肌肉強直症之分子診斷

Molecular Diagnosis of Hereditary Myotonic Disorders

蔡慧思(Hui-Szu Tsai)

指導教授 ： 李銘仁

國立臺灣大學/醫學院/分子醫學研究所/碩士(2012年)

https://doi.org/10.6342/NTU.2012.00684

摘要

肌強直症(Myotonic disorders)是一種肌肉收縮後不易放鬆的現象，患者的骨骼肌會出現自發性收縮現象，也常常在自主性收縮或是電刺激之後無法正常地馬上放鬆。依臨床表徵可分為失養性肌肉強直症(Myotonic dystrophies)與非失養性肌肉強直症(Nondystrophic myotonias)，其原因分別有遺傳性與後天性，通常來說，非失養性肌肉肌強直症患者在神經傳導檢查是正常的，肌肉組織切片檢查也極少有異常問題，僅能由肌電圖檢查發現異常。若要探究真正致病原因則必須倚靠分子診斷，SCN4A與CLCN-1突變是引發非失養性肌肉肌強直症機率較高的兩個基因，但其相關研究並不多，且SNC4A與CLCN-1基因突變所造成的表現型(phenotype)又非常多樣化，因此本研究計畫期望能以分子診斷的方法，鑑別出真正患有先天性肌肉強直症的病患，增加在台華人SNC4A與CLCN-1突變資料庫的內容、瞭解突變點位和臨床症狀的相關性，作為未來鑑別診斷和遺傳諮詢的參考依據。
本研究收集分別來自於七個家族的12個受試者進行分析，研究過程中為受試者進行家族史調查、生理檢查與基因分析。結果發現在臨床表現上，個案之間嚴重度差異很大，常規的神經學檢查只能在肌電圖中發現有肌強直現象；基因分析結果則發現七個家族中有兩個為CLCN1基因變異、有五個為SCN4A基因變異，其中CLCN1 Leu198Arg和SCN4A Ala1737Thr為新發現的胺基酸置換，屬於SNP或有病理意義的突變仍須進一步探討。CLCN1基因突變造成肌肉強直症的發生率約十萬分之一，然而SCN4A基因突變造成肌肉強直症的總和發生率略高，比對本研究結果，若依照目前的檢查流程，分子檢查應首先考慮進行SCN4A的基因分析。

關鍵字

先天性肌肉肌強直症 ； 鈉離子通道 ； 氯離子通道 ； SCN4A基因 ； CLCN-1基因

並列摘要

Myotonia is the delayed relaxation of skeletal muscle after voluntary contraction which might cause trouble in daily life. Myotonic disorders include the myotonic dys-trophies and nondystrophic myotonias (NDM). Mutations in the genes encoding chlo-ride (CLCN1) or sodium (SCN4A) channels result in muscle fiber hyperexcitability in patients with NDM. The phenotype of NDM is variable leading to difficulties in clinical diagnosis. The aim of the study is to identify the mutations in the two responsible genes from patients with NDM and to correlate the clinical phenotypes and genotypes.
We have 12 volunteers from 7 Taiwanese families with the problem of NDM. Mu-tation screening identified 2 families with CLCN1 mutations and 5 with SCN4A muta-tions. Clinically, patients with CLCN1 mutations (L198R and A402V) demonstrated marked myotonia with hypertrophic muscles. The age of onset of the patients is early at the first decade. Five index patients harbor four individual SCN4A mutations (V445M, V781I, T1313M and A1737T) with variable clinical features such as potassi-um-aggravated myotonia, paramyotonia congenita, or hyperkalemic-periodic paralysis. The age of onset is also quite young, at 1st ~2nd decades of life. Two mutations, L198R in CLCN1 and A1737T in SCN4A genes are novel. In our experience, it seems that fre-quency of a SCN4A mutation is higher than that of the CLCN1 mutation in Taiwanese patients with NDM. Herein, the details of the phenotypes of each mutant genotype have been discussed.

並列關鍵字

Myotonic disorder ； sodium channel ； chloride channel ； SCN4A gene ； CLCN-1 gene

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