頭部震顫伴小腦萎縮一例臨床表型及基因突變分析

謝坤銘 顧衛(wèi)紅 郝瑩 陳園園 張瑾 張鑫

頭部震顫伴小腦萎縮一例臨床表型及基因突變分析

謝坤銘 顧衛(wèi)紅 郝瑩 陳園園 張瑾 張鑫

目的通過對1例頭部震顫伴小腦萎縮患者臨床表型和基因檢測結(jié)果進行綜合分析,明確診斷疾病并探討基因檢測結(jié)果的解讀方法.方法與結(jié)果采集1例30歲男性患者臨床表型,進行二代基因測序和Sanger測序驗證,通過中文人類表型標(biāo)準用語、基因檢索工具Phenomizer、Ensembl數(shù)據(jù)庫、在線人類孟德爾遺傳數(shù)據(jù)庫相關(guān)信息,對基因檢測結(jié)果進行解讀.結(jié)果顯示,患者存在脊髓小腦共濟失調(diào)19型(SCA19型)致病基因KCND3基因雜合突變c.1057A>G(p.Ser353Gly),其父母均未攜帶該突變基因;患者還存在帕金森病20型致病基因SYNJ1基因雜合突變c.4436C>T(p.Thr1479Ile),其母攜帶該突變基因.表型相似度分析顯示,患者表型與SCA19型一致,KCND3基因變異位點c.1057A>G在不同物種同源基因中具有高度保守性.結(jié)論通過對患者臨床表型和基因檢測結(jié)果綜合分析,KCND3基因雜合突變c.1057A>G(p.Ser353Gly)為致病性突變.

脊髓小腦共濟失調(diào); 表型; 基因; 突變

共濟失調(diào)作為常見的神經(jīng)系統(tǒng)疾病表現(xiàn),涉及 多種病因,包括單基因遺傳病、散發(fā)性神經(jīng)變性病和獲得性疾病.從遺傳學(xué)角度看,神經(jīng)系統(tǒng)遺傳性疾病約占所有遺傳性疾病的60%,遺傳性共濟失調(diào)占神經(jīng)系統(tǒng)遺傳性疾病的10%～15%,迄今已報道100余種類型[1].遺傳模式可以分為常染色體顯性遺傳(AD)、常染色體隱性遺傳(AR)、X連鎖遺傳和線粒體母系遺傳,具有高度臨床異質(zhì)性和遺傳異質(zhì)性,其中,脊髓小腦共濟失調(diào)(SCA)呈常染色體顯性遺傳[2?3],臨床主要表現(xiàn)為平衡障礙、肢體協(xié)調(diào)障礙、步態(tài)不穩(wěn)、構(gòu)音障礙和眼球運動障礙等,且伴復(fù)雜神經(jīng)系統(tǒng)損害,如錐體系、錐體外系、視覺、聽覺、脊髓和周圍神經(jīng)系統(tǒng)損害等,主要病理損害部位為小腦、腦干和脊髓.目前報道的亞型達40余種[4?5].本文詳細分析1例頭部震顫伴小腦萎縮患者的臨床表型并對其基因檢測結(jié)果進行深入解讀.

病例資料

一、臨床特征

患者 男性,30歲,因頭頸部不自主晃動2年,于2013年11月6日至中日友好醫(yī)院運動障礙與神經(jīng)遺傳病專病門診就診.患者2年前無明顯誘因出現(xiàn)頭頸部不自主晃動,發(fā)作時間持續(xù)1～2 min或數(shù)天不等,肩部晃動僵硬,緊張和精細動作時易發(fā)作,進行性加重;言語模糊,構(gòu)音不清,偶有吞咽困難,睡眠時好時壞,可見胸悶、呼吸困難、反復(fù)發(fā)作的神經(jīng)性皮炎.既往史和個人史無特殊.父母身體健康,非近親婚配,無明確家族性遺傳性疾病病史.門診神經(jīng)系統(tǒng)檢查:神志清楚,輕度構(gòu)音障礙;眼球各向活動不充分,外展露白,未見眼震;頭部陣發(fā)性晃動;四肢肌力5級,雙上肢肌張力降低,腱反射減弱,雙下肢肌張力正常,腱反射正常,足跖反射正常,病理反射未引出;雙側(cè)指鼻試驗、跟?膝?脛試驗穩(wěn)準.簡易智能狀態(tài)檢查量表(MMSE)評分正常.實驗室檢查各項指標(biāo)均于正常值范圍.影像學(xué)檢查:頭部MRI顯示小腦重度萎縮,腦干中度萎縮(圖1).神經(jīng)電生理學(xué)檢查:心電圖、肌電圖和腦電圖均未見明顯異常.結(jié)合臨床表現(xiàn)和家族史,臨床擬診為常染色體隱性遺傳性共濟失調(diào).予金剛烷胺50 mg/次、2次/d,苯海索(安坦)1 mg/次、2次/d,氯硝西泮1 mg/d口服治療.至2016年3月復(fù)診時頭部晃動明顯緩解.

