title: Martinique Crinkled Retinal Pigment Epitheliopathy: Clinical Stages and Pathophysiologic Insights.
abstract: 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.
  
  
  
  Clinical and molecular study.
  
  
  
  A total of 45 patients from 3 generations belonging to a family originating from Martinique with an autosomal dominant MCRPE were examined.
  
  
  
  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.
  
  
  
  The MCRPE natural history in view of MAPKAPK3 function and Mapkapk3(-/-) mouse retinal lesions.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Ophthalmology, University Hospital of Fort de France, Martinique (FWI), France.
authors.forename: Albert
authors.initials: A
authors.lastname: Jean-Charles
authors.affiliation: Department of Ophthalmology, University Hospital of Fort de France, Martinique (FWI), France.
authors.forename: Harold
authors.initials: H
authors.lastname: Merle
authors.affiliation: Fondation Adolphe de Rothschild, Paris, France; CHNO des Quinze-Vingts, DHU Sight Restore, INSERM-DHOS CIC1423, Paris - Sorborne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision, Paris - Institute of Ophthalmology, University College of London, London, United Kingdom.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Audo
authors.affiliation: Eye Clinic Ernest Hemingway, Fort de France, Martinique, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Desoudin
authors.affiliation: Institute for Neurosciences of Montpellier U1051, University of Montpellier - University Hospital, Genetics of Sensory Diseases, Montpellier, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Bocquet
authors.affiliation: Institute for Neurosciences of Montpellier U1051, University of Montpellier - University Hospital, Genetics of Sensory Diseases, Montpellier, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Baudoin
authors.affiliation: Fondation Adolphe de Rothschild, Paris, France.
authors.forename: Moro
authors.initials: M
authors.lastname: Sidibe
authors.affiliation: Fondation Adolphe de Rothschild, Paris, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Mauget-Faÿsse
authors.affiliation: Fondation Adolphe de Rothschild, Paris, France; Eye Clinic, Maison Rouge, Strasbourg, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wolff
authors.affiliation: Institute for Neurosciences of Montpellier U1051, University of Montpellier - University Hospital, Genetics of Sensory Diseases, Montpellier, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Fichard
authors.affiliation: Institute for Neurosciences of Montpellier U1051, University of Montpellier - University Hospital, Genetics of Sensory Diseases, Montpellier, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Lenaers
authors.affiliation: Fondation Adolphe de Rothschild, Paris, France; CHNO des Quinze-Vingts, DHU Sight Restore, INSERM-DHOS CIC1423, Paris - Sorborne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision, Paris - Institute of Ophthalmology, University College of London, London, United Kingdom; Académie des Sciences, Institut de France, Paris, France.
authors.forename: José-Alain
authors.initials: JA
authors.lastname: Sahel
authors.affiliation: Department of Ophthalmology, Lariboisière Hospital, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Gaudric
authors.affiliation: Ophthalmic Center for Imaging and Laser, Paris, France; Department of Ophthalmology, Intercity Hospital and University Paris Est, Créteil, France.
authors.forename: Salomon Yves
authors.initials: SY
authors.lastname: Cohen
authors.affiliation: Institute for Neurosciences of Montpellier U1051, University of Montpellier - University Hospital, Genetics of Sensory Diseases, Montpellier, France.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Hamel
authors.affiliation: Institute for Neurosciences of Montpellier U1051, University of Montpellier - University Hospital, Genetics of Sensory Diseases, Montpellier, France. Electronic address: isabelannemeunier@yahoo.fr.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Meunier
mesh_terms: D000328:Adult; D000818:Animals; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D005260:Female; D005451:Fluorescein Angiography; D005654:Fundus Oculi; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008395:Martinique; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D058499:Retinal Dystrophies / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000378:metabolism / Q000473:pathology*; D041623:Tomography, Optical Coherence
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D004247:DNA; C098416:MAP-kinase-activated kinase 3; D017346:Protein Serine-Threonine Kinases