台大郭夢菲MRA診斷 毛毛樣病 (Moyamoya Disease)

磁振血管造影 揪出腦部毛毛樣病【台灣醒報╱記者李昀澔╱台北報導】2014.04.30 07:45 pm小朋友也會腦中風！台大醫院小兒神經外科主任郭夢菲30日發表與科技部合作「腦血管毛毛樣病」的研究成果時指出，運用磁振血管造影（MRA）診斷，較磁振造影（MRI）精準，也可代替斷層掃描，避免兒童過早暴露於輻射線。科技部政務次長錢宗良表示，毛毛病與基因突變有關，若找到血液中的「生物標記」，透過驗血就能早期診斷。毛毛樣病患者多為東亞兒童，最初由日本人發現，係由於腦部大血管因不明原因逐漸狹窄，為維持正常供血，人體會自然長出許多彎曲的小血管取代大血管功能，從X光片上看起來就像一叢毛或霧；正常兒童即便用力吹氣球或大聲哭鬧，也不致癱軟，但病童光是將熱湯吹涼而不斷吹氣，就可能導致腦血管急速收縮，輸往腦部血量減少，引發癱軟、無力等症狀。

【哭鬧後異常癱軟】由於孩童哭鬧後往往因疲倦而睡著，病童即便出現癱軟症狀，睡醒後血流即恢復正常，家長因而忽略了異常症狀，常導致持續性的癱瘓、語言障礙、癲癇、智力發展遲緩等嚴重症狀出現後才就醫，若延至成人期才病發，極可能演變為容易致命的出血性腦中風。台灣每10萬人中約有1.61人罹患毛毛樣病，每年新診斷病例約為20至30人，日本毛毛樣病發生率在1997年之前約為台灣的17.5倍，近年則約7.5倍，南韓患者也較台灣多；郭夢菲指出，東亞人種基因類似，國內也有3成患者檢出東方人最常見的「RNF213」遺傳基因突變，因此未來必須再精進診斷技術，才能釐清台灣人罹病比例是否較其他東亞國家低。

【手術治療有效】郭夢菲主導的團隊發現，國內有4分之一、特別是5歲以下的毛毛樣病童有癲癇症狀，治療這類癲癇必須解決腦部缺血問題，單憑傳統治療難以改善；治療毛毛樣病最有效的方式，就是透過各種顱內外直接或間接的「血管吻合」，也就是接合血管的手術，讓腦部恢復正常供血。動手術前必須先確認腦內缺血的部位，傳統檢測毛毛樣病的腦血管攝影技術，需將細管深入體內血管，屬侵入性檢查，合併電腦斷層需接觸輻射物質，郭夢菲並不建議兒童使用，而相對安全的MRI卻無法得到精確結果；郭夢菲改以MRA之腦灌流造影技術替代，準確度極高，也方便患者術後長期追蹤。

【尋求驗血診斷】由於健保並非無限制地給付磁振造影檢查，郭夢菲等人便著手研究毛毛樣病患者在腦血管狹窄初期的血液內物質變化，希望找到某些代謝物質等「生物標記」，以協助早期診斷及術後追蹤。郭夢菲表示，國內患者年齡多為5至15歲，女性患者約為男性的1.3倍；病童智商雖與常人無異，但深入分析後發現幾乎都有某種認知功能缺陷，例如學習新單字，或「提取」腦部資訊速度較慢等問題。經過血管吻合手術後，幾乎所有患者頭痛、失語、癲癇、不自主運動的症狀都有改善，多年後追蹤都沒有再次中風，「顯示這類腦中風『可治癒』，值得發展早期診斷技術。」【2014/04/30 台灣醒報】

Molecular Analysis of RNF213 Gene for Moyamoya Disease in the Chinese Han Population, Published: October 23, 2012DOI: 10.1371/journal.pone.0048179

Background Moyamoya disease (MMD) is an uncommon cerebrovascular disorder characterized by progressive occlusion of the internal carotid artery causing cerebral ischemia and hemorrhage. Genetic factors in the etiology and pathogenesis of MMD are being increasingly recognized. Previous studies have shown that the RNF213 gene was related to MMD susceptibility in the Japanese population. However, there is no large scale study of the association between this gene and MMD in the Chinese Han population. Thus we designed this case-control study to validate the R4810K mutation and to define the further spectrum of RNF213 mutations in Han Chinese.

Methodology/Principal Findings Genotyping of the R4810K mutation in the RNF213 gene was performed in 170 MMD cases and 507 controls from a Chinese Han population. The R4810K mutation was identified in 22 of 170 MMD cases (13%), including 21 heterozygotes and a single familial homozygote. Two of the 507 controls (0.4%) were heterozygous R4810K carriers. The R4810K mutation greatly increased the risk for MMD (OR = 36.7, 95% CI: 8.6~156.6, P = 6.1 E-15). The allele frequency of R4810K was significantly different between patients with ischemia and hemorrhage (OR = 5.4, 95% CI: 1.8~16.1, P = 0.001). Genomic sequencing covering RNF213 exon 40 to exon 68 also identified eight other non-R4810K variants; P4007R, Q4367L, A4399T, T4586P, L4631V, E4950D, A5021V and M5136I. Among them A4399T polymorphism was found in 28/170 cases (16.5%) and 45/507 controls (8.9%) and was associated with MMD (OR = 2.0, 95% CI: 1.2~3.3, P = 0.004), especially with hemorrhage (OR = 2.8, 95% CI: 1.2~6.5, P = 0.014).

Conclusions RNF213 mutations are associated with MMD susceptibility in Han Chinese. The ischemic type MMD is particularly related to the R4810K mutation. However, A4399T is also a susceptible variant for MMD, primarily associated with hemorrhage. Identification of novel variants in the RNF213 gene further highlights the genetic heterogeneity of MMD.