Worldwide distribution of PSEN1 Met146Leu mutation A large variability for a founder mutation
Worldwide distribution of PSEN1 Met146Leu mutation A large variability for a founder mutation
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DOI：
10.1212/wnl.0b013e3181d52785
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发表时间：
2010-03-09
期刊：
影响因子：
9.9
通讯作者：
Puccio, G.
中科院分区：
文献类型：
--
作者：
Bruni, A. C.;Bernardi, L.;Puccio, G.
目的：大种类分离性家族性阿尔茨海默病（FAD）为研究早老素1 （PSEN1）突变的临床变变性提供了机会。两个早发性FAD （EOFAD）卡拉布里亚家族具有PSEN1 Met146Leu （ATG/CTG）突变，构成了一个独特的群体，来自一个遥远的共同祖先。最近，在世界范围内发现了其他几个具有相同突变的EOFAD家族。方法：通过家谱和分子分析，在不同地理来源的家庭中寻找PSEN1 Met146Leu突变的共同始祖。我们还通过临床、神经心理学和分子方法研究了50例患者（平均发病年龄40.0±4.8岁）发病时的表型变异性。结果：来自世界各地的EOFAD Met146Leu家族在17世纪以前起源于意大利南部，具有亲缘关系，构成一个单一的家族。发病时的表型变异是广泛的：可以识别出4种不同的临床表现，其中2种是AD的典型表现（记忆缺陷和空间和时间定向障碍），而其他表现则是额叶损伤的表现。麻木亚组和执行障碍亚组可能与眶内侧前额皮质和背外侧前额皮质功能障碍有关。结论：家谱和分子研究结果表明，本研究分析的来自世界各地的PSEN1 Met146Leu家族是相关的，代表了一个起源于意大利南部的单一家族。显著的表型变异可能反映了不同皮质区域的病理过程早期受累。虽然临床表型变化很大，但病变的神经病理和生化特征解释了阿尔茨海默病性质的神经退行性过程。神经病学(R) 2010；74: 798 - 806
Objective: Large kindreds segregating familial Alzheimer disease (FAD) offer the opportunity of studying clinical variability as observed for presenilin 1 (PSEN1) mutations. Two early-onset FAD (EOFAD) Calabrian families with PSEN1 Met146Leu (ATG/CTG) mutation constitute a unique population descending from a remote common ancestor. Recently, several other EOFAD families with the same mutation have been described worldwide.Methods: We searched for a common founder of the PSEN1 Met146Leu mutation in families with different geographic origins by genealogic and molecular analyses. We also investigated the phenotypic variability at onset in a group of 50 patients (mean age at onset 40.0 +/- 4.8 years) by clinical, neuropsychological, and molecular methodologies.Results: EOFAD Met146Leu families from around the world resulted to be related and constitute a single kindred originating from Southern Italy before the 17th century. Phenotypic variability at onset is broad: 4 different clinical presentations may be recognized, 2 classic for AD (memory deficits and spatial and temporal disorientation), whereas the others are expressions of frontal impairment. The apathetic and dysexecutive subgroups could be related to orbital-medial prefrontal cortex and dorsolateral prefrontal cortex dysfunction.Conclusions: Genealogic and molecular findings provided evidence that the PSEN1 Met146Leu families from around the world analyzed in this study are related and represent a single kindred originating from Southern Italy. The marked phenotypic variability might reflect early involvement by the pathologic process of different cortical areas. Although the clinical phenotype is quite variable, the neuropathologic and biochemical characteristics of the lesions account for neurodegenerative processes unmistakably of Alzheimer nature. Neurology (R) 2010; 74: 798-806