本文選題：脊髓小腦共濟(jì)失調(diào) + 三核苷酸重復(fù)��； 參考：《新疆醫(yī)科大學(xué)》2014年博士論文

【摘要】：目的：1）研究新疆地區(qū)維吾爾族脊髓小腦性共濟(jì)失調(diào)12亞型（SCA12）致病基因的CAG三核苷酸病理重復(fù)次數(shù)范圍及臨床特點(diǎn)；2）通過測(cè)量表觀擴(kuò)散系數(shù)（ADC）、各向異性分?jǐn)?shù)（FA）兩個(gè)指標(biāo)研究脊髓小腦性共濟(jì)失調(diào)12亞型腦白質(zhì)微細(xì)結(jié)構(gòu)損害的影像學(xué)特點(diǎn)；3）探討新疆維吾爾族帶有帕金森癥狀的遺傳性脊髓小腦型共濟(jì)失調(diào)12型的發(fā)病是否與帕金森病的發(fā)病有共同的發(fā)病基礎(chǔ)，，是否由α-突觸核蛋白異常聚集所致。方法：1）依據(jù)Harding標(biāo)準(zhǔn)，我們針對(duì)一個(gè)2年前經(jīng)基因診斷確診為SCA12亞型的維吾爾族家系，進(jìn)行跟蹤隨訪，應(yīng)用聚合酶鏈反應(yīng)、瓊脂糖凝膠電泳、T載體分子克隆技術(shù)并結(jié)合酶切鑒定等技術(shù)對(duì)其中13例患者、54例家系“健康”個(gè)體進(jìn)行分子遺傳學(xué)診斷，同時(shí)對(duì)致病基因CAG三核苷酸病理重復(fù)次數(shù)進(jìn)行突變分析；2）針對(duì)一個(gè)經(jīng)基因診斷為SCA12亞型的家系成員，包括13例患者，5個(gè)癥狀前患者，通過磁共振擴(kuò)散張量的兩個(gè)指標(biāo)：表觀擴(kuò)散系數(shù)（ADC）、各向異性分?jǐn)?shù)（FA），選擇測(cè)量感興趣區(qū)域：腦橋、小腦上腳、小腦中腳、小腦蚓部、大腦皮層、小腦半球進(jìn)行測(cè)量；3）經(jīng)基因診斷SCA12患者13人，家系癥狀前患者5人，正常28人進(jìn)行酶聯(lián)免疫吸附試驗(yàn)（ELISA法）測(cè)量血漿α-突觸核蛋白濃度。結(jié)果：1）發(fā)現(xiàn)該家系SCA12型患者13例，癥狀前患者5例。患者CAG重復(fù)數(shù)目范圍為48 54次；癥狀前患者CAG重復(fù)數(shù)目范圍為49 52次。正常人PPP2R2B基因CAG重復(fù)數(shù)目范圍為9 16次。SCA12患者CAG序列重復(fù)次數(shù)與SARA評(píng)分兩變量呈正相關(guān)關(guān)系（0.708，P＜0.05）；2）和對(duì)照組相比，SCA12亞型患者在小腦皮層、小腦上腳、大腦皮層、小腦蚓部區(qū)域ADC值上升；SCA12亞型患者在小腦皮層，癥狀前患者在小腦皮層、小腦蚓部的FA值明顯降低。病程、共濟(jì)失調(diào)量表評(píng)分、小腦蚓部的ADC值之間具有高度正相關(guān)；3）SCA12患者組與癥狀前患者組、正常對(duì)照組三組α-突觸核蛋白表達(dá)水平不完全相同（P＜0.05），SCA12患者組濃度的總體平均值最高。但是SCA12患者發(fā)病年齡、病程與α-突觸核蛋白濃度無相關(guān)關(guān)系。結(jié)論：1）患者病程越長(zhǎng)，CAG重復(fù)數(shù)目越高，SARA評(píng)分越高，共濟(jì)失調(diào)患者的病情越嚴(yán)重。SCA12型的48次CAG病理重復(fù)次數(shù)為國(guó)內(nèi)外報(bào)道的最小CAG病理重復(fù)次數(shù)；此發(fā)現(xiàn)進(jìn)一步縮短了正常與異常重復(fù)次數(shù)之間的差距。對(duì)維吾爾族SCA12型的基因突變特點(diǎn)進(jìn)行分析，從而對(duì)于該類疾病的準(zhǔn)確分類、病因探討、治療、產(chǎn)前診斷等具有重要的意義；2）SCA12亞型患者腦白質(zhì)微細(xì)結(jié)構(gòu)存在損害；SCA12癥狀前患者腦白質(zhì)微細(xì)結(jié)構(gòu)損害可能最早在小腦皮層、小腦蚓部發(fā)生。小腦蚓部的ADC值可能成為反映SCA12患者共濟(jì)失調(diào)嚴(yán)重程度、認(rèn)知障礙程度的一個(gè)重要量化指標(biāo)；3）帶有帕金森癥狀的SCA12型α-突觸核蛋白的表達(dá)水平升高，可能和帕金森病存在著共同的發(fā)病基礎(chǔ)。檢測(cè)帶有帕金森癥狀的SCA12患者的α-突觸核蛋白可能作為評(píng)估疾病嚴(yán)重程度的較為敏感的一個(gè)生物學(xué)指標(biāo)。
[Abstract]:Objective: to study the range and clinical characteristics of CAG trinucleotides (CAG trinucleotide repeat) in Uygur patients with spinal cerebellar ataxia subtype 12 (SCA12) in Xinjiang. Objective to study the imaging features of microstructural damage in white matter of cerebellar ataxia 12 subtype of spinal cord. (3) to explore whether the incidence of hereditary spinal cerebellar ataxia 12 with Parkinson's symptoms in Xinjiang Uygur is associated with Parkin. The incidence of Sentinia has a common basis. Whether it is caused by abnormal aggregation of 偽-synaptophysin. Methods according to Harding criteria, we followed up a Uygur family with SCA12 subtype diagnosed by gene diagnosis 2 years ago and used polymerase chain reaction (PCR). The molecular cloning technique of T-vector by agarose gel electrophoresis and restriction endonuclease identification were used to diagnose the molecular genetics of 54 healthy individuals from 54 families of 13 patients. At the same time, the number of pathological repeats of the pathogenic gene CAG trinucleotide was analyzed for a family member diagnosed by gene as SCA12 subtype, including 