探讨1例儿童时期以癫痫起病的早发型阿尔茨海默病患者及其大家系的早老素基因1(PSEN1)突变情况。

选择2014年11月28日至2015年11月14日在北京大学第一医院神经内科门诊确诊为早发型阿尔茨海默病患者(先证者)及其大家系(Ⅰ～Ⅳ代)为研究对象。本例先证者为男性，现年36岁，因"癫痫，异常家族史"就诊，于本院进行遗传咨询，希望明确病因。早发型阿尔茨海默病诊断标准：①发病年龄<65岁；②临床检查结果支持痴呆的证据；③超过2个领域存在认知障碍；④进行性记忆力下降伴其他认知障碍；⑤无意识障碍；⑥无其他系统性疾病或脑疾病可解释的记忆和认知障碍。收集先证者及其家系成员临床资料，采用靶向捕获二代测序(TGS)技术对其进行基因分析，发现PSEN1突变后，对所有外显子和内含子边界PSEN1进行聚合酶链反应(PCR)检测，采用Sanger方法进行基因突变验证。本研究遵循的程序符合北京大学第一医院人体试验委员会所制定的伦理学标准，得到该委员会批准，并与受试者签署临床研究知情同意书。

①本例先证者(Ⅲ₁₆)于12岁时出现癫痫发作，15岁开始口服丙戊酸钠治疗后癫痫发作被控制，33岁停药后复发，再次采取丙戊酸钠缓释片治疗后癫痫被控制。本例先证者在本院进行相关检查的结果显示，智力、运动功能发育正常，头颅MRI检查结果未见异常，最终临床诊断为"原发性癫痫" 。但是，患者自述于35岁开始出现记忆力下降，定向功能减退。②先证者的祖母(Ⅰ₂)于30多岁出现精神障碍，40岁左右死亡。先证者的父亲(Ⅱ₆)、2位伯父(Ⅱ₂与Ⅱ₃)、2位姑姑(Ⅱ₄与Ⅱ₅)均于35岁左右出现进行性记忆力下降、智能倒退，均于40岁左右死亡，并符合早发型阿尔茨海默病诊断标准，而被诊断为早发型阿尔茨海默病患者。③TGS检测结果显示，先证者PSEN1基因的第5外显子c.346G>A(p.Glu116Lys)杂合突变，先证者之子(Ⅳ₁₈，12岁)，先证者四姑的长子(Ⅲ₁₁，45岁)及长子之子(Ⅳ₁₁，7岁)，先证者五姑的三女儿(Ⅲ₁₅，29岁)，均为PSEN1基因的第5外显子c.346G>A(p.Glu116Lys)杂合突变携带者，均尚无进行性记忆力下降、智能倒退等早发型阿尔茨海默病临床症状。

明确早发型阿尔茨海默病患者家系的临床和分子遗传学特征，可为该病患者准确的遗传咨询和进一步的产前诊断奠定基础。

To investigate the etiology of early-onset Alzheimer disease which caused by presenilin 1 (PSEN1) mutation in one case of early-onset Alzheimer disease patient with initial symptom of epilepsy childhood and his large family.

From November 28, 2014 to November 14, 2015, one case of patient with initial symptom of epilepsy from age of 12 years old who was diagnosed as early-onset Alzheimer disease (the proband) in Department of Neurology of Peking University First Hospital and his large family genealogy (Ⅰ-Ⅳ generations)were recruited as research objects. Diagnostic criteria of Alzheimer disease were as follows. ①Age of onset less than 65 years old. ②The clinical examination evidence supported the diagnosis for dementia; ③Cognitive impairment showed in more than two fields. ④The progressive decline of memory and with other cognitive disorders. ⑤Without disturbance of consciousness. ⑥Without other systemic diseases and the memory and cognitive impairment which can be explained by the brain diseases. The proband, a male, 36 years old had seizures from the age of 12-year-old. He visited the hospital to seek for etiological and to study for his abnormal family history. Clinical data and genomic DNA of the proband and his family members were collected. Targeted next-generation sequencing (TGS) was performed to detect the PSEN1 mutation in the proband. All exons and exon-intron boundaries of PSEN1 were checked by polymerase chain reaction (PCR). Sanger sequencing was used to verify the corresponding mutation. The procedure of this study was consistent with ethical standard established by the committee of investigation in human beings of Peking University First Hospital. And it was approved by this committee. Informed consent was obtained from all participants.

①The proband (Ⅲ₁₆) presented with seizures when he was 12 years old. After treated by sodium valproate from the age of 15 years old, the seizure was not observed. He had normal psychomotor development. His cranial MRI showed no abnormality. Relapse occurred when he stopped the drug at the age of 33 years old and sodium valproate remained effective. Primary epilepsy was suspected. However, he have presented with memory loss and disorientation since the age of 35 years old. ②His grandmother (Ⅰ₂) had psychiatric disorder in her thirties and died at around 40 years old. His father (Ⅱ₆), two aunts(Ⅱ₄and Ⅱ₅)and two uncles(Ⅱ₂and Ⅱ₃) presented with similar symptoms, progressive memory loss and mental retroversion at the age of about 35 years old, died in their forties, indicating early-onset Alzheimer disease. ③The sequencing results showed that, in exon 5 of PSEN1of the proband, a reported heterozygous mutation (c.346G>A, p. Glu116Lys) was identified. The same heterozygous mutation was found respectively in his son, a son (Ⅲ_11,45 years old) and a grandson (Ⅳ_11,7 years old) of a paternal aunt, and a daughter (Ⅲ_15,29 years old) of another paternal aunt. The son of the paternal aunt who had the same mutation with the proband was 45 years old without any symptoms.

Clinical and molecular genetic features of the proband′s pedigree were clearly definite. The results confirmed the diagnosis of early-onset Alzheimer disease. It will be helpful for the genetic counseling and the prenatal diagnosis of the next generation of the family.