二、基因檢測

分別抽取患者及其父母外周靜脈血5 ml,送檢北京金準基因科技有限責(zé)任公司,進行3994種人類孟德爾遺傳性疾病致病基因外顯子二代基因測序和家系驗證.對候選變異位點采用Sanger測序進行家系驗證,提示患者存在2種可能的致病性突變:(1)KCND3基因雜合突變c.1057A>G(p.Ser353Gly).Sanger測序顯示其父母均未攜帶該突變基因(圖2).KCND3基因與SCA19型相關(guān),呈常染色體顯性遺傳,理論上1條染色體突變即可致病.(2)SYNJ1基因雜合突變c.4436C>T(p.Thr1479Ile).Sanger測序證實此突變來自其母(圖3).SYNJ1基因與帕金森病20型(PARK20型)相關(guān),呈常染色體隱性遺傳,理論上必須2條等位染色體同時出現(xiàn)致病性突變方可致病(即純合突變或復(fù)合雜合突變致病).

圖1 頭部MRI檢查顯示,小腦呈現(xiàn)重度萎縮(粗箭頭所示),腦干呈現(xiàn)中度萎縮(細箭頭所示)1a 橫斷面T1WI 1b 矢狀位T2WIFigure1 Head MRIshowed severecerebellaratrophy(thick arrows indicate)and moderate brain stem atrophy(thin arrow indicates). AxialT1WI(Panel1a). SagittalT2WI(Panel 1b).

三、突變的致病性分析

突變的致病性分析步驟為:(1)將核心表型轉(zhuǎn)化為中文人類表型標(biāo)準用語/人類表型標(biāo)準用語(CHPO/HPO,http://www.chinahpo.org/).(2)候選基因篩選,根據(jù)對應(yīng)的CHPO/HPO詞匯,采用基因檢索工具Phenomizer(http://compbio.charite.de/phenomizer/)檢索候選基因.(3)根據(jù)美國醫(yī)學(xué)遺傳學(xué)和基因組學(xué)會(ACMG)制定的變異位點分級指南(http://wintervar.wglab.org/),輸入突變基因信息,結(jié)合核心表型、家族史和遺傳模式,即可判斷突變基因的致病性."Pathogenic"表示已知致病性突變,"likely pathogenic"表示疑似致病性突變,"VUS"表示臨床意義不明的突變,"likely benign"表示疑似良性突變,"benign"表示良性突變.(4)保守性分析,通過 Ensembl數(shù)據(jù)庫(http://useast.ensembl.org/index.html)獲取多物種相關(guān)基因序列,采用BioEdit軟件(http://www.bioedit.com/)比對變異位點在不同物種的序列保守性.(5)表型相似度分析,通過檢索在線人類孟德爾遺傳數(shù)據(jù)庫(http://www.omim.org/)比對疾病表型與患者表型.

1.核心表型轉(zhuǎn)化為中文人類表型標(biāo)準用語 采用CHPO搜索引擎檢索本文患者的核心表型,結(jié)果參見表1.

圖2 該例患者及其父母KCND3基因Sanger測序所見 2a 患者存在KCND3基因c.1057A>G(p.Ser353Gly)雜合突變(紅色圓圈所示)2b 其父不攜帶KCND3基因突變(紅色圓圈所示)2c其母不攜帶KCND3基因突變(紅色圓圈所示)Figure 2 The Sanger sequencing of KCND3 gene of the patient and his parents.Heterozygous mutation of KCND3 gene c.1057A>G(p.Ser353Gly)in the patient(red circle indicates,Panel 2a).No KCND3 gene mutation in the patient's father(red circle indicates,Panel 2b)and mother(red circle indicates,Panel 2c).

圖3 該例患者及其父母SYNJ1基因Sanger測序所見 3a 患者存在SYNJ1基因c.4436C>T(p.Thr1479Ile)雜合突變(紅色圓圈所示) 3b 其父不攜帶SYNJ1基因突變(紅色圓圈所示)3c 其母存在SYNJ1基因c.4436C>T(p.Thr1479Ile)雜合突變(紅色圓圈所示)Figure 3 The Sanger sequencing of SYNJ1 gene of the patient and his parents.Heterozygous mutation of SYNJ1 gene c.4436C>T(p.Thr1479Ile)in the patient(red circle indicates,Panel 3a).No SYNJ1 gene mutation in the patient's father(red circle indicates,Panel 3b).Heterozygous mutation of SYNJ1 gene c.4436C>T(p.Thr1479Ile)in the patient's mother(red circle indicates,Panel 3c).

