Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson's disease:: clinical, pathological, olfactory and functional imaging and genetic data
Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson's disease:: clinical, pathological, olfactory and functional imaging and genetic data
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DOI：
10.1093/brain/awh667
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发表时间：
2005-12-01
期刊：
影响因子：
14.5
通讯作者：
Wood, NW
中科院分区：
文献类型：
--
作者：
Khan, NL;Jain, S;Wood, NW
我们已经确定，在一系列的118例家族性帕金森病中LRRK 2突变的频率为5.1%。在最大的常染色体显性遗传，晚发型帕金森氏病，受影响的科目共享Y1699 C错义突变，我们提供了详细的临床，病理和影像学报告。在这个大的英国家族的表型包括不对称，左旋多巴反应性帕金森病，单侧腿部震颤在发病和足部肌张力障碍的突出特点。认知功能无明显异常，但有明显的行为障碍。我们观察到连续几代的发病年龄较低。1例患者的组织学检查显示黑质细胞丢失和路易体形成，伴有少量皮质路易体。（18）另一名患者的F-多巴正电子发射断层扫描（PET）显示了特发性帕金森病典型的黑质纹状体功能障碍模式。（18）在确定疾病位点之前，未受影响的家庭成员的F-多巴-PET扫描未检测到亚临床黑质纹状体功能障碍。在受影响的受试者的嗅觉进行了评估和路易体被确定在嗅球以及皮质和脑干的一名死者。为了评估该基因突变在其他家族性病例中的作用，我们对117例其他较小的英国家族性帕金森病患者的LRRK 2的所有51个外显子进行了突变筛查。最常见的突变是G2019 S，我们还发现了两个新的突变，R1941 H和T2356 I，在编码序列。这些数据表明，由LRRK 2突变引起的帕金森综合征可能是常染色体显性帕金森病最常见的基因座，其表型、病理学和体内成像与特发性迟发性帕金森病相似。
We have established that the frequency of LRRK2 mutations in a series of 118 cases of familial Parkinson's disease is 5.1%. In the largest family with autosomal dominant, late-onset Parkinson's disease where affected subjects share a Y1699C missense mutation we provide a detailed clinical, pathological and imaging report. The phenotype in this large British kindred included asymmetrical, levodopa-responsive parkinsonism where unilateral leg tremor at onset and foot dystonia were prominent features. There was no significant abnormality of cognition but there was prominent behavioural disorder. We observed a lower age of onset in successive generations. Histopathology in one patient showed substantia nigra cell loss and Lewy body formation, with small numbers of cortical Lewy bodies. (18)F-dopa positron emission tomography (PET) in another patient showed a pattern of nigrostriatal dysfunction typical of idiopathic Parkinson's disease. (18)F-dopa-PET scans in unaffected family members prior to identifying the disease locus did not detect subclinical nigrostriatal dysfunction. Olfaction was assessed in affected subjects and Lewy bodies were identified in the olfactory bulb as well as cortex and brainstem of one deceased patient. In order to assess the role of mutations in this gene in other familial cases we undertook a mutation screen of all 51 exons of LRRK2 in 117 other smaller British kindreds with familial Parkinson's disease. The commonest mutation was G2019S and we also identified two novel mutations, R1941H and T2356I, in the coding sequence. These data suggest that parkinsonism caused by mutations in LRRK2 is likely to represent the commonest locus for autosomal dominant Parkinson's disease with a phenotype, pathology and in vivo imaging similar to idiopathic, late-onset Parkinson's disease.