本文選題：先天性眼外肌纖維化 + 常染色體顯性遺傳��； 參考：《南昌大學(xué)》2016年博士論文

【摘要】：目的:對(duì)中國(guó)先天性眼外肌纖維化(congenital fibrosis of the extraocular muscles,CFEOM)家系進(jìn)行致病基因定位及疾病分型,研究其中樞神經(jīng)系統(tǒng)功能性改變,進(jìn)一步認(rèn)識(shí)和理解其神經(jīng)源性的病變機(jī)制,為尚處初級(jí)研究階段的CFEOM患者大腦fMRI變化規(guī)律提供更多臨床依據(jù)。方法:1、致病基因定位與疾病分型1.1對(duì)2個(gè)CFEOM家系9名患者采集病史、體格檢查、抽取外周靜脈血5-8ml并提取基因組DNA。首先通過(guò)候選基因法對(duì)己知的主要基因突變位點(diǎn)進(jìn)行探查,采取直接DNA序列分析,再通過(guò)SSCP證實(shí)突變位點(diǎn),隨機(jī)選取100名健康且無(wú)血緣關(guān)系中國(guó)人作對(duì)照組,以排除基因多態(tài)性可能。若仍未發(fā)現(xiàn),則檢測(cè)范圍擴(kuò)大到目前已報(bào)道的其它基因突變位點(diǎn),或再運(yùn)用連鎖分析及全外顯子測(cè)序進(jìn)行檢測(cè)。1.2通過(guò)查找致病基因發(fā)現(xiàn)已知或未知的突變位點(diǎn),結(jié)合CFEOM家系患者臨床表型進(jìn)行疾病分型。2、神經(jīng)功能檢測(cè)與分析對(duì)2個(gè)家系典型CFEOM患者和正常對(duì)照組行全腦靜息態(tài)功能磁共振檢查及三維腦結(jié)構(gòu)成像。正常組與病人組根據(jù)年齡及性別按2:1匹配。2.1首先對(duì)所有受試者進(jìn)行全腦常規(guī)橫斷位MRI掃描以排除顱腦器質(zhì)性病變。常規(guī)顱腦MRI掃描未見(jiàn)異常者繼續(xù)行rs-fMRI掃描。2.2 rs-fMRI掃描:采用實(shí)時(shí)功能成像程序(Real-Time Imaging Processing,RTIP)方式及梯度回波-回波平面成像(Gradient-Recalled Echo-Planar Imaging,GRE-EPI)序列。2.3觀察指標(biāo)與分析:首先對(duì)采集的數(shù)據(jù)運(yùn)用RESET軟件進(jìn)行預(yù)處理及校正,使用SPM8軟件進(jìn)行統(tǒng)計(jì)分析。對(duì)病變組與對(duì)照組的低頻振幅(ALFF)、局域一致性(ReHo)、功能連接(FC)以及基于體素的形態(tài)學(xué)分析法(VBM)的腦結(jié)構(gòu)變化進(jìn)行比較分析。結(jié)果:1、臨床研究1.1家系1五代中9人患病,均具有典型cfeom外觀特征。致病基因位于kif21a基因外顯子21,2860ct(r954w),為雜合錯(cuò)義突變。1.2家系2四代中4人患病,除一人臨床表型不典型外,其他三人都具有典型的cfeom外觀特征。致病基因位于tbuu3基因外顯子4,1249ga(d417n),為雜合錯(cuò)義突變。1.3兩個(gè)家系所有患者神經(jīng)影像檢查頭顱mri形態(tài)上未見(jiàn)明顯發(fā)育不良。2、靜息態(tài)功能磁共振研究病患組8人:男6人,女2人,年齡13-58歲,平均年齡35.38歲(sd=14.02),正常對(duì)照組16人:男12人,女4人,年齡12-58歲,平均年齡36.26歲(sd=15.64),兩組性別(chi-squaretestp=0.925)、年齡(p=0.822)比較無(wú)統(tǒng)計(jì)學(xué)差異。2.1rs-fmri分析結(jié)果:2.1.1alff:與正常對(duì)照組比較,病患組alff增強(qiáng)的腦區(qū):小腦扁桃體、左顳下回;減弱的腦區(qū):右頂上小葉。2.1.2reho:與正常對(duì)照組比較,病患組reho增強(qiáng)的腦區(qū):右頂葉角回、左舌回、左島葉中央溝蓋、右中央前回;減弱的腦區(qū):左小腦后葉。2.1.3fc:與正常對(duì)照組比較,以右額中回后部為種子區(qū)(roi)時(shí),病患組無(wú)fc增加的腦區(qū),減弱的腦區(qū):右中央后回、左頂上小葉;以左額中回后部為種子區(qū)時(shí),fc增加的腦區(qū):右小腦前葉、小腦蚓部,無(wú)減弱的腦區(qū)。2.2vbm全腦灰、白質(zhì)體積分析結(jié)果:2.2.1灰質(zhì)體積:與正常對(duì)照組相比,病患組灰質(zhì)體積增加的腦區(qū):左輔助運(yùn)動(dòng)區(qū)、右頂下小葉、右額下回眶部;體積減少區(qū):右額下回、左額上回。2.2.2白質(zhì)體積:與正常對(duì)照組相比,病患組的白質(zhì)無(wú)體積增加的腦區(qū);減少的腦區(qū):左丘腦、右枕下回、右杏仁核、胼胝體壓部、右頂葉角回、右顳上回。結(jié)論:1、運(yùn)用候選基因法確定2個(gè)cfeom家系致病基因定位分別為kif21a基因2860ct(r954w)和tubb3基因1249ga(d417n),均為雜合錯(cuò)義突變。2、cfeom1與cfeom3臨床表型存在交叉,1型具更穩(wěn)定的cfeom臨床特征,3型表型更多樣及外顯不全。家系1屬于cfeom1a型,遺傳方式為常染色體完全外顯的顯性遺傳;家系2屬于cfeom3a型,遺傳方式為常染色體不完全外顯的顯性遺傳。3、2個(gè)CFEOM家系患者頭顱常規(guī)MRI形態(tài)上均未見(jiàn)明顯發(fā)育不良。4、全腦靜息態(tài)功能磁共振研究顯示CFEOM患者存在多個(gè)皮質(zhì)中樞信號(hào)序列的變化,與患者異常心理和情緒、理解和辨別、運(yùn)動(dòng)和控制等腦區(qū)功能改變有關(guān)。以不同半球額中回后部(側(cè)目中樞)為種子區(qū)的功能連接異常區(qū)域顯示與患者視覺(jué)感知、運(yùn)動(dòng)學(xué)習(xí)及環(huán)境適應(yīng)等相關(guān)。5、基于體素的形態(tài)學(xué)分析研究顯示CFEOM患者灰、白質(zhì)體積改變范圍較廣,涉及多個(gè)中樞神經(jīng)功能區(qū)域,主要為邊緣系統(tǒng)皮質(zhì)與皮質(zhì)下結(jié)構(gòu);大腦白質(zhì)存在廣泛體積減少區(qū),提示顱內(nèi)神經(jīng)纖維傳導(dǎo)功能下降,符合中樞神經(jīng)源性肌病特征。
