and red blood cell [RBC] membranes). Fatty acid levels were compared to normal controls, and only values two standard deviations above or below normal controls were further evaluated. RESULTS: The family segregated a REP1 mutation, suggesting choroideremia (CHM). We then found crystals in peripheral blood lymphocytes and discovered significant plasma fatty acid abnormalities and RBC membrane abnormalities (i.e., elevated plasmalogens). To replicate our discoveries, we expanded the cohort to nine CHM patients, genotyped them for REP1 mutations, and found the same abnormalities (crystals and fatty acid abnormalities) in all patients. CONCLUSIONS: Previously, CHM was thought to be restricted to the retina. We show, to our knowledge for the first time, that CHM is a systemic condition with prominent crystals in lymphocytes and significant fatty acid abnormalities.
PURPOSE: Photoreceptor neuronal degenerations are common, incurable causes of humanblindness affecting 1 in 2000 patients worldwide. Only half of all patients are associated with known mutations in over 250 disease genes, prompting our research program to identify the remaining new genes. Most retinal degenerations are restricted to the retina, but photoreceptor degenerations can also be found in a wide variety of systemic diseases. We identified an X-linked family from Sri Lanka with a severe choroidal degeneration and postulated a new disease entity. Because of phenotypic overlaps with Bietti's crystalline dystrophy, which was recently found to have systemic features, we hypothesized that a systemic disease may be present in this new disease as well. METHODS: For phenotyping, we performed detailed eye exams with in vivo retinal imaging by optical coherence tomography. For genotyping, we performed whole exome sequencing, followed by Sanger sequencing confirmations and cosegregation. Systemic investigations included electron microscopy studies of peripheral blood cells in patients and in normal controls and detailed fatty acid profiles (both plasma and red blood cell [RBC] membranes). Fatty acid levels were compared to normal controls, and only values two standard deviations above or below normal controls were further evaluated. RESULTS: The family segregated a REP1 mutation, suggesting choroideremia (CHM). We then found crystals in peripheral blood lymphocytes and discovered significant plasma fatty acid abnormalities and RBC membrane abnormalities (i.e., elevated plasmalogens). To replicate our discoveries, we expanded the cohort to nine CHMpatients, genotyped them for REP1 mutations, and found the same abnormalities (crystals and fatty acid abnormalities) in all patients. CONCLUSIONS: Previously, CHM was thought to be restricted to the retina. We show, to our knowledge for the first time, that CHM is a systemic condition with prominent crystals in lymphocytes and significant fatty acid abnormalities.
Authors: J Lee; X Jiao; J F Hejtmancik; M Kaiser-Kupfer; W A Gahl; T C Markello; J Guo; G J Chader Journal: Invest Ophthalmol Vis Sci Date: 2001-07 Impact factor: 4.799
Authors: J A van den Hurk; M Schwartz; H van Bokhoven; T J van de Pol; L Bogerd; A J Pinckers; E M Bleeker-Wagemakers; I H Pawlowitzki; K Rüther; H H Ropers; F P Cremers Journal: Hum Mutat Date: 1997 Impact factor: 4.878
Authors: E J Schaefer; S J Robins; G M Patton; M A Sandberg; C A Weigel-DiFranco; B Rosner; E L Berson Journal: J Lipid Res Date: 1995-07 Impact factor: 5.922
Authors: Monika Köhnke; Christine Delon; Marcus L Hastie; Uyen T T Nguyen; Yao-Wen Wu; Herbert Waldmann; Roger S Goody; Jeffrey J Gorman; Kirill Alexandrov Journal: PLoS One Date: 2013-12-16 Impact factor: 3.240
Authors: Tomas S Aleman; Grace Han; Leona W Serrano; Nicole M Fuerst; Emily S Charlson; Denise J Pearson; Daniel C Chung; Anastasia Traband; Wei Pan; Gui-Shuang Ying; Jean Bennett; Albert M Maguire; Jessica I W Morgan Journal: Ophthalmology Date: 2016-12-13 Impact factor: 12.079
Authors: Dulce Lima Cunha; Rose Richardson; Dhani Tracey-White; Alessandro Abbouda; Andreas Mitsios; Verena Horneffer-van der Sluis; Panteleimon Takis; Nicholas Owen; Jane Skinner; Ailsa A Welch; Mariya Moosajee Journal: JCI Insight Date: 2021-05-10