Martinique Crinkled Retinal Pigment Epitheliopathy

Albert Jean-Charles (1) , Harold Merle (1) , Isabelle Audo (2, 3, 4) , Catherine Desoudin , Beatrice Bocquet (5, 6) , Corinne Baudoin (5, 6) , Moro Sidibe (2) , Martine Mauget-Faysse (2) , Benjamin Wolff (2) , Agnès Fichard (5, 6) , Guy Lenaers (5, 6) , José-Alain Sahel (2, 3, 4, 7) , Alain Gaudric (8) , Salomon Yves Cohen (9) , Christian P. Hamel (5, 6) , Isabelle Meunier (5, 6)

1 CHU de la Martinique [Fort de France]
2 Fondation Ophtalmologique Adolphe de Rothschild [Paris]
3 CHNO - Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts
4 Institut de la Vision
5 INM - Institut des Neurosciences de Montpellier
6 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
7 Académie des sciences [Paris, France]
8 Hôpital Lariboisière
9 CHI Créteil

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.

Domaines: Organes des sens

Albert Jean-Charles, Harold Merle, Isabelle Audo, Catherine Desoudin, Beatrice Bocquet, et al.. Martinique Crinkled Retinal Pigment Epitheliopathy. Ophthalmology: Journal of The American Academy of Ophthalmology, 2016, 123 (10), pp.2196 - 2204. ⟨10.1016/j.ophtha.2016.06.028⟩. ⟨hal-01839931⟩