2.基于人類表型標(biāo)準用語篩選候選基因 通過基因檢索工具Phenomizer,篩選致病基因,結(jié)果顯示,相關(guān)度最大的基因為KCND3基因(P=0.000).

3.確定致病性突變 根據(jù)美國醫(yī)學(xué)遺傳學(xué)和基因組學(xué)會制定的變異位點分級指南,KCND3基因為"pathogenic",即致病性突變;SYNJ1基因為"likely pathogenic",即疑似致病性突變.

4.保守性分析 通過Ensemble數(shù)據(jù)庫檢索KCND3基因及其他物種同源基因序列,采用BioEdit軟件進行比對分析,結(jié)果顯示,變異位點在不同物種的進化中具有高度保守性(圖4).

5.表型相似度分析 通過在線人類孟德爾遺傳數(shù)據(jù)庫檢索KCND3和SYNJ1基因相關(guān)疾病表型,與患者表型進行比對.核心表型為小腦萎縮、頭頸部不自主晃動、腱反射減弱、構(gòu)音障礙和吞咽困難,與KCND3基因的疾病表型(SCA19型)高度相似,提示為致病基因(表2).SYNJ1基因的疾病表型為PARK20型,表現(xiàn)為面具臉、目光凝視、眼瞼失用癥、掃視障礙、核上性凝視麻痹、下頜震顫、動作遲緩、肌僵直、拖步、姿勢不穩(wěn)、震顫、肌張力障礙、認知功能障礙和早發(fā)型癲發(fā)作,頭部MRI顯示大腦皮質(zhì)萎縮[6?7],與患者表型不符,排除SYNJ1基因致病的可能.經(jīng)基因檢測最終明確診斷為SCA19型,繼續(xù)予藥物治療以緩解相應(yīng)癥狀.

討 論

脊髓小腦共濟失調(diào)呈常染色體顯性遺傳,自1993年SCA1型致病基因定位以來,根據(jù)研究者對其致病基因定位的時間順序,由國際人類基因組組織基因命名委員會(HGNC)命名,至2017年5月已定位43個致病基因位點,其中28種致病基因已被克隆(http://neuromuscular.wustl.edu/ataxia/domatax.html).脊髓小腦共濟失調(diào)家系中大部分為致病基因動態(tài)突變,采用毛細管電泳片段分析法可檢出.隨著二代基因測序技術(shù)的發(fā)展,越來越多的非動態(tài)突變逐漸被發(fā)現(xiàn),其致病性尚待進一步明確.

表1 該例患者核心表型及其對應(yīng)的CHPO/HPOTable 1. The core phenotype and corresponding CHPO/HPO of the patient

圖4 保守性分析顯示,KCND3基因變異位點c.1057A>G在不同物種同源基因中具有高度保守性Figure 4 Conservation analysis showed the variation locus of KCND3 gene c.1057A>G was highly conservative with the homologous gene in different species.

該例患者28歲起病,無明確家族史,最初考慮為常染色體隱性遺傳性共濟失調(diào),通過二代基因測序并結(jié)合臨床表型分析,檢出SCA19型相關(guān)基因KCND3基因雜合突變c.1057A>G(p.Ser353Gly),為新發(fā)突變,且在進化過程中高度保守.

SCA19型發(fā)病年齡多樣化,自青年至中年均可發(fā)病,進展緩慢.已報道的家系多有小腦萎縮癥狀,以頭部晃動發(fā)病,伴輕至中度構(gòu)音障礙,其他癥狀還包括凝視誘發(fā)眼震,吞咽困難,小腦、步態(tài)、軀干、肢體共濟失調(diào),腱反射減弱,姿勢性震顫,肌陣攣,認知功能障礙和踝振動覺受損等[8].SCA19型最早發(fā)現(xiàn)于一荷蘭家系,先證者約31歲時以頭部晃動發(fā)病,繼而出現(xiàn)構(gòu)音障礙,逐漸出現(xiàn)行走困難,神經(jīng)系統(tǒng)查體顯示不規(guī)則震顫,頻率緩慢,姿勢變化和站立時頭頸部不自主晃動,細小眼震,眼球各向活動充分,關(guān)節(jié)位置覺受損、雙足振動覺減退,四肢協(xié)調(diào)性受到嚴重影響,表現(xiàn)出辨距不良和快復(fù)輪替動作笨拙,共濟失調(diào)步態(tài)[9].Verbeek等[10]通過全基因組測序(WGS)將致病基因定位于1p21～q21.2003年一中國脊髓小腦共濟失調(diào)家系致病基因定位于1p21～q23,當(dāng)時被國際人類基因組組織基因命名委員會命名為SCA22型[11].但在2004年,Schelhaas等[12]發(fā)現(xiàn)SCA19型和SCA22型的基因突變位點相重合,至此認為二者為脊髓小腦共濟失調(diào)的同一亞型.2012年,Duarri等[13]的研究顯示,KCND3基因為SCA19型致病基因.

