發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙臨床表型分析

田沃土 黃嘯君 沈雋逸 徐洋奇 陳生弟 曹立

.神經(jīng)系統(tǒng)遺傳性疾病.

發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙臨床表型分析

田沃土 黃嘯君 沈雋逸 徐洋奇 陳生弟 曹立

研究背景發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙是一組由突然動作誘發(fā)的非隨意性運(yùn)動障礙性疾病,表現(xiàn)為反復(fù)發(fā)作的短暫性肌張力障礙或舞蹈樣動作,具有高度臨床和遺傳異質(zhì)性.本研究旨在總結(jié)中國發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙臨床表型特點.方法采集195例原發(fā)性發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙患者臨床資料,采用自行設(shè)計的發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙登記表記錄并整理,分析和總結(jié)發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙臨床表型特點,并比較家族性與散發(fā)性患者臨床表型差異.結(jié)果195例發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙患者男女比例為4.42∶1,平均發(fā)病年齡為(12.32±3.49)歲,單純型162例(83.08%)、復(fù)雜型33例(16.92%),16例(8.21%)合并特發(fā)性震顫,144例(73.85%)發(fā)作前有先兆,發(fā)作形式包括肌張力障礙(134例,68.72%)、舞蹈樣動作(8例,4.10%)和二者混合形式(53例,27.18%),134例(68.72%)發(fā)作時面部受累,115例(58.97%)發(fā)作頻率<10次/d、54例(27.69%)10～20次/d、26例(13.33%)>20～30 次/d,117例(60%)發(fā)作持續(xù)時間<10 s、58例(29.74%)>10～30 s、20例(10.26%)>30～60 s,散發(fā)性131例(67.18%)、家族性64例(32.82%),78例(40%)未服用藥物,117例(60%)服用抗癲藥物患者中106例癥狀完全控制、8例偶有發(fā)作、3例未見明顯緩解.其中,家族性組發(fā)病年齡低于(t=2.376,P=0.019)、發(fā)作持續(xù)時間短于(χ2=7.731,P=0.021)散發(fā)性組.結(jié)論通過大樣本臨床數(shù)據(jù)分析和總結(jié)中國發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙臨床表型特點,以期為臨床診斷與治療提供幫助.

運(yùn)動障礙; 表型

發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙[PKD,在線人類孟德爾遺傳數(shù)據(jù)庫(OMIM)編號:128200]是發(fā)作性運(yùn)動障礙的最常見類型,系一組突然動作誘發(fā)的非隨意性運(yùn)動障礙性疾病,發(fā)作時以異常運(yùn)動或姿勢為特征,如肌張力障礙、舞蹈樣動作、手足徐動、投擲樣動作等,可持續(xù)數(shù)秒至數(shù)十秒,發(fā)作間期正常[1].自2011年首個致病基因PRRT2基因克隆以來,發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙在分子生物學(xué)和功能影像學(xué)等領(lǐng)域取得顯著進(jìn)展[2?8],逐漸受到臨床醫(yī)師和研究者們的關(guān)注.本研究回顧分析195例發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙患者的臨床資料,總結(jié)中國發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙的臨床表型特點.

對象與方法

一、研究對象

選擇2008年8月-2016年12月在上海交通大學(xué)醫(yī)學(xué)院附屬瑞金醫(yī)院神經(jīng)科就診的原發(fā)性發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙患者共195例,均符合原發(fā)性發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙診斷標(biāo)準(zhǔn)[1]:由突然動作誘發(fā);發(fā)作持續(xù)時間短暫(<1 min);發(fā)作期意識清晰;發(fā)病年齡1～20歲,如有家族史,發(fā)病年齡適當(dāng)增寬;苯妥英鈉或卡馬西平可以有效控制癲發(fā)作;神經(jīng)系統(tǒng)檢查和神經(jīng)電生理學(xué)檢查正常;同時能夠配合完整的神經(jīng)系統(tǒng)查體和詳細(xì)的病史采集.排除其他繼發(fā)性因素,如癲、多發(fā)性硬化(MS)、中樞神經(jīng)系統(tǒng)感染、代謝性疾病(如甲狀腺功能減退癥或甲狀腺功能亢進(jìn)癥)、心源性運(yùn)動障礙等.本研究經(jīng)上海交通大學(xué)醫(yī)學(xué)院附屬瑞金醫(yī)院道德倫理委員會審核批準(zhǔn),所有患者及其家屬均知情同意并簽署知情同意書.

