Department of Ophthalmology, University Hospital of Fort de France, Martinique (FWI), France.
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.
Ophthalmology. 2016 Oct;123(10):2196-204. doi: 10.1016/j.ophtha.2016.06.028. Epub 2016 Jul 26.
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.
根据丝裂原活化蛋白激酶激活的蛋白激酶 3（MAPKAPK3）相关突变基因的知识，重新评估常染色体显性遗传性马丁尼克卷曲状视网膜色素上皮病变（MCRPE），该基因是 p38 丝裂原活化蛋白激酶途径的一个作用因子。
临床和分子研究。
共检查了来自 3 代的 45 名来自马提尼克岛的常染色体显性 MCRPE 家族患者。
对所有临床受累患者和因果突变携带者进行最佳矫正视力、眼底照片和光谱域光学相干断层扫描（SD OCT）检查，并对其中 10 名患者在初次就诊后 4 年进行复查。比较 Mapkapk3（-/-）小鼠的组织学视网膜病变与人类疾病。
根据 MAPKAPK3 功能和 Mapkapk3（-/-）小鼠视网膜病变观察 MCRPE 的自然病史。
18 名患者存在 c.518T>C 突变。一名 20 岁的无症状杂合女性眼底和 SD OCT 正常（0 期）。所有 30 岁以上的 c.518T>C 杂合患者均有典型的干燥土壤眼底模式（1 期和 2 期）。7 例出现并发症（3 期），包括息肉样脉络膜血管病变（PCV）和黄斑纤维化或萎缩。一名患者为纯合子，表现为严重的布鲁赫膜（BM）增厚和黄斑渗出，周边视网膜呈干燥土壤样。最年长的杂合子患者因周边钱币状色素改变而失明（4 期）。4 年后，10 名患者中有 6 名视力无变化。在那些黄斑病变优先扩展和融合的患者中，干燥土壤的基本病变明显扩大。这些发现与小鼠模型中随年龄增长而观察到的 BM 进行性增厚一致。随访期间，未发生 PCV。
MCRPE 是一种常染色体显性、完全外显的视网膜变性疾病，具有临床前阶段，发病年龄大于 30 岁，视力保持至出现黄斑并发症。MCRPE 的自然病史与 MAPKAPK3 在 BM 建模、血管内皮生长因子活性、视网膜色素上皮对衰老和氧化应激的反应中的作用有关。