[Abstract]:Objective: To study the gene localization and disease classification of congenital fibrosis of the extraocular muscles (CFEOM) family in China, study the functional changes of the armature nervous system, and further understand and understand the mechanism of the neurogenic pathological changes for the changes of the fMRI changes in the brain of CFEOM patients at the primary stage of study. The rules provided more clinical basis. Methods: 1, the pathogenic gene location and the disease classification 1.1 pairs of 2 CFEOM families 9 patients to collect medical history, physical examination, extraction of peripheral venous blood 5-8ml and extract the genomic DNA. first through the candidate gene method to explore the known major gene mutation site, direct DNA sequence analysis, and then through the SSCP syndrome 100 healthy and unrelated Chinese people were randomly selected as the control group to exclude genetic polymorphisms. If not found, the detection range was extended to other gene mutations at present, or the detection of.1.2 by linkage analysis and exon sequencing was used to detect the known or not. The known mutation site, combined with the clinical phenotype of the CFEOM family with the clinical phenotype of the disease classification.2, and the neural function test and analysis of 2 families with typical CFEOM patients and the normal control group, the whole brain resting state functional magnetic resonance imaging (fMRI) and the three-dimensional brain structure imaging were performed. The normal group and the patient group were based on the age and sex of the 2:1 matching.2.1 to all the subjects first. General cerebral conventional transversal MRI scan was performed to eliminate craniocerebral organic lesions. Rs-fMRI scanning.2.2 rs-fMRI scan was continued without abnormal brain MRI scan: the real-time functional imaging program (Real-Time Imaging Processing, RTIP) and gradient echo echo plane imaging (Gradient-Recalled Echo-Planar Imaging) sequence .2.3 observation and analysis: first, the collected data were pre processed and corrected by RESET software, and the SPM8 software was used for statistical analysis. The low frequency amplitude (ALFF), local conformance (ReHo), functional connectivity (FC), and the morpheme based morphologic analysis (VBM) were compared and analyzed. The results were as follows: 1, 9 of the 1.1 families and 1 five generations of the clinical study have a typical CFEOM appearance. The pathogenic gene is located in the exon 212860ct (r954w) of the KIF21A gene, and 4 in the.1.2 family of the heterozygous mutation.1.2 family, and the other three people have typical CFEOM appearance except one person's clinical phenotype. The pathogenic gene is located outside the tbuu3 gene. 41249ga (d417n), for all patients with heterozygous missense mutation.1.3, all patients with two families had no apparent dysplasia.2 in the head MRI morphology. Resting state function magnetic resonance (fMRI) was used to study 8 patients: 6 men, 2 women, 13-58 years old, 35.38 years old (sd=14.02), and 16 men in normal control group: 12 men, 4 women, and average age 12-58 years old. Average age was 12-58 years old. Age 36.26 (sd=15.64), two groups of sex (chi-squaretestp=0.925), age (p=0.822) no statistical