二、研究方法

1.臨床資料采集 采用上海交通大學(xué)醫(yī)學(xué)院附屬瑞金醫(yī)院神經(jīng)科自行設(shè)計的發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙登記表,由神經(jīng)科醫(yī)師和研究生記錄并整理發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙患者的臨床資料,包括性別,年齡,發(fā)病年齡,發(fā)作類型,嬰兒驚厥、偏頭痛、發(fā)作性共濟(jì)失調(diào)等其他發(fā)作性疾病病史,合并癥,先兆比例,發(fā)作形式,累及部位,面部受累,發(fā)作頻率,發(fā)作持續(xù)時間,家族史,自愈傾向等,將上述臨床資料錄入計算機(jī)并建立數(shù)據(jù)庫,比較家族性與散發(fā)性發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙臨床表型特點.

2.統(tǒng)計分析方法 采用SPSS 16.0統(tǒng)計軟件進(jìn)行數(shù)據(jù)處理與分析.計數(shù)資料以相對數(shù)構(gòu)成比(%)或率(%)表示,采用χ2檢驗;計量資料以均數(shù)±標(biāo)準(zhǔn)差(x±s)表示,采用兩獨立樣本的t檢驗.以P≤0.05為差異具有統(tǒng)計學(xué)意義.

結(jié) 果

一、發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙的臨床表型

195例發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙患者,男性159例,女性36例;年齡8～65歲,平均(29.43±13.41)歲;發(fā)病年齡4個月至27歲,平均(12.32±3.49)歲,其中161例(82.56%)于7～15歲(青少年期)發(fā)病;單純型發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙162例(83.08%),復(fù)雜型發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙33例(16.92%),其中19例有嬰兒驚厥病史、13例有偏頭痛病史、1例有發(fā)作性共濟(jì)失調(diào)病史;合并特發(fā)性震顫16例(8.21%);所有患者(195例,100%)均由突然動作誘發(fā),亦可由突然加速(137例,70.26%)和意圖動作(67例,34.36%)誘發(fā),其中114例(58.46%)和36例(18.46%)分別于情緒緊張和疲勞狀態(tài)下癥狀加重;144例(73.85%)發(fā)作前有先兆,主要來自單側(cè)或雙側(cè)肢體遠(yuǎn)端并向近端蔓延;發(fā)作形式包括肌張力障礙(134例,68.72%)、舞蹈樣動作(8例,4.10%)和二者混合形式(53例,27.18%);發(fā)作時80例(41.03%)累及單側(cè)肢體,43例(22.05%)累及雙側(cè)肢體,49例(25.13%)累及單側(cè)或雙側(cè)肢體,23例(11.79%)雙側(cè)交替發(fā)作;134例(68.72%)發(fā)作時有面部障礙,表現(xiàn)為表情僵硬、瞪眼、齜牙、咧嘴和構(gòu)音障礙等;115例(58.97%)發(fā)作頻率<10次/d,54例(27.69%)發(fā)作頻率為10～20次/d,26例(13.33%)發(fā)作頻率>20～30次/d;117例(60%)發(fā)作持續(xù)時間<10 s、58例(29.74%)10～30 s、20例(10.26%)>30～60 s;散發(fā)性發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙131例(67.18%),家族性發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙64例(32.82%);83例(42.56%)完全或不完全自愈,自愈年齡19～34歲、平均(21.51±4.42)歲;78例(40%)未服用藥物,117例(60%)服用抗癲藥物(AEDs)患者中89例予卡馬西平、17例予奧卡西平、11例予其他抗癲藥物(如苯妥英鈉、托吡酯、丙戊酸鈉、拉莫三嗪和氯硝西泮);服用卡馬西平(50～100 mg/d)的89例患者中86例完全控制、2例部分控制、1例未見明顯緩解,服用奧卡西平(75～150 mg/d)的17例患者中13例癥狀完全控制、4例部分控制,總體而言,服用抗癲藥物的117例患者中106例(90.60%)癥狀完全控制、8例(6.84%)發(fā)作頻率下降但偶有發(fā)作、3例(2.56%)未見明顯緩解(1例予卡馬西平,2例予丙戊酸鈉).

