Matsukawa Takashi, Porto Kristine Joyce L, Mitsui Jun, Chikada Ayaka, Ishiura Hiroyuki, Takahashi Yuji, Nakamoto Fumiko Kusunoki, Seki Tomonari, Shiio Yasushi, Toda Tatsushi, Tsuji Shoji
Department of Molecular Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Cerebellum. 2024 Feb;23(1):22-30. doi: 10.1007/s12311-022-01426-z. Epub 2022 Sep 13.
While multiple system atrophy (MSA) has been considered a sporadic disease, there were previously reported multiplex families with MSA. Furthermore, several families with multiple patients with MSA and Parkinson's disease (PD) have been reported. As genetic risk factors for MSA, functionally impaired variants in COQ2 and Gaucher-disease-causing GBA variants have been reported. While it has been established that GBA variants are associated with PD, COQ2 may also be associated with PD. In 672 patients with MSA, we identified 12 multiplex families of patients with MSA and PD in first-degree relatives. We conducted a detailed analysis of the clinical presentations of these patients and genetic analyses of GBA and COQ2. In the multiplex families, a patient with MSA with predominant parkinsonism (MSA-P) was observed in nine families, while a patient with MSA cerebellar subtype (MSA-C) was observed in three families. Six families had siblings with MSA and PD, five families had a parent-offspring pair with MSA and PD, and in one family, a sibling and a parent of an MSA patient had PD. In genetic analyses of these patients, GBA variants were identified in one of the 12 MSA patients and two of the seven PD patients. Functionally impaired variants of COQ2 were identified in two of the 12 MSA patients and not identified in the seven PD patients. This study further emphasizes the occurrence of MSA and PD in first-degree relatives, raising the possibility that a common genetic basis underlies MSA and PD. Even though variants of COQ2 and GBA were identified in some patients in multiplex families with MSA and PD, it is necessary to further explore as yet unidentified genetic risk factors shared by MSA and PD.
虽然多系统萎缩（MSA）一直被认为是一种散发性疾病，但此前曾有报道称存在MSA的多个患病家族。此外，还报道了几个有多名MSA患者和帕金森病（PD）患者的家族。作为MSA的遗传风险因素，已报道了COQ2功能受损变体和导致戈谢病的GBA变体。虽然已经确定GBA变体与PD有关，但COQ2也可能与PD有关。在672例MSA患者中，我们在一级亲属中识别出12个MSA和PD患者的多个患病家族。我们对这些患者的临床表现进行了详细分析，并对GBA和COQ2进行了基因分析。在这些多个患病家族中，9个家族中观察到以帕金森综合征为主的MSA患者（MSA-P），3个家族中观察到小脑亚型MSA患者（MSA-C）。6个家族中有兄弟姐妹同时患有MSA和PD，5个家族中有父母与子女同时患有MSA和PD，在1个家族中，1名MSA患者的1个兄弟姐妹和1名父母患有PD。在对这些患者的基因分析中，12例MSA患者中有1例、7例PD患者中有2例检测到GBA变体。12例MSA患者中有2例检测到COQ2功能受损变体，7例PD患者中未检测到。本研究进一步强调了一级亲属中MSA和PD的发生，增加了MSA和PD存在共同遗传基础的可能性。尽管在MSA和PD的多个患病家族中的一些患者中检测到了COQ2和GBA变体，但仍有必要进一步探索MSA和PD共同的尚未确定的遗传风险因素。
