本文選題：發(fā)作性運動誘發(fā)性運動障礙 + 臨床特征��； 參考：《浙江大學》2014年博士論文

【摘要】：發(fā)作性運動障礙(Paroxysmal dyskinesia PxD)是一組具有高度臨床異質性的運動障礙性疾病,依據(jù)發(fā)作前先兆、發(fā)作期表現(xiàn)、持續(xù)時間、病程長短及病因等進行分類。其中發(fā)作性運動誘發(fā)性運動障礙(Paroxysmal Kinesigenic dyskinesiasPKD)是最常見的類型,臨床表現(xiàn)獨特主要為突然運動或改變運動方式后出現(xiàn)的不自主運動,包括肌張力障礙的姿勢、舞蹈樣動作、手足徐動癥、偏身投擲及各種不自主運動的組合,飲用咖啡、機體疲勞、寒冷時可能降低發(fā)作的閾值。發(fā)作可以是單側或雙側或左右交替發(fā)生,有時累及面部和口咽肌肉時可出現(xiàn)發(fā)音困難。根據(jù)病因的不同可以分為原發(fā)性和繼發(fā)性發(fā)作性運動障礙。PKD具有家族史的患者約占到40-70%,符合常染色體顯性遺傳規(guī)律。由于PKD臨床表現(xiàn)具有發(fā)作性、短暫性和刻板性特征,因而常被誤診為癲癇。目前認為PKD的致病基因是位于16號染色體上的PRRT2(Proline-RichTransmembrane Protein2)基因,該基因是富含脯氨酸的跨膜蛋白,且是一種突觸前膜蛋白,在細胞胞吐作用和神經(jīng)遞質的釋放過程中發(fā)揮重要的作用,但基因突變致病的具體機制仍不清楚,臨床表型與基因型的關系也不明確。迄今為止已報道大約超過300個PKD家系及散發(fā)患者含有PRRT2基因突變。超過80%的家系報道突變類型為c.649-650insC; p.Arg217Profs*8,其他突變類型還包括錯義突變、無義突變及剪切位點的突變,這些突變常導致截短蛋白的形成,從而使得蛋白的細胞內(nèi)定位及表達量發(fā)生明顯的變化。目前為止大概有15個不同的錯義突變報道,而這些錯義突變的位點多集中在以往認為是跨膜轉運結構域的C末端。同時功能研究發(fā)現(xiàn)PRRT2基因在錐體外系、皮層等高表達,且隨年齡增長表達量下降。 而功能磁共振成像(functional magnetic resonance imaging,fMRI)是一種在活體人腦中定位各功能區(qū)的有效方法,其中靜息態(tài)功能磁共振研究具有較高的空間分辨率,且無需任務設計的復雜,有助于在活體條件下研究PKD患者靜息狀態(tài)時腦功能活動的異常。既往也有研究對PKD患者應用靜息態(tài)功能磁共振研究發(fā)現(xiàn)存在基底節(jié)區(qū)的信號異常,提示與PRRT2的基因表達存在一定的關聯(lián)性。 因而為進一步明確PKD患者的臨床特點、PRRT2基因的突變情況及在靜息態(tài)磁共振是否存在一致的功能改變,本課題分兩部分：第一部分回顧分析了72例PKD患者的臨床特點并對其中27例患者進行PRRT2基因突變檢測,旨在綜合分析疾病的臨床特點,提高對PKD的診療水平；并了解PRRT2基因突變情況,為進一步研究疾病基因突變型與臨床表型關系及具體的致病機理奠定基礎。第二部分選擇29例PKD患者利用靜息態(tài)功能磁共振技術,采用ALFF方法計算PKD患者和正常對照的靜息態(tài)全腦自發(fā)腦活動模式；并計算PKD患者與正常對照的ReHo圖,對比分析PKD患者的局部腦區(qū)之間活動的一致性特征,為進一步在體研究PKD的發(fā)病機理提供依據(jù)。 第一部分運動誘發(fā)性運動障礙患者的臨床特征分析及PRRT2基因突變檢測目的： 回顧分析PKD家系和散發(fā)患者的臨床資料,綜合分析疾病的臨床特點,加深臨床對疾病的認識,以進一步提高對PKD的診療水平；同時對其中27例患者進行PRRT2基因突變檢測,旨在了解PRRT2基因突變情況,為進一步研究疾病基因突變型與表型關系及具體的致病機理奠定基礎。 方法： 對64例散發(fā)性PKD患者和8例遺傳性PKD先證者的臨床資料、神經(jīng)系統(tǒng)體格檢查、電生理及影像資料等結果進行系統(tǒng)回顧性分析。同時對4例具有家族史的患者及23例散發(fā)患者抽提外周血DNA進行PRRT2基因全部外顯子及剪切相關內(nèi)含子區(qū)域突變檢測分析。 結果： PKD患者男女比例約3.5：1,平均發(fā)病年齡12.93±3.96歲,臨床發(fā)作常在突然運動、改變運動形式及緊張時出現(xiàn),發(fā)作表現(xiàn)為單側或雙側肢體異常運動,肢體、軀干或面部均可受累。每次發(fā)作持續(xù)數(shù)秒至數(shù)十秒,最長不超過1.5分鐘,多伴有先兆,應用抗癲癇藥物效果良好。PRRT2基因外顯子的基因突變檢測分析共發(fā)現(xiàn)4例突變c.981ATCATG p.327IleMet; c.649-650insC p.Arg217Profs*8; c.649CGATGA p.217ArgTer(end); c.5GCAGTA p.2AlaVal。其中c.5GCAGTA p.2AlaVal為新發(fā)突變,且突變型與臨床表型無直接相關性。 結論： 1.發(fā)作性運動誘發(fā)性運動障礙(PKD)是發(fā)作性肌張力障礙中最常見的一種類型,臨床表現(xiàn)具有異質性。主要為突然運動、改變運動方式、緊張及寒冷后出現(xiàn)的肢體、軀干或面部的不自主運動；2.PRRT2基因突變研究發(fā)現(xiàn)其中位于非編碼區(qū)的c5GCAGTA p.2AlaVal為國內(nèi)外首次報道；PRRT2在散發(fā)患者中突變頻率約30%,可能存在除PRRT2基因之外的致病因素；基因突變型與臨床表型無明顯相關性。 第二部分運動誘發(fā)性運動障礙患者靜息態(tài)功能磁共振研究 目的： 利用靜息態(tài)功能磁共振技術,采用ALFF方法對比分析PKD患者和正常對照的靜息態(tài)全腦自發(fā)腦活動模式；并計算PKD患者與正常對照的ReHo圖,對比分析PKD患者的局部腦區(qū)之間活動的一致性特征,為進一步在體研究PKD的發(fā)病機理提供依據(jù)。 方法： 對29例PKD患者和14例正常對照進行靜息態(tài)磁共振掃描,利用REST、DPARSF和SPM8軟件完成功能像的預處理,分別進行ALFF分析及ReHo值的計算,采用單樣本t檢驗,得到兩組被試組內(nèi)的全腦低頻振幅模式及ReHo統(tǒng)計圖；采用雙樣本t檢驗,對PKD組與正常對照組ALFF圖和ReHo圖進行組間比較分析。 