二、家族性與散發(fā)性發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙的臨床表型比較

195例發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙患者根據(jù)是否有家族史分為家族性發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙組(家族性組)和散發(fā)性發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙組(散發(fā)性組).(1)家族性組:64例患者,男性48例,女性16例;年齡8～65歲,平均(30.09±11.55)歲;發(fā)病年齡4個月至27歲,平均(11.48±3.83)歲;單純型發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙54例(84.38%),復(fù)雜型發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙10例(15.63%),其中3例有嬰兒驚厥病史、7例偏頭痛病史;合并特發(fā)性震顫6例(9.38%);44例(68.75%)發(fā)作前有先兆;發(fā)作形式表現(xiàn)為肌張力障礙50例(78.13%)、舞蹈樣動作2例(3.13%)和二者混合形式12例(18.75%);發(fā)作時25例(39.06%)累及單側(cè)肢體,12例(18.75%)累及雙側(cè)肢體,14例(21.88%)累及單側(cè)或雙側(cè)肢體,13例(20.31%)雙側(cè)交替發(fā)作;47例(73.44%)發(fā)作時累及面部;39例(60.94%)發(fā)作頻率 <10次/d,17例(26.56%)10～20次/d,8例(12.50%)>20～30次/d;47例(73.44%)發(fā)作持續(xù)時間 <10 s、14例(21.88%)為10～30 s、3例(4.69%)>30～60 s;39例(60.94%)未服用藥物,25例(39.06%)服用抗癲藥物患者中23例癥狀完全控制、2例部分控制.(2)散發(fā)性組:131例患者,男性111例,女性20例;年齡9～41歲,平均(23.70±18.01)歲;發(fā)病年齡6～23歲,平均(12.73±3.25)歲;單純型發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙108例(82.44%),復(fù)雜型發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙23例(17.56%),其中16例有嬰兒驚厥病史、6例偏頭痛病史、1例發(fā)作性共濟(jì)失調(diào)病史;合并特發(fā)性震顫10例(7.63%);100例(76.34%)發(fā)作前有先兆;發(fā)作形式表現(xiàn)為肌張力障礙84例(64.12%)、舞蹈樣動作6例(4.58%)和二者混合形式41例(31.30%);發(fā)作時55例(41.98%)累及單側(cè)肢體,31例(23.66%)累及雙側(cè)肢體,35例(26.72%)累及單側(cè)或雙側(cè)肢體,10例(7.63%)雙側(cè)交替發(fā)作;87例(66.41%)發(fā)作時累及面部;76例(58.02%)發(fā)作頻率<10次/d,37例(28.24%)發(fā)作頻率10～20次/d,18例(13.74%)>20～30次/d;70例(53.44%)發(fā)作持續(xù)時間 <10 s、44例(33.59%)10～30 s、17例(12.98%)>30～60 s;39例(29.77%)未服用藥物,92例(70.23%)服用抗癲藥物患者中83例癥狀完全控制、6例部分控制、3例未見明顯緩解.由表1可見,兩組患者臨床表型比較,性別、發(fā)作類型、合并癥、先兆比例、發(fā)作形式、累及部位、面部受累、發(fā)作頻率、服用抗癲藥物比例和藥物療效差異無統(tǒng)計學(xué)意義(均P>0.05),而家族性組發(fā)病年齡低于(P=0.019)、發(fā)作持續(xù)時間短于(P=0.021)散發(fā)性組且差異有統(tǒng)計學(xué)意義.

表1 家族性組與散發(fā)性組患者臨床表型的比較Table 1. Comparison of general data between familial and sporadic PKD patients

