Abstract
摘要:Moyamoya 病(MMD)是一種以雙側內頸動脈狹窄及側支血管異常為特徵的漸進性動脈狹窄疾病。狹窄閉塞的變化可能會導致短暫性腦缺血發作和/或腦梗塞,有側支血管之破裂導致顱內出血。 MMD 的自然進展過程可以是緩慢的神經系統功能退化到神經功能的迅速破壞。一些已知的預後因素,包括術前腦梗塞,發病年齡早,智力障礙,癲癇,以及漸進性後大腦動脈(PCA)狹窄等。外科血行重建可以改善腦血流動力學和防止缺血性症狀的進一步侵犯。因此,早期診斷與手術治療對於受影響病人的個人健康和社會經濟因素是非常重要的。遺傳因素在MMD 的致病原因上是有其臨床意義的。 MMD 有近50%是10 歲以下的兒童。在日本的MMD 患者,10〜15%被發現其家族史是陽性。在全球最近的研究已發現有五個基因遺傳位點和MMD 有連鎖關係。此外,在兩個候選基因,RNF213 和ACTA2找到的突變,已經被發現是造成日本和歐洲人的MMD。到目前為止,並沒有台灣和中國大陸的MMD 病患的基因遺傳數據的報導。我們已經收集了三個年輕發病的MMD 家族,與至少50 個零星MMD 的兒童的腦血管疾病診療資料。本研究的目的是要通過對疾病基因的研究,發現MMD 的致病機制。在此研究中我們設立三個具體目標。在第一年,我們將詳細檢視MMD 的家庭成員和零星病例的臨床特徵。其次,將在家庭中的指標個案進行兩個已知基因,RNF213 和ACTA2 的突變篩檢。如果發現突變在任何一個基因,我們將在第二年在散發的MMD 病例中進行進一步的Haplotype 的評估。進一步確認這個病和這個基因的關聯性。第三年的研究重點,將是製造一個遺傳變異的小鼠模型,以供後續研究MMD 致病機轉之用。如果在第一年,未能找出致病基因的突變,我們會將指標個案和他們的父母的DNA 進行全基因體外顯子定序。任何核甘酸變異,我們將透過dbSNP 和1000Gemome 的基因資料庫中的數據以及MMD 的連鎖分析資料來過濾。在第三年,我們將從帶有指標個案序列變異的候選基因中挑出Haplotype,然後將測試這些Haplotypes 是否和MMD 的致病機率有相關。
Abstract: Moyamoya disease (MMD) shows progressive arteriopathy characterized by bilateral internalcarotid artery stenosis and abnormal collateral vessels. The steno-occlusive change can resultin transient ischemic attacks and/or cerebral infarction, and sometimes rupture of thecollateral vessels leading to intracranial hemorrhage. The nature history of MMD varies fromslow progression to rapid neurological decline. A few established prognostic factors includepreoperative infarctions, early age at onset, intellectual impairment, seizure, and progressiveposterior cerebral artery (PCA) stenosis. Surgical revascularization can improve thecerebrovascular hemodynamics and prevent further attacks in the ischemic type of MMD.Therefore, early diagnosis with surgical intervention is important to both individual health andsocio-economy of the affected patient.It is known that genetic factors underlying MMD are of clinical relevance. Children under 10years of age account for nearly 50% of all MMD cases. A positive family history was found in10 ~ 15% of MMD patients from Japanese. Five genetic linked loci have been found in recentstudies worldwide. Furthermore, mutations in two candidate genes, RNF213 and ACTA2,were identified and responsible to the MMD in Japanese and European populations. Up todate, no genetic data of Taiwanese and Chinese population have been reported. We havealready collected three families with young onset MMD and at least 50 sporadic MMDchildren in cerebrovascular clinic. The object of the research is to elucidate the pathogenicmechanisms of MMD through the identification of the disease causative genes. Three specificaims have been set. In the first year, we would characterize the clinical features of the MMDfamilies and sporadic cases in detail. Mutation screening in two responsible gene, RNF213and ACTA2 would be screened in the index cases in these families. If the mutations wereidentified, further evaluation of the haplotypes in the sporadic cases would be carried out inthe second year. The construction of a genetic manipulated mouse model would be carried outin the final year. If failed to identify a pathogenic mutation, the DNA from the index cases andtheir parents would be sent for exome sequencing. The variants would then be filtered usingthe data from dbSNP and 1000 Genome databases as well as the MMD linkage analysis.Haplotypes from the candidate gene which harbor the sequence variant from the index cases,would then be test whether it is the pathological allele.
Keyword(s)
毛毛樣病變
台灣家族
基因RNF213
ACTA2
haplotype
moyamoya
Taiwanese
RNF213
ACTA2
haplotype