Alain Gaudric, A. Jean-Charles, Harold Merle, Benjamin Wolff, Christian P. Hamel, Guy Lenaers, Martine Mauget-Faÿsse, José-Alain Sahel, Isabelle Meunier, Béatrice Bocquet, Agnès Fichard, Isabelle Audo, Moro Sidibe, Salomon Y. Cohen, Corinne Baudoin, Catherine Desoudin, CHU de la Martinique [Fort de France], Fondation Ophtalmologique Adolphe de Rothschild [Paris], Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), Institut de la Vision, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Académie des Sciences, Institut de France, Hôpital Lariboisière, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), CHI Créteil, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier (INM), Académie des Sciences [Paris], CIC Quinze-Vingts, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7)
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.