討 論

發(fā)作性運(yùn)動障礙是一類以反復(fù)發(fā)作的非隨意性運(yùn)動障礙為主要特征的罕見神經(jīng)系統(tǒng)疾病,具有高度臨床異質(zhì)性和遺傳異質(zhì)性.發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙是發(fā)作性運(yùn)動障礙的最常見類型[9],按照病因可以分為原發(fā)性和繼發(fā)性,其中,原發(fā)性發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙根據(jù)有無家族史又分為家族性和散發(fā)性,家族性發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙呈常染色體顯性遺傳.2011年首次證實PRRT2基因是發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙的致病基因之一,定位于16p11.2,包含4個外顯子,熱點突變?yōu)閏.649dupC(p.Arg217ProfsX8)[2?3,10?11],編碼富含脯氨酸跨膜蛋白2(PRRT2).PRRT2蛋白是由340個氨基酸組成的一次跨膜蛋白,其氨基末端(N末端)較長朝向胞內(nèi),羧基末端(C末端)較短朝向胞外[12].PRRT2蛋白表達(dá)于神經(jīng)元突觸,通過與突觸結(jié)合蛋白1/2(Syt1/2)相互作用參與鈣離子的快速識別,從而參與神經(jīng)遞質(zhì)的釋放過程[13?14].嬰兒驚厥、良性家族性嬰兒驚厥(BFIS)、嬰兒驚厥伴陣發(fā)性舞蹈手足徐動癥、家族性偏癱型偏頭痛、發(fā)作性共濟(jì)失調(diào)、熱性驚厥、偏頭痛、發(fā)作性非運(yùn)動誘發(fā)性運(yùn)動障礙及家族性和散發(fā)性發(fā)作性過度運(yùn)動誘發(fā)性運(yùn)動障礙患者也存在PRRT2基因突變.提示上述發(fā)作性疾病包括發(fā)作性動作誘發(fā)性運(yùn)動障礙可能屬PRRT2基因相關(guān)疾病譜范疇,統(tǒng)稱為PRRT2相關(guān)疾病(PRD)[15?18].在目前報道的病例中,約61.5%家族性發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙為PRRT2基因突變所致,此外,尚有12.5%～89.5%散發(fā)性發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙無PRRT2基因突變[5,19?20],提示存在除PRRT2基因外的其他可能致病基因.

在本研究中,發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙患者發(fā)病年齡4個月至27歲,以7～15歲青少年為高發(fā),男女比例4.42∶1,散發(fā)性病例男女比例5.55∶1.發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙多由突然動作誘發(fā),如起立、接電話或起跑等,運(yùn)動速度和幅度改變以及意圖動作或在持續(xù)動作中加入其他動作時可誘發(fā),此外情緒緊張、疲勞等亦可誘發(fā).73.85%患者發(fā)作前有發(fā)作預(yù)感,表現(xiàn)為受累肢體無力感、受累部位肌肉緊張感、淺感覺不一和頭暈等.部分患者在先兆癥狀后通過減慢患肢動作以阻止發(fā)作.發(fā)作形式包括肌張力障礙、舞蹈樣動作或混合發(fā)作,多為單側(cè)發(fā)作,亦可雙側(cè)同時或交替發(fā)作.同一家系發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙患者臨床表現(xiàn)相似[15].有2/3患者發(fā)作時累及面部肌肉,出現(xiàn)擠眉弄眼和構(gòu)音障礙.發(fā)作頻率多于青春期達(dá)高峰,自發(fā)緩解年齡為20～30歲,部分患者30歲后很少發(fā)作甚至完全自愈.比較家族性與散發(fā)性發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙患者的臨床表型特點,發(fā)現(xiàn)家族性患者發(fā)病年齡較早、發(fā)作持續(xù)時間較短,而其他臨床表現(xiàn)無差異.原發(fā)性發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙應(yīng)與癲、心源性運(yùn)動障礙、癔癥、特發(fā)性肌張力障礙、先天性肌強(qiáng)直等相鑒別,并排除可能的繼發(fā)性因素,如顱腦創(chuàng)傷、中樞神經(jīng)系統(tǒng)腫瘤、中樞神經(jīng)系統(tǒng)感染、甲狀腺疾病和自身免疫性疾病等[1,21?23].