結果： PKD和對照組的單樣本結果模式基本一致,ALFF值組間比較發(fā)現(xiàn),PKD患者的后扣帶皮層和運動前皮質ALFF值顯著高于正常對照；而額下回、視覺皮層、海馬、顳極以及舌回的ALFF值顯著低于正常對照；ReHo值組間比較發(fā)現(xiàn),PKD患者的默認網(wǎng)絡相關腦區(qū)局部一致性增強,如楔前葉/后扣帶皮層、頂下小葉和額上回,運動前皮質的局部一致性也顯著高于正常對照；而左側顳上回的局部一致性顯著低于正常對照。 結論： 本研究采用靜息態(tài)fMRI為研究范式,從局部獨立活動和局部連接特征兩個方面刻畫了PKD患者的腦功能特征。研究結果表明,無論是用ALFF和ReHo都發(fā)現(xiàn)患者運動前皮層的活動特征存在異常：獨立活動增強、局部連接增強。提示運動前皮層是理解PKD病理生理機制的重要節(jié)點。為后續(xù)的研究提供了感興趣區(qū)。發(fā)作間期所觀察到的這種高興奮性或許能為評估患者病情提供客觀的影像學標。
[Abstract]:Paroxysmal dyskinesia (Paroxysmal dyskinesia PxD) is a group of highly clinically heterogeneous dyskinesia. It is classified according to preparoxysmal precursory, episodic performance, duration, duration of disease and etiology, and the most common type of Paroxysmal Kinesigenic dyskinesiasPKD is paroxysmal motor induced dyskinesia (Kinesigenic dyskinesiasPKD) Involuntary movement, especially after sudden movement or change of movement, including dystonia posture, dystonia, huttocystoesoootism, body throwing and various combinations of involuntary movements. Drinking coffee, body fatigue, and cold may reduce the threshold of seizures. Seizures can be unilateral or bilateral or left. It occurs alternately on the right, sometimes involving the facial and oropharyngeal muscles, which can be dysphagiated. According to the difference of the cause, the patients with primary and secondary paroxysmal dyskinesia account for about 40-70%, which conforms to the autosomal dominant inheritance law. The clinical manifestations of PKD are characterized by episodes, transient and stereotyped characteristics, because of PKD clinical manifestations. It is often misdiagnosed as epilepsy. It is believed that the PKD gene is the PRRT2 (Proline-RichTransmembrane Protein2) gene located on chromosome 16. The gene is a proline rich transmembrane protein and a presynaptic membrane protein that plays an important role in the process of cell emetic and neurotransmitter release, but gene mutation The specific mechanism of the disease is still unclear, and the relationship between the clinical phenotype and genotype is not clear. Up to 300 PKD families and sporadic patients have been reported to have PRRT2 mutations. More than 80% of the families reported mutations in c.649-650insC; p.Arg217Profs*8, and other types of mutation, nonsense mutation and shear. Mutations in the loci, which often lead to the formation of truncated proteins, make a significant change in the intracellular localization and expression of the protein. So far, there are about 15 different missense mutations reported, and these missense mutations are mostly concentrated in the C terminal, which was previously thought to be transmembrane transshipment domains. And functional research found that PRR T2 gene was highly expressed in extrapyramidal and cortical regions, and decreased with age.
