BACKGROUND Knowledge on clinical profiles of late-onset phenotypes of Fabry disease (FD) is essential to better define their natural history. Our study aims to demonstrate a founder effect of FD due to the GLA gene mutation c.337T>C (p.F113L) in the Portuguese region of Guimarães; and to characterize the clinical profile of this late-onset phenotype in a large cohort of genetically related adult patients, living in the same region. METHODS AND RESULTS FD screening was performed in 150 adult patients with hypertrophic cardiomyopathy (HCM) and found 25 Fabry patients (16.6%). The p.F113L mutation was found in 21 of them, leading to a genealogy study and haplotype analysis of the p.F113L patients. Genealogy research revealed a 12-generation family tree with a common ancestor to p.F113L patients, suggesting a founder effect that was supported by haplotype findings. Pedigree analysis was performed and 120 consecutive p.F113L patients underwent a predefined diagnostic evaluation of FD multiorgan involvement. This late-onset phenotype was characterized by common and/or potentially severe cardiac manifestations (left ventricular hypertrophy 40.8%, atrial fibrillation 5%, non-sustained ventricular tachycardia 12.5%, atrioventricular block 18.3%, bifascicular block 13.4%). Extracardiac manifestations included albuminuria>30 mg/24 h 36.1%, chronic kidney disease≥G3 7.6%, brain white matter lesions 54.4%, stroke 3.3%, sensorineural deafness 44.5%, cornea verticillata 13.9%. Plasma lyso-GB3 was undetectable in females, regardless of clinical manifestations. CONCLUSION A founder effect of FD due to p.F113L mutation was documented by genealogy and genetics in a Portuguese region. In this late-onset phenotype, although cardiac manifestations carry the highest prognostic impact, extracardiac involvement is common.

中文翻译：

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由于p.F113L突变而导致的Fabry疾病的奠基者效应：迟发表型的临床表现。

背景技术关于法布里病（FD）的迟发表型的临床概况的知识对于更好地定义其自然病史是必不可少的。我们的研究旨在证明在葡萄牙吉马良斯地区，由于GLA基因突变c.337T> C（p.F113L）而导致的FD创始效应。并表征居住在同一地区的大量遗传相关成年患者中这种晚发表型的临床特征。方法和结果在150例成人肥厚型心肌病（HCM）患者中进行了FD筛查，发现25例法布里患者（16.6％）。在其中的21个中发现了p.F113L突变，导致对p.F113L患者进行了族谱研究和单倍型分析。族谱研究显示p.F113L患者有共同祖先的12代家谱，提示单倍型发现支持创始人效应。进行了谱系分析，并对120例连续的p.F113L患者进行了FD多器官受累的预定义诊断评估。这种迟发性表型的特征是常见和/或潜在的严重心脏表现（左心室肥大40.8％，房颤5％，非持续性室性心动过速12.5％，房室传导阻滞18.3％，双心室传导阻滞13.4％）。心外表现包括蛋白尿> 30 mg / 24 h 36.1％，慢性肾脏疾病≥G37.6％，脑白质病变54.4％，中风3.3％，感音神经性耳聋44.5％，角膜黄斑13.9％。不论临床表现如何，女性均未检测到血浆溶血GB3。结论FD引起的FD的创始人效应。通过家谱和遗传学在葡萄牙地区记录了F113L突变。在这种晚期发病表型中，尽管心脏表现对预后的影响最大，但心外膜受累是常见的。