KCND3蛋白系編碼電壓門控性鉀離子通道(VGKC)的Shal家族α亞單位,對細胞膜復(fù)極化具有重要作用[14],包括6個跨膜片段和細胞內(nèi)氨基末端(N末端)和羧基末端(C末端).逆轉(zhuǎn)錄?聚合酶鏈反應(yīng)(RT?PCR)和測序分析證實1個剪切位點突變KCND3L,插入編碼1個含19個氨基酸的多肽鏈,包含1個磷酸化位點,其中較短亞型為KCND3S[15].Northern blotting法檢測顯示,長度為8.50X103bp的轉(zhuǎn)錄本在腦和心臟呈高表達,而在腎臟、肝臟、肺、胰腺、脾或骨骼肌中未檢測到[16].這種長轉(zhuǎn)錄本主要見于丘腦、尾狀核、白質(zhì)和骨骺,短轉(zhuǎn)錄本主要見于額葉、枕葉和小腦皮質(zhì)[17].1999年首次在人類大腦和心臟中克隆出KCND3基因,RT?PCR法發(fā)現(xiàn)僅KCND3基因長片段在心臟表達[18],包含7個外顯子,長度約25X 103bp,而較短亞型由6個外顯子編碼.KCND3基因突變導(dǎo)致其編碼的電壓門控性鉀離子通道特性改變,引起智力障礙、癲發(fā)作、注意力缺陷、多動、斜視和口唇失用等癥狀[19].

該例患者頭頸部不自主晃動,肩部晃動僵硬,緊張和精細動作時易發(fā)作,進行性加重,言語模糊;神經(jīng)系統(tǒng)檢查,輕度構(gòu)音障礙,眼球各向活動不充分,未見眼震,陣發(fā)性頭部晃動,四肢肌力5級,雙上肢肌張力偏低,腱反射減弱,雙下肢肌張力正常,腱反射適中,足跖反射正常,雙側(cè)指鼻試驗、跟?膝?脛試驗穩(wěn)準;頭部MRI顯示明顯小腦萎縮,上述表型與荷蘭SCA19型家系臨床表型相似.

SYNJ1基因相關(guān)疾病表型為PARK20型,臨床特點為運動遲緩、肌肉僵直、靜止性震顫、姿勢不穩(wěn)、核上性凝視麻痹、癡呆、肌張力障礙和全面性強直?陣攣發(fā)作(GTCS)[20],左旋多巴或其他擬多巴胺類藥治療有效[21].該例患者帕金森病癥狀并不明顯,且該突變位點源自其母,其父無突變,該基因為常染色體隱性遺傳,因此考慮SYNJ1基因致病的可能性不大.

表2 該例患者KCND3基因相關(guān)疾病表型與患者表型相似度分析Table 2. Phenotypic similarity analysis of the patient

在對該例患者臨床表型和基因檢測結(jié)果進行綜合分析解讀過程中,我們采用CHPO/HPO,有助于表型標(biāo)準化并連接基因數(shù)據(jù)庫進行解讀.HPO旨在提供人類疾病中用于描述表型異常的標(biāo)準詞匯,從醫(yī)學(xué)文獻、Orphanet數(shù)據(jù)庫、DECIPHER數(shù)據(jù)庫和在線人類孟德爾遺傳數(shù)據(jù)庫獲得的信息進行開發(fā),目前包含11 896個名詞,同時還提供一套針對約4000種疾病的注釋.HPO一直持續(xù)進行詞條維護和完善.目前國內(nèi)大部分醫(yī)療和科研工作者所使用的表型描述詞匯并無統(tǒng)一標(biāo)準,大多數(shù)醫(yī)院信息系統(tǒng)中記錄的臨床表型數(shù)據(jù)均為非結(jié)構(gòu)化的自然詞匯,給人類疾病尤其是遺傳性疾病的臨床研究和交流帶來不便,對后期數(shù)據(jù)挖掘和分析也造成很大困擾,因此,在中國建立一套標(biāo)準的臨床表型詞匯非常重要.CHPO作為開放平臺,旨在聯(lián)合各相關(guān)領(lǐng)域?qū)I(yè)人士,逐步建立中文臨床表型詞匯標(biāo)準,并指導(dǎo)和服務(wù)于中文使用者的臨床和科研工作,目前已建立搜索引擎http://www.chinahpo.org/.