綜上所述,本研究從大樣本水平描述和總結(jié)中國發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙的臨床表型特點,并比較家族性與散發(fā)性患者臨床表型差異.在臨床實踐中,應(yīng)進(jìn)一步提高臨床醫(yī)師對發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙的認(rèn)識,重視臨床醫(yī)師(包括神經(jīng)內(nèi)科和兒科醫(yī)師)的培訓(xùn),明確診斷標(biāo)準(zhǔn)和鑒別診斷要點,幫助患者第一時間診斷,并使其明確經(jīng)合理的藥物治療可以有效控制疾病,且隨年齡的增長可能出現(xiàn)自發(fā)性緩解.盡管發(fā)作性運(yùn)動誘發(fā)性運(yùn)動障礙的發(fā)病機(jī)制以及臨床表型與基因型的關(guān)系尚未明確,但隨著研究的不斷深入,其臨床異質(zhì)性和遺傳異質(zhì)性之謎將被解開,同時也將給新致病基因的發(fā)現(xiàn)和發(fā)病機(jī)制的研究提供新的視野.

[1]Bruno MK,Hallett M,Gwinn?Hardy K,Sorensen B,Considine E,Tucker S,Lynch DR,Mathews KD,Swoboda KJ,Harris J,Soong BW,Ashizawa T,Jankovic J,Renner D,Fu YH,Ptacek LJ.Clinical evaluation of idiopathic paroxysmal kinesigenic dyskinesia:new diagnostic criteria.Neurology,2004,63:2280?2287.

[2]Chen WJ,Lin Y,Xiong ZQ,Wei W,Ni W,Tan GH,Guo SL,He J,Chen YF,Zhang QJ,Li HF,Lin Y,Murong SX,Xu J,Wang N,Wu ZY.Exomesequencingidentifiestruncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia.Nat Genet,2011,43:1252?1255.

[3]Wang JL,Cao L,Li XH,Hu ZM,Li JD,Zhang JG,Liang Y,San A,Li N,Chen SQ,Guo JF,Jiang H,Shen L,Zheng L,Mao X,Yan WQ,Zhou Y,Shi YT,Ai SX,Dai MZ,Zhang P,Xia K,Chen SD,Tang BS.Identification of PRRT2 as the causative gene of paroxysmal kinesigenic dyskinesias.Brain,2011,134:3493?3501.

[4]Ebrahimi?Fakhari D,Saffari A,Westenberger A,Klein C.The evolving spectrum of PRRT2?associated paroxysmal diseases.Brain,2015,138:3476?3495.

[5]Huang XJ,Wang T,Wang JL,Liu XL,Che XQ,Li J,Mao X,Zhang M,Bi GH,Wu L,Zhang Y,Wang JY,Shen JY,Tang BS,Cao L,Chen SD.Paroxysmalkinesigenic dyskinesia:clinical and genetic analyses of 110 patients.Neurology,2015,85:1546?1553.

[6]Valtorta F,BenfenatiF,Zara F,MeldolesiJ.Part2:from paroxysmal disorders to regulation of synaptic function.Trends Neurosci,2016,39:668?679.

[7]Hsu WY,Kwan SY,Liao KK,Chen RS,Lin YY.Altered inhibitory modulation of somatosensory cortices in paroxysmal kinesigenic dyskinesia.Mov Disord,2013,28:1728?1731.

[8]Hsiao FJ,Hsu WY,Chen WT,Chen RS,Lin YY.Abnormal somatosensory synchronization in patients with paroxysmal kinesigenic dyskinesia:a magnetoencephalographic study.Clin EEG Neurosci,2017,48:288?294.

[9]Erro R,Sheerin UM,Bhatia KP.Paroxysmaldyskinesias revisited:a review of 500 genetically proven cases and a new classification.Mov Disord,2014,29:1108?1116.

[10]van Vliet R,Breedveld G,de Rijk?van Andel J,Brilstra E,Verbeek N,Verschuuren?Bemelmans C,Boon M,Samijn J,Diderich K,van de Laar I,Oostra B,Bonifati V,Maat?Kievit A.PRRT2 phenotypes and penetrance of paroxysmal kinesigenic dyskinesia and infantile convulsions.Neurology,2012,79:777?784.

[11]Wu L,Tang HD,Huang XJ,Zheng L,Liu XL,Wang T,Wang JY,Cao L,Chen SD.PRRT2 truncated mutations lead to nonsense?mediated mRNA decay in paroxysmal kinesigenic dyskinesia.Parkinsonism Relat Disord,2014,20:1399?1404.

