一个罕见脑桥小脑发育不全家系临床研究及遗传学分析

发布时间：2018-06-04 00:13

本文选题：脑桥小脑发育不全 + 全外显子组测序　；参考：《安徽医科大学》2016年硕士论文

【摘要】：研究背景脑桥小脑发育不全(Pontocerebellar Hypoplasia,PCH)是一组少见的常染色体隐性遗传的神经系统变性疾病,通常在出生前发病。其共同特征包括脑桥、小脑发育不全、萎缩,进行性加重的小头畸形和不同程度的脑室扩大,有时大脑也可受累[1]。其临床症状可表现为严重的认知障碍,运动障碍以及癫痫发作。目前该疾病可分为8种亚型,针对不同亚型的致病机制也有所报。对PCH的治疗措施有限,仅以支持治疗为主,且预后较差。目的通过对一个脑桥小脑发育不全(PCH)家系研究,进一步了解并探讨PCH的临床特点及致病基因,为该疾病的诊断、预后评估提供依据。方法收集一个脑桥小脑发育不全的家系成员(先证者、先证者弟弟、先证者父亲、先证者母亲)的临床资料,了解该家系的发病情况及临床特点,同时进行详细的神经系统的检查及脑电、头颅MRI检查;应用简易智能精神状态检查量表(mini-mental stateexamination,MMSE)、蒙特利尔认知评估量表(Montreal Cognitive Assessment,Mo CA)对家系成员进行评分、并绘制系谱图、进行脑电、头颅磁共振检查,征得该家系成员知情同意,采集其中4名家系成员外周静脉血各4ml,进行全外显子组测序分析(数据分析模式仅限于孟德尔遗传病),在验证已知相关突变基因的基础上,进一步筛选出未知相关突变基因,并对其进行Sanger测序验证;以进一步完善本家系疾患的基因普并支持其诊断。结果(1)该家系成员无三代以内近亲婚姻的情况,家系中除先证者及其弟弟,其他成员没有类似疾患发生。先证者及其弟弟发病年龄,发病症状几乎一致,神经系统检查结果相似,如3岁左右癫痫发作,认知障碍,走直线不稳,肌张力低下,腱反射消失;(2)脑电图显示各导联棘波发放;(3)头颅MRI显示小脑,脑干不同程度的发育不良。(4)神经心理学量表:先证者:Mo Ca评分4分,MMSE评分8分;先证者弟弟:Mo Ca评分21分,MMSE评分22分;先证者父亲:Mo Ca评分24分,MMSE评分30分;先证者母亲:Mo Ca评分28分,MMSE评分29分;(4)全外显子组测序发现了1个突变,是否和该家系疾病有关,有待进一步研究。结论(1)本研究未发现该疾病已知的相关基突变因;(2)未筛选出临床表型与遗传方式相匹配的突变基因作Sanger测序;(3)发现了1个基因突变,符合常染色隐性遗传,但是否与该疾病相关,有待进一步研究。
[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.
【学位授予单位】：安徽医科大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R742

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