Primary familial brain calcification presenting as paroxysmal kinesigenic dyskinesia: Genetic and functional analyses
Primary familial brain calcification presenting as paroxysmal kinesigenic dyskinesia: Genetic and functional analyses
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DOI：
10.1016/j.neulet.2019.134543
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发表时间：
2020-01-01
影响因子：
2.5
通讯作者：
Cao, Li
中科院分区：
文献类型：
--
作者：
Zhan, Fei-Xia;Tian, Wo-Tu;Cao, Li
背景资料：原发性家族性脑钙化是一种罕见的神经退行性疾病，其特征是双侧对称性脑内钙沉积。有证据表明PFBC可能与阵发性运动诱发性运动障碍（PKD）有关。我们的目的是调查PFBC患者表现为PKD的遗传原因，并进一步探讨所确定的突变的致病性影响。进行临床评估，包括实验室检查，头部计算机断层扫描（CT），然后进行外显子组测序。筛选PFBC基因的变异体，并应用桑格测序、分离分析等方法进行验证。结果：在4例PKD样PFBC患者中，3例出现脑钙化，1例携带PFBC突变但无脑钙化。总结其临床特点。结果发现PFBC基因存在3种杂合突变（2种新的，1种已报道的），进一步的功能研究表明，突变蛋白的异常积累和Pi摄取减少，聚集的PDGFB与野生型相比不能引起膜皱褶。结论：PKD可能是PFBC的一种表现，脑钙化可能是继发性PKD的原因之一。因此，在诊断PKD或PFBC之前，应进行全面的评估，包括头部CT或阵发性运动障碍和PFBC的遗传筛查。此外，阴性脑钙化可能不排除PFBC的可能性。原发性钙化的发病机制可能与突变引起的蛋白质功能障碍或信号转导缺陷有关。
Background: Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by calcium deposition in bilateral and symmetric brain. Evidence suggested that PFBC might be associated with paroxysmal kinesigenic dyskinesia (PKD). We aim to investigate the genetic causes in PFBC patients manifested as PKD, and further to explore the pathogenic impact of the identified mutations.Methods: 4 PKD-mimic PFBC patients were investigated in the study. Clinical assessment including laboratory tests, head computed tomography (CT) were conducted and followed by exome sequencing. Variants of PFBC genes were screened, and Sanger sequencing, segregation analysis were applied to confirm the findings. Functional assessment of the identified mutations was further analyzed.Results: Among the 4 PKD-mimic PFBC patients, 3 presented with brain calcification, and 1 was identified carrying a PFBC mutation but without brain calcification. The clinical characteristics were summarized. Three heterozygous variants (2 novel, 1 documented) in PFBC genes were found. Further functional study showed abnormal accumulation and reduced uptake of Pi of the mutant protein, and the aggregated PDGFB failing to induce membrane ruffles compared with wild-type.Conclusions: PKD can be a manifestation of PFBC, and brain calcification may be a cause of secondary PKD. So thoroughly evaluation including head CT or genetic screening for paroxysmal dyskinesia and PFBC should be applied before the diagnosis of PKD or PFBC. Moreover, negative brain calcification may not exclude the possibility of PFBC. The possible pathogenesis of primary calcification lie in the dysfunction of the protein or defective signal transduction caused by the mutations.