本研究通過對1例無明確家族史的頭部震顫伴小腦萎縮患者的臨床表型和基因數(shù)據(jù)進行綜合分析,探討表型標(biāo)準化結(jié)合分析軟件工具進行基因檢測選點和結(jié)果解讀的方法和流程:(1)將患者核心表型轉(zhuǎn)化為CHPO/HPO.(2)將患者的HPO結(jié)果輸入基因檢索工具,如Phenomizer,篩選可能的候選致病基因.(3)將二代基因測序檢出的基因變異位點與上述分析結(jié)果相結(jié)合進行選點.(4)根據(jù)美國醫(yī)學(xué)遺傳學(xué)和基因組學(xué)會制定的變異位點分級指南進行致病性評價.(5)表型相似度分析,基于在線人類孟德爾遺傳數(shù)據(jù)庫記錄的臨床表型與患者表型進行細致比對.隨著二代基因測序技術(shù)的快速發(fā)展,基因檢測費用下降,在高通量測序獲得大量變異選點過程中,表型數(shù)據(jù)與基因數(shù)據(jù)的有效連接至關(guān)重要.整個流程涉及多個環(huán)節(jié),由不同專業(yè)背景的人員和機構(gòu)參與,如何確保信息的可靠性,以及在傳遞過程中避免信息丟失和發(fā)生偏倚,需建立共同語言.HPO即為很好的連接方式,可以將醫(yī)師所了解的患者表型信息、檢測機構(gòu)獲得的患者基因信息、疾病和基因數(shù)據(jù)庫三者進行連接,為遺傳性疾病的診斷提供重要支持工具.

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Clinical phenotype and genetic mutation of one case with head tremor and cerebellar atrophy

XIE Kun?ming1,GU Wei?hong2,HAO Ying2,CHEN Yuan?yuan2,ZHANG Jin2,ZHANG Xin21Grade 2014,College of Traditional Chinese Medicine,Beijing University of Chinese Medicine,Beijing 100029,China
2Movement Disorder&Neurogenetics Research Center,China?Japan Friendship Hospital,Beijing 100029,China Corresponding author:GU Wei?hong(Email:jane55.gu@vip.sina.com)

ObjectiveTo make the diagnosis for a patient presented with head tremor and cerebellar atrophy by integrating clinical features and accessory examination with genetic testing and to explore the interpretation of genetic testing results.MethodsA 30?year?old male patient's medical information,clinical pheontype,family history and accessory examinations were collected.The next?generation sequencing(NGS)of exons in 3994 causative genes of Mendelian inheritance diseases and the family tree verification were carried out.China Human Phenotype Ontology(CHPO),Phenomizer,Ensembl and Online Mendelian Inheritance in Man(OMIM)database were used to interpret the genetic test results.ResultsThe patient carried heterozygous mutation of spinocerebellar ataxia type 19(SCA19)related KCND3 gene c.1057A>G(p.Ser353Gly),but his parents did not carry this mutation.The patient also carried heterozygous mutation of parkinsonism type 20(PARK20)related SYNJ1 gene c.4436C>T(p.Thr1479Ile)which was also seen in his mother.Phenotypic similarity analysis showed the patient's phenotype was correspond with the phenotype of SCA19,and the variation locus of KCND3 gene c.1057A>G was highly conservative with homologous gene in different species.ConclusionsBy means of the integration of clinical phenotype with the result of genetic test,KCND3 gene c.1057A>G(p.Ser353Gly)carried in the patient is the pathogenic mutation.

Spinocerebellar ataxias; Phenotype; Genes; Mutation

This study was supported by Grant Awarded 2010-2012 from Ministry of Health Foundation of China.

10.3969/j.issn.1672?6731.2017.07.007

衛(wèi)生部部署(管)醫(yī)院2010-2012年度臨床學(xué)科重點項目

100029北京中醫(yī)藥大學(xué)中醫(yī)學(xué)院2014級(謝坤銘);100029北京,中日友好醫(yī)院運動障礙與神經(jīng)遺傳病研究中心(顧衛(wèi)紅,郝瑩,陳園園,張瑾,張鑫)

顧衛(wèi)紅(Email:jane55.gu@vip.sina.com)

2017?06?08)