[12]Rossi P,Sterlini B,Castroflorio E,Marte A,Onofri F,Valtorta F,Maragliano L,Corradi A,Benfenati F.A novel topology of proline?rich transmembrane protein 2(PRRT2):hints foe an intracellular function at the synapse.J Biol Chem,2016,291:6111?6123.

[13]Valente P,Castroflorio E,RossiP,Fadda M,SterliniB,CervigniRI,Prestigio C,GiovediS,OnofriF,Mura E,Guarnieri FC,Marte A,Orlando M,Zara F,Fassio A,Valtorta F,BaldelliP,CorradiA,BenfenatiF.PRRT2 isa key component of the Ca(2+)?dependent neurotransmitter release machinery.Cell Rep,2016,15:117?131.

[14]Li M,Niu F,Zhu X,Wu X,Shen N,Peng X,Liu Y.PRRT2 mutant leads to dysfunction of glutamate signaling.Int J Mol Sci,2015,16:9134?9151.

[15]Becker F,Schubert J,Striano P,Anttonen AK,Liukkonen E,Gaily E,Gerloff C,Müller S,Heu?inger N,Kellinghaus C,Robbiano A,Polvi A,Zittel S,Oertzen TJ,Rostasy K,Sch?ls L,Warner T,Munchau A,Lehesjoki AE,Zara F,Lerche H,Weber YG.PRRT2?related disorders:further PKD and ICCA cases and review of the literature.J Neurol,2013,260:1234?1244.

[16]Méneret A,Roze E.Paroxysmal movement disorders:an update.Rev Neurol(Paris),2016,172:433?445.

[17]Méneret A,Grabli D,Depienne C,Gaudebout C,Picard F,Dürr A,Lagroua I,Bouteiller D,Mignot C,Doummar D,Anheim M,Tranchant C,Burbaud P,Jedynak CP,Gras D,Steschenko D,Devos D,Billette de VillemeurT,Vidailhet M,Brice A,Roze E.PRRT2 mutations:a major cause of paroxysmal kinesigenic dyskinesia in the European population.Neurology,2012,79:170?174.

[18]Torisu H,Watanabe K,Shimojima K,Sugawara M,Sanefuji M,Ishizaki Y,Sakai Y,Yamashita H,Yamamoto T,Hara T.Girl with a PRRT2 mutation and infantile focalepilepsy with bilateral spikes.Brain Dev,2014,36:342?345.

[19]Heron SE,Dibbens LM.Role of PRRT2 in common paroxysmal neurological disorders:a gene with remarkable pleiotropy.J Med Genet,2013,50:133?139.

[20]Lee YC,Lee MJ,Yu HY,Chen C,Hsu CH,Lin KP,Liao KK,Chang MH,Liao YC,Soong BW.PRRT2 mutationsin paroxysmal kinesigenic dyskinesia with infantile convulsions in a Taiwanese cohort.PLoS One,2012,7:E38543.

[21]Thomas KP, Muthugovindan D, Singer HS. Paroxysmal kinesigenic dyskinesias and pseudohypo?parathyroidism type Ⅰb.Pediatr Neurol,2010,43:61?64.

[22]HuangXJ,CaoL,Chen SD.Progress in theresearch of genetics and clinical manifestation of paroxysmal kinesigenic dyskinesia.Zhongguo Xian Dai Shen Jing Ji Bing Za Zhi,2013,13:457?462[.黃嘯君,曹立,陳生弟.發(fā)作性動作誘發(fā)性運(yùn)動障礙臨床表現(xiàn)及遺傳學(xué)研究進(jìn)展.中國現(xiàn)代神經(jīng)疾病雜志,2013,13:457?462.]

[23]Wang JD,Bi GR,Cong SY,Zheng DM,Xu FF.Four cases of paroxysmal kinesigenic dyskinesia.Zhongguo Xian Dai Shen Jing Ji Bing Za Zhi,2009,9:309?310[.王建東,畢國榮,叢樹艷,鄭東明,徐菲菲.發(fā)作性運(yùn)動誘發(fā)舞蹈手足徐動癥四例.中國現(xiàn)代神經(jīng)疾病雜志,2009,9:309?310.]