Functional magnetic resonance imaging (fMRI) is an effective method to locate various functional areas in the living human brain. The resting state functional magnetic resonance (fMRI) study has high spatial resolution and does not need the complexity of task design. It is helpful for the study of the brain function activity in the resting state of PKD patients under the living condition. Previous studies have also studied the application of resting state functional magnetic resonance (fMRI) to PKD patients to find that there is a signal anomaly in the basal ganglia, suggesting a certain correlation with the gene expression of PRRT2.
Therefore, in order to further clarify the clinical characteristics of PKD patients, the mutation of PRRT2 gene and whether there is a consistent functional change in resting state magnetic resonance, this topic is divided into two parts: the first part reviewed and analyzed the clinical characteristics of 72 cases of PKD patients and 27 patients with PRRT2 mutation detection, aiming at the comprehensive analysis of the clinical symptoms of the disease. Characteristics, improve the diagnosis and treatment of PKD, and understand the mutation of PRRT2 gene, in order to further study the relationship between the mutation of the disease gene and the clinical phenotype and the specific pathogenesis. The second part selected 29 cases of PKD patients to use the resting state function magnetic resonance technique and the ALFF square method to calculate the rest state of the patients with PKD and the normal control. The spontaneous brain activity pattern of the brain and the ReHo map of the PKD patients and the normal control were calculated, and the conformance characteristics of the activities between the local brain regions of the PKD patients were compared and analyzed to provide the basis for further study of the pathogenesis of PKD in vivo.
Part one: analysis of clinical characteristics and PRRT2 gene mutation in patients with exercise-induced dyskinesia.
The clinical data of PKD family and sporadic patients were reviewed, the clinical features of the disease were analyzed, and the clinical knowledge of the disease was deepened to further improve the level of diagnosis and treatment of PKD. At the same time, the mutation detection of PRRT2 gene was carried out in 27 of the patients to understand the mutation of the PRRT2 gene and to further study the mutant and phenotype of the disease gene. It lays the foundation for the relationship and the specific pathogenicity mechanism.
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本文編號：1820639