13 patients and 5 presymptomatic patients. Diffusion of Zhang Liang by magnetic resonance: apparent diffusion coefficient (Zhang Liang), anisotropic fraction (FAA), measurement of areas of interest: pontine, superior cerebellar foot, middle cerebellar foot, cerebellar vermis, cerebral cortex, The plasma levels of 偽 -synaptophysin were measured in 13 patients with SCA12 diagnosed by gene, 5 patients with pre-symptomatic disease and 28 normal subjects by enzyme-linked immunosorbent assay (Elisa). Results (1) 13 cases of SCA12 type and 5 cases of pre-symptomatic patients were found in this pedigree. The number of CAG repeats in patients ranged from 48 to 54, and that of CAG from pre-symptom to pre-symptom was 49 and 52. The number of CAG repeats of PPP2R2B gene in normal subjects ranged from 9 to 16 times. The number of CAG repeats in patients with SCA12 was positively correlated with the two variables of SARA score (P < 0. 05, P < 0. 05) compared with the control group, the patients with subtype SCA12 were in the cerebellar cortex, superior cerebellar foot, and cerebral cortex. The ADC value of cerebellar vermis region increased and the FA value of SCA12 subtype patients decreased significantly in cerebellar cortex, presymptomatic patients in cerebellar cortex and cerebellar vermis. There was a high positive correlation between the ADC values of cerebellar vermis and presymptomatic patients, and the average of 偽 -synaptophysin expression in the three groups of normal control group was not exactly the same (P < 0.05). The average value of 偽 -synaptic protein expression was the highest in the three groups (P < 0.05). However, there was no correlation between the age and course of SCA12 and the concentration of 偽-synaptophysin. Conclusion (1) the longer the course of disease, the higher the number of CAG repeats and the higher the score of SARA, the more serious the condition of patients with ataxia. The 48 CAG pathological repeats of type SCA12 are the minimum number of CAG pathological repeats reported at home and abroad. This finding further shortens the gap between normal and abnormal repetition times. The characteristics of SCA12 gene mutation in Uygur nationality were analyzed, and the classification, etiology and treatment of the disease were discussed. Prenatal diagnosis is of great significance in the diagnosis of white matter microstructures in the white matter of patients with SCA12 subtype. Before SCA12 symptoms, the white matter microstructures in patients with SCA12 may occur at the earliest in the cerebellar cortex and cerebellar vermis. The ADC value of cerebellar vermis may be an important quantitative index to reflect the severity of ataxia and cognitive impairment in patients with SCA12. (3) the expression of SCA12 type 偽 -synaptophysin with Parkinson's symptoms is increased. There may be a common pathogenesis with Parkinson's disease. The detection of 偽-synaptophysin in SCA12 patients with Parkinson's symptoms may be a sensitive biological marker for evaluating the severity of the disease.
【學(xué)位授予單位】：新疆醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類號(hào)】：R744.7

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