title: Choroideremia Is a Systemic Disease With Lymphocyte Crystals and Plasma Lipid and RBC Membrane Abnormalities.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Paediatric Surgery, Human Genetics and Ophthalmology, McGill University, Montreal, Quebec, Canada 2McGill Ocular Genetics Laboratory, Montreal, Quebec, Canada.
authors.forename: Alice Yang
authors.initials: AY
authors.lastname: Zhang
authors.affiliation: Department of Paediatric Surgery, Human Genetics and Ophthalmology, McGill University, Montreal, Quebec, Canada 2McGill Ocular Genetics Laboratory, Montreal, Quebec, Canada.
authors.forename: Naveen
authors.initials: N
authors.lastname: Mysore
authors.affiliation: Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada 4Facility for Electron Microscopy Research, McGill University, Montreal, Quebec, Canada.
authors.forename: Hojatollah
authors.initials: H
authors.lastname: Vali
authors.affiliation: McGill Ocular Genetics Laboratory, Montreal, Quebec, Canada.
authors.forename: Jamie
authors.initials: J
authors.lastname: Koenekoop
authors.affiliation: McGill Ocular Genetics Laboratory, Montreal, Quebec, Canada.
authors.forename: Sang Ni
authors.initials: SN
authors.lastname: Cao
authors.affiliation: McGill Ocular Genetics Laboratory, Montreal, Quebec, Canada.
authors.forename: Shen
authors.initials: S
authors.lastname: Li
authors.affiliation: McGill Ocular Genetics Laboratory, Montreal, Quebec, Canada.
authors.forename: Huanan
authors.initials: H
authors.lastname: Ren
authors.affiliation: McGill Ocular Genetics Laboratory, Montreal, Quebec, Canada.
authors.forename: Vafa
authors.initials: V
authors.lastname: Keser
authors.affiliation: McGill Ocular Genetics Laboratory, Montreal, Quebec, Canada.
authors.forename: Irma
authors.initials: I
authors.lastname: Lopez-Solache
authors.affiliation: Department of Paediatric Surgery, Human Genetics and Ophthalmology, McGill University, Montreal, Quebec, Canada 2McGill Ocular Genetics Laboratory, Montreal, Quebec, Canada.
authors.forename: Sorath Noorani
authors.initials: SN
authors.lastname: Siddiqui
authors.affiliation: Department of Paediatric Surgery, Human Genetics and Ophthalmology, McGill University, Montreal, Quebec, Canada 2McGill Ocular Genetics Laboratory, Montreal, Quebec, Canada.
authors.forename: Ayesha
authors.initials: A
authors.lastname: Khan
authors.affiliation: Facility for Electron Microscopy Research, McGill University, Montreal, Quebec, Canada.
authors.forename: Jeannie
authors.initials: J
authors.lastname: Mui
authors.affiliation: Facility for Electron Microscopy Research, McGill University, Montreal, Quebec, Canada.
authors.forename: Kelly
authors.initials: K
authors.lastname: Sears
authors.affiliation: Department of Pathology, Montreal Children's Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Jim
authors.initials: J
authors.lastname: Dixon
authors.affiliation: Faculty of Medicine, Human Genetics, McGill University, Montreal, Quebec, Canada 7Quebec Genome Centre, Montreal, Quebec, Canada.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schwartzentruber
authors.affiliation: Faculty of Medicine, Human Genetics, McGill University, Montreal, Quebec, Canada 7Quebec Genome Centre, Montreal, Quebec, Canada.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.affiliation: Faculty of Medicine, Human Genetics, McGill University, Montreal, Quebec, Canada 8Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada.
authors.forename: Nancy
authors.initials: N
authors.lastname: Braverman
authors.affiliation: Department of Paediatric Surgery, Human Genetics and Ophthalmology, McGill University, Montreal, Quebec, Canada 2McGill Ocular Genetics Laboratory, Montreal, Quebec, Canada.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Koenekoop
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D015794:Choroideremia / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D003317:Corneal Dystrophies, Hereditary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D004910:Erythrocyte Membrane / Q000378:metabolism* / Q000648:ultrastructure; D005260:Female; D005838:Genotype; D006801:Humans; D008055:Lipids / Q000097:blood*; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D008854:Microscopy, Electron; D008875:Middle Aged; D009154:Mutation; D012160:Retina / Q000378:metabolism* / Q000648:ultrastructure; D012164:Retinal Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D041623:Tomography, Optical Coherence
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C081787:CHM protein, human; D008055:Lipids; D004247:DNA