PMID- 27474146 OWN - NLM STAT- MEDLINE DCOM- 20170626 LR - 20211204 IS - 1549-4713 (Electronic) IS - 0161-6420 (Linking) VI - 123 IP - 10 DP - 2016 Oct TI - Martinique Crinkled Retinal Pigment Epitheliopathy: Clinical Stages and Pathophysiologic Insights. PG - 2196-204 LID - S0161-6420(16)30496-1 [pii] LID - 10.1016/j.ophtha.2016.06.028 [doi] AB - PURPOSE: To reappraise the autosomal dominant Martinique crinkled retinal pigment epitheliopathy (MCRPE) in light of the knowledge of its associated mutated gene mitogen-activated protein kinase-activated protein kinase 3 (MAPKAPK3), an actor in the p38 mitogen-activated protein kinase pathway. DESIGN: Clinical and molecular study. PARTICIPANTS: A total of 45 patients from 3 generations belonging to a family originating from Martinique with an autosomal dominant MCRPE were examined. METHODS: Best-corrected visual acuity, fundus photographs, and spectral-domain optical coherence tomography (SD OCT) of all clinically affected patients and carriers for the causal mutation were reviewed at the initial visit and 4 years later for 10 of them. Histologic retinal lesions of Mapkapk3(-/-) mice were compared with those of the human disease. MAIN OUTCOME MEASURES: The MCRPE natural history in view of MAPKAPK3 function and Mapkapk3(-/-) mouse retinal lesions. RESULTS: Eighteen patients had the c.518T>C mutation. One heterozygous woman aged 20 years was asymptomatic with normal fundus and SD OCT (stage 0). All c.518T>C heterozygous patients older than 30 years of age had the characteristic dried-out soil fundus pattern (stages 1 and 2). Complications (stage 3) were observed in 7 cases, including polypoidal choroidal vasculopathy (PCV) and macular fibrosis or atrophy. One patient was homozygous and had a form with severe Bruch's membrane (BM) thickening and macular exudation with a dried-out soil pattern in the peripheral retina. The oldest heterozygous patient, who was legally blind, had peripheral nummular pigmentary changes (stage 4). After 4 years, visual acuity was unchanged in 6 of 10 patients. The dried-out soil elementary lesions radically enlarged in patients with a preferential macular extension and confluence. These findings are in line with the progressive thickening of BM noted with age in the mouse model. During follow-up, there was no occurrence of PCV. CONCLUSIONS: MCRPE is an autosomal dominant, fully penetrant retinal dystrophy with a preclinical stage, an onset after the age of 30 years, and a preserved visual acuity until occurrence of macular complications. The natural history of MCRPE is in relation to the role of MAPKAPK3 in BM modeling, vascular endothelial growth factor activity, retinal pigment epithelial responses to aging, and oxidative stress. CI - Copyright (c) 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved. FAU - Jean-Charles, Albert AU - Jean-Charles A AD - Department of Ophthalmology, University Hospital of Fort de France, Martinique (FWI), France. FAU - Merle, Harold AU - Merle H AD - Department of Ophthalmology, University Hospital of Fort de France, Martinique (FWI), France. FAU - Audo, Isabelle AU - Audo I AD - Fondation Adolphe de Rothschild, Paris, France; CHNO des Quinze-Vingts, DHU Sight Restore, INSERM-DHOS CIC1423, Paris - Sorborne Universites, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision, Paris - Institute of Ophthalmology, University College of London, London, United Kingdom. FAU - Desoudin, Catherine AU - Desoudin C AD - Eye Clinic Ernest Hemingway, Fort de France, Martinique, France. FAU - Bocquet, Beatrice AU - Bocquet B AD - Institute for Neurosciences of Montpellier U1051, University of Montpellier - University Hospital, Genetics of Sensory Diseases, Montpellier, France. FAU - Baudoin, Corinne AU - Baudoin C AD - Institute for Neurosciences of Montpellier U1051, University of Montpellier - University Hospital, Genetics of Sensory Diseases, Montpellier, France. FAU - Sidibe, Moro AU - Sidibe M AD - Fondation Adolphe de Rothschild, Paris, France. FAU - Mauget-Faysse, Martine AU - Mauget-Faysse M AD - Fondation Adolphe de Rothschild, Paris, France. FAU - Wolff, Benjamin AU - Wolff B AD - Fondation Adolphe de Rothschild, Paris, France; Eye Clinic, Maison Rouge, Strasbourg, France. FAU - Fichard, Agnes AU - Fichard A AD - Institute for Neurosciences of Montpellier U1051, University of Montpellier - University Hospital, Genetics of Sensory Diseases, Montpellier, France. FAU - Lenaers, Guy AU - Lenaers G AD - Institute for Neurosciences of Montpellier U1051, University of Montpellier - University Hospital, Genetics of Sensory Diseases, Montpellier, France. FAU - Sahel, Jose-Alain AU - Sahel JA AD - Fondation Adolphe de Rothschild, Paris, France; CHNO des Quinze-Vingts, DHU Sight Restore, INSERM-DHOS CIC1423, Paris - Sorborne Universites, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision, Paris - Institute of Ophthalmology, University College of London, London, United Kingdom; Academie des Sciences, Institut de France, Paris, France. FAU - Gaudric, Alain AU - Gaudric A AD - Department of Ophthalmology, Lariboisiere Hospital, Paris, France. FAU - Cohen, Salomon Yves AU - Cohen SY AD - Ophthalmic Center for Imaging and Laser, Paris, France; Department of Ophthalmology, Intercity Hospital and University Paris Est, Creteil, France. FAU - Hamel, Christian P AU - Hamel CP AD - Institute for Neurosciences of Montpellier U1051, University of Montpellier - University Hospital, Genetics of Sensory Diseases, Montpellier, France. FAU - Meunier, Isabelle AU - Meunier I AD - Institute for Neurosciences of Montpellier U1051, University of Montpellier - University Hospital, Genetics of Sensory Diseases, Montpellier, France. Electronic address: isabelannemeunier@yahoo.fr. LA - eng PT - Journal Article PT - Multicenter Study DEP - 20160726 PL - United States TA - Ophthalmology JT - Ophthalmology JID - 7802443 RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 9007-49-2 (DNA) RN - EC 2.7.1.- (MAP-kinase-activated kinase 3) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) SB - IM MH - Adult MH - Animals MH - DNA/*genetics MH - DNA Mutational Analysis MH - Disease Models, Animal MH - Female MH - Fluorescein Angiography MH - Fundus Oculi MH - Humans MH - Intracellular Signaling Peptides and Proteins/*genetics/metabolism MH - Male MH - Martinique MH - Mice MH - Mice, Transgenic MH - *Mutation MH - Pedigree MH - Protein Serine-Threonine Kinases/*genetics/metabolism MH - Retinal Dystrophies/diagnosis/*genetics/metabolism MH - Retinal Pigment Epithelium/metabolism/*pathology MH - Tomography, Optical Coherence EDAT- 2016/07/31 06:00 MHDA- 2017/06/27 06:00 CRDT- 2016/07/31 06:00 PHST- 2016/03/18 00:00 [received] PHST- 2016/05/30 00:00 [revised] PHST- 2016/06/06 00:00 [accepted] PHST- 2016/07/31 06:00 [entrez] PHST- 2016/07/31 06:00 [pubmed] PHST- 2017/06/27 06:00 [medline] AID - S0161-6420(16)30496-1 [pii] AID - 10.1016/j.ophtha.2016.06.028 [doi] PST - ppublish SO - Ophthalmology. 2016 Oct;123(10):2196-204. doi: 10.1016/j.ophtha.2016.06.028. Epub 2016 Jul 26.