difference.2.1rs-fmri analysis results: 2.1.1alff: and normal control group, Alff enhanced brain area of the patient group: cerebellar tonsil, left temporal gyrus, and weakened brain area: right upper lobule.2.1.2reho: compared with normal control group, ReHo group ReHo The enhanced brain area: right parietal gyrus, left lingual gyrus, left central sulcus cover, right central anterior gyrus; weakened brain area: the left posterior lobe.2.1.3fc: was compared with the normal control group, with the right middle back and posterior part of the seed region (ROI), the patient group had no FC increase in the brain area and the weakened brain area: right central posterior gyrus and left upper lobule; the left middle posterior part was the seed area. At the time, FC increased brain area: right cerebellar anterior lobe, cerebellar vermis, no weakened brain.2.2vbm whole brain ash, white matter volume analysis results: 2.2.1 gray matter volume: compared with normal control group, the volume of gray matter volume increased in the patient group: left auxiliary motor area, right inferior lobule, right inferior frontal gyrus; right frontal gyrus, left upper.2.2.2 white matter Volume: compared with the normal control group, the white matter had no volume increase in the brain area; the reduced brain area: left thalamus, right occipital gyrus, right amygdala, corpus callosum pressure, right parietal gyrus, right temporal gyrus. Conclusion: 1, KIF21A gene 2860ct (r954w) and tubb3 gene 1249ga (d41) were identified by candidate gene method. 7n) were heterozygous mutation.2, CFEOM1 and CFEOM3 clinical phenotype intersecting, the 1 type has more stable CFEOM clinical features, 3 phenotype diversity and exotoxicity. Family 1 belongs to cfeom1a type, hereditary mode is autosomal explicit explicit inheritance; family 2 belongs to cfeom3a type, hereditary mode is autosomal incomplete explicit dominance There was no obvious dysplasia.4 in the routine MRI morphology of the patients with.3,2 CFEOM family, and the study of resting state functional magnetic resonance (fMRI) showed that there were many changes of the central signal sequence of the cortex in the patients with CFEOM, which was related to the abnormal mental and emotional, understanding and discrimination, movement and control of brain function changes in patients with different hemispheres. The posterior (lateral center) area of the functional connectivity of the seed region shows.5 related to visual perception, exercise learning and environmental adaptation. The morphological analysis of voxel shows that CFEOM patients are grey with a wide range of white matter volume, involving several central nervous power areas, mainly the cortex of the marginal system and subcortical structure. There is a wide volume reduction area in the white matter of the brain, suggesting that the decrease of intracranial nerve fiber conduction function is consistent with the characteristics of central neurogenic myopathy.

【學(xué)位授予單位】：南昌大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R777.4

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