Clinical phenotype analysis of paroxysmal kinesigenic dyskinesia

TIAN Wo?tu1,HUANG Xiao?jun2,SHEN Jun?yi1,XU Yang?qi1,CHEN Sheng?di1,CAO Li11Department of Neurology and Institute of Neurology,Ruijin Hospital,School of Medicine,Shanghai Jiaotong University,Shanghai 200025,China
2Department of Neurology,North Department of Ruijin Hospital,School of Medicine,Shanghai Jiaotong University,Shanghai 201801,China

CAO Li(Email:caoli2000@yeah.net)

BackgroundParoxysmal kinesigenic dyskinesia(PKD)is a disorder characterized by recurrent and brief dystonic or choreoathetoid attacks that are induced by sudden voluntary movement with highly clinical and genetic heterogeneity.We aimed to investigate the clinical features of PKD in a large Chinese population.MethodsOne hundred and ninety five patients diagnosed as primary PKD were recruited.For all of the participants,neurological examinations were conducted and clinical manifestations were recorded and summarized in self?made uniform registration form for PKD patients. Clinical characteristics were statistically analyzed and compared between familial and sporadic PKD patients.ResultsAmong all of the 195 PKD patients in the present study,the gender ratio was 4.42∶1(male∶female).The average age of onset was(12.32±3.49)years.There were 162 patients(83.08%)manifestated with pure form and 33(16.92%)with complicated form of PKD.Among them 16 patients(8.21%)had essential tremor(ET),and 144 patients(73.85%)had premonitory symptom.The percentage of patients manifested as dystonia,chorea and mixed form during episodic attacks were 68.72%(134/195),4.10%(8/195)and 27.18%(53/195)repectively.There were 134 cases(68.72%)had facial involvement.It was recorded that 115(58.97%),54(27.69%)and 26(13.33%)patients had frequency of attack<10 times/d,10-20 times/d and>20-30 times/d respectively. The percentages of patients whose duration of attack<10 s,10-30 s and>30-60 s were 60%(117/195),29.74%(58/195)and 10.26%(20/195)respectively.There were 64 patietns(32.82%)with family history of PKD and 131(67.18%)were sporadic PKD patients.Up to 40%(78/195)of patients did not require/take medications,as they had minor clinical manifestations or concerns about the side effects of anticonvulsants. Among 117 patients(60%)prescribed with anticonvulsants,114 patients showed a good response,including complete control(N=106)and partial control(N=8),and 3 patients were nonresponsive.In comparison with sporadic PKD patients,familial PKD patients had earlier age of onset(t=2.376,P=0.019)and shorter duration of attack(χ2=7.731,P=0.021)respectively.ConclusionsWe summarized the clinical characteristics of PKD patients in mainland China.Through the analysis of large sample data,we hope to improve and standardize the diagnosis and treatment of PKD clinically.

Movement disorders; Phenotype

10.3969/j.issn.1672?6731.2017.07.006

國家自然科學(xué)基金資助項目(項目編號:81571086);國家自然科學(xué)基金資助項目(項目編號:81271262);國家自然科學(xué)基金青年科學(xué)基金資助項目(項目編號:81600978);上海交通大學(xué)醫(yī)學(xué)院高峰高原計劃(項目編號:20161401);上海交通大學(xué)"醫(yī)工交叉研究基金"資助項目(項目編號:YG2016MS64);上海交通大學(xué)醫(yī)學(xué)院"大學(xué)生創(chuàng)新訓(xùn)練計劃"(項目編號:2015045)

200025上海交通大學(xué)醫(yī)學(xué)院附屬瑞金醫(yī)院神經(jīng)科 上海交通大學(xué)醫(yī)學(xué)院神經(jīng)病學(xué)研究所(田沃土,沈雋逸,徐洋奇,陳生弟,曹立);201801上海交通大學(xué)醫(yī)學(xué)院附屬瑞金醫(yī)院北院神經(jīng)內(nèi)科(黃嘯君)

曹立(Email:caoli2000@yeah.net)

This study was supported by the National Natural Science Foundation of China(No.81571086,81271262),the National Natural Science Foundation of China for Young Scientists(No.81600978),Shanghai Jiaotong University School of Medicine Peak and Plateau Program(No.20161401),Crossing Program between Medicine and Industry supported by Shanghai Jiaotong University(No.YG2016MS64),and Shanghai Jiaotong University School of Medicine Undergraduate Innovation Training Program(No.2015045).

2017?06?20)