本文選題：腦橋小腦發(fā)育不全 + 全外顯子組測序��； 參考：《安徽醫(yī)科大學》2016年碩士論文

【摘要】：研究背景腦橋小腦發(fā)育不全(Pontocerebellar Hypoplasia,PCH)是一組少見的常染色體隱性遺傳的神經(jīng)系統(tǒng)變性疾病,通常在出生前發(fā)病。其共同特征包括腦橋、小腦發(fā)育不全、萎縮,進行性加重的小頭畸形和不同程度的腦室擴大,有時大腦也可受累[1]。其臨床癥狀可表現(xiàn)為嚴重的認知障礙,運動障礙以及癲癇發(fā)作。目前該疾病可分為8種亞型,針對不同亞型的致病機制也有所報。對PCH的治療措施有限,僅以支持治療為主,且預后較差。目的通過對一個腦橋小腦發(fā)育不全(PCH)家系研究,進一步了解并探討PCH的臨床特點及致病基因,為該疾病的診斷、預后評估提供依據(jù)。方法收集一個腦橋小腦發(fā)育不全的家系成員(先證者、先證者弟弟、先證者父親、先證者母親)的臨床資料,了解該家系的發(fā)病情況及臨床特點,同時進行詳細的神經(jīng)系統(tǒng)的檢查及腦電、頭顱MRI檢查;應用簡易智能精神狀態(tài)檢查量表(mini-mental stateexamination,MMSE)、蒙特利爾認知評估量表(Montreal Cognitive Assessment,Mo CA)對家系成員進行評分、并繪制系譜圖、進行腦電、頭顱磁共振檢查,征得該家系成員知情同意,采集其中4名家系成員外周靜脈血各4ml,進行全外顯子組測序分析(數(shù)據(jù)分析模式僅限于孟德爾遺傳病),在驗證已知相關突變基因的基礎上,進一步篩選出未知相關突變基因,并對其進行Sanger測序驗證;以進一步完善本家系疾患的基因普并支持其診斷。結(jié)果(1)該家系成員無三代以內(nèi)近親婚姻的情況,家系中除先證者及其弟弟,其他成員沒有類似疾患發(fā)生。先證者及其弟弟發(fā)病年齡,發(fā)病癥狀幾乎一致,神經(jīng)系統(tǒng)檢查結(jié)果相似,如3歲左右癲癇發(fā)作,認知障礙,走直線不穩(wěn),肌張力低下,腱反射消失;(2)腦電圖顯示各導聯(lián)棘波發(fā)放;(3)頭顱MRI顯示小腦,腦干不同程度的發(fā)育不良。(4)神經(jīng)心理學量表:先證者:Mo Ca評分4分,MMSE評分8分;先證者弟弟:Mo Ca評分21分,MMSE評分22分;先證者父親:Mo Ca評分24分,MMSE評分30分;先證者母親:Mo Ca評分28分,MMSE評分29分;(4)全外顯子組測序發(fā)現(xiàn)了1個突變,是否和該家系疾病有關,有待進一步研究。結(jié)論(1)本研究未發(fā)現(xiàn)該疾病已知的相關基突變因;(2)未篩選出臨床表型與遺傳方式相匹配的突變基因作Sanger測序;(3)發(fā)現(xiàn)了1個基因突變,符合常染色隱性遺傳,但是否與該疾病相關,有待進一步研究。
[Abstract]:Background Pontocerebellar Hypoplasia (PCH) is a rare group of autosomal recessive neurodegenerative diseases usually occurring before birth. Common features include pons, cerebellar dysplasia, atrophy, progressive microcephaly and varying degrees of ventricular enlargement, sometimes involving the brain [1]. Its clinical symptoms can be characterized by severe cognitive impairment, motor disorder and seizures. At present, the disease can be divided into 8 subtypes, and the pathogenesis of different subtypes is also reported. The treatment of PCH is limited, only supportive treatment, and poor prognosis. Objective to study a pedigree of pons cerebellar dysplasia (pons) and to explore the clinical features and pathogenic genes of PCH in order to provide evidence for the diagnosis and prognosis evaluation of the disease. Methods the clinical data of a family member (proband, proband brother, proband father, proband mother) with cerebellopontine dysplasia were collected to find out the incidence and clinical characteristics of the pedigree. At the same time, a detailed examination of the nervous system, EEG and MRI were performed, and the mini-mental state examination scale (MMSE), the Montreal Cognitive Assessment scale (MMSE) and the Montreal Cognitive Assessment scale (MMSE) were used to evaluate the family members and draw pedigree diagrams for EEG. Cranial magnetic resonance imaging, with the informed consent of the member of the family, The peripheral venous blood of 4 family members were collected and sequenced in the whole exon group. (the data analysis model was limited to Mendelian disease. Based on the verification of known mutation genes, unknown mutation genes were further screened. Sanger sequencing was performed to further improve the gene expression of the disease and to support the diagnosis of the disease. Results 1) the family members had no close relatives within three generations, except the proband and their younger brother, there were no similar diseases in the family. The proband and his younger brother had almost the same onset age, almost identical symptoms, and similar neurological examination results, such as seizures about 3 years old, cognitive disorders, straight line instability, and hypotonia. MRI showed cerebellum and brainstem dysplasia in different degrees. Neuropsychological scale: proband: proband 4: Mo score 4 and MMSE score 8; The proband's younger brother: Mo Ca score 21 points and MMSE score 22 points; proband father: Mo Ca score 24 points and MMSE score 30 points; proband mother: Mo Ca score 28 points; MMSE score 29 points;) Total exon group sequencing found a mutation, whether it is related to the family disease. Further study is needed. Conclusion 1) in this study, we did not find a known cause of the associated mutation of the disease. (2) A mutation gene matching clinical phenotypic and genetic pattern was not screened for Sanger sequencing. (3) A gene mutation was found, which was consistent with the recessive heredity of normal staining. But whether or not it is related to the disease needs further study.
【學位授予單位】：安徽醫(yī)科大學
【學位級別】：碩士
【學位授予年份】：2016
【分類號】：R742

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