Fanciulli Alessandra, Leys Fabian, Lehner Fabienne, Sidoroff Victoria, Ruf Viktoria C, Raccagni Cecilia, Mahlknecht Philipp, Kuipers Demy J S, van IJcken Wilfred F J, Stockner Heike, Musacchio Thomas, Volkmann Jens, Monoranu Camelia Maria, Stankovic Iva, Breedveld Guido, Ferraro Federico, Fevga Christina, Windl Otto, Herms Jochen, Kiechl Stefan, Poewe Werner, Seppi Klaus, Stefanova Nadia, Scholz Sonja W, Bonifati Vincenzo, Wenning Gregor K
Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Munich, Germany.
Brain Commun. 2022 Jul 4;4(4):fcac175. doi: 10.1093/braincomms/fcac175. eCollection 2022.
Multiple system atrophy is considered a sporadic disease, but neuropathologically confirmed cases with a family history of parkinsonism have been occasionally described. Here we report a North-Bavarian (colloquially, Lion's tail region) six-generation pedigree, including neuropathologically confirmed multiple system atrophy and Parkinson's disease with dementia. Between 2012 and 2020, we examined all living and consenting family members of age and calculated the risk of prodromal Parkinson's disease in those without overt parkinsonism. The index case and one paternal cousin with Parkinson's disease with dementia died at follow-up and underwent neuropathological examination. Genetic analysis was performed in both and another family member with Parkinson's disease. The index case was a female patient with cerebellar variant multiple system atrophy and a positive maternal and paternal family history for Parkinson's disease and dementia in multiple generations. The families of the index case and her spouse were genealogically related, and one of the spouse's siblings met the criteria for possible prodromal Parkinson's disease. Neuropathological examination confirmed multiple system atrophy in the index case and advanced Lewy body disease, as well as tau pathology in her cousin. A comprehensive analysis of genes known to cause hereditary forms of parkinsonism or multiple system atrophy lookalikes was unremarkable in the index case and the other two affected family members. Here, we report an extensive European pedigree with multiple system atrophy and Parkinson`s disease suggesting a complex underlying α-synucleinopathy as confirmed on neuropathological examination. The exclusion of known genetic causes of parkinsonism or multiple system atrophy lookalikes suggests that variants in additional, still unknown genes, linked to α-synucleinopathy lesions underlie such neurodegenerative clustering.
多系统萎缩被认为是一种散发性疾病，但偶尔也会有帕金森病家族史且经神经病理学确诊的病例报道。在此，我们报告一个来自北巴伐利亚（俗称“狮尾地区”）的六代家系，其中包括经神经病理学确诊的多系统萎缩以及帕金森病合并痴呆。在2012年至2020年期间，我们对所有在世且同意参与研究的适龄家庭成员进行了检查，并计算了那些没有明显帕金森病症状的人患前驱帕金森病的风险。索引病例和一名患有帕金森病合并痴呆的父系表亲在随访期间死亡，并接受了神经病理学检查。对这两人以及另一名患有帕金森病的家庭成员进行了基因分析。索引病例是一名患有小脑型多系统萎缩的女性患者，其母系和父系家族多代均有帕金森病和痴呆的阳性家族史。索引病例及其配偶的家族有亲缘关系，配偶的一名兄弟姐妹符合可能的前驱帕金森病标准。神经病理学检查证实索引病例患有多系统萎缩，其表亲患有晚期路易体病以及tau病理学改变。对已知会导致遗传性帕金森病或类似多系统萎缩疾病的基因进行的全面分析在索引病例和其他两名受影响的家庭成员中未发现异常。在此，我们报告一个广泛的欧洲家系，其中有多系统萎缩和帕金森病，提示经神经病理学检查证实存在一种复杂的潜在α-突触核蛋白病。排除已知的帕金森病或类似多系统萎缩疾病的遗传病因表明，与α-突触核蛋白病病变相关的其他未知基因变异是这种神经退行性聚集的基础。
