摘要：

目的: 总结以痉挛性截瘫为首发症状的早发型家族性阿尔茨海默病（EOFAD）3型一家系临床表现及基因变异特征。方法与结果: 首都医科大学宣武医院2021年3月30日收治1例以痉挛性截瘫为首发症状的29岁男性患者，头部MRI显示双侧额叶皮质下和颞叶多发缺血灶，胸椎MRI呈轻度萎缩性改变。追问病史，患者之父首发症状与之相似且迅速进展，表现为痉挛性瘫痪、言语障碍、认知功能障碍和精神行为异常，发病至死亡时间7年，呈相对恶性病程。全外显子组测序（WES）显示患者存在PSEN1基因外显子7 c.668A ＞ G（p.Gln223Arg）错义突变，经Sanger测序验证其母和其姐未携带该变异，推测该变异源自其父，根据美国医学遗传学和基因组学会分级该突变位点为可能致病。患者诊断为痉挛性截瘫，该家系诊断为EOFAD3型家系。结论: PSEN1基因外显子7 c.668A ＞ G（p.Gln223Arg）错义突变为该家系致病性变异，导致以痉挛性截瘫为首发症状的罕见EOFAD3型，详细的家系调查结合WES测序有助于提高疾病诊断率。

关键词: 阿尔茨海默病, 截瘫, 基因, 突变, 误义, 系谱

Abstract:

Objective: To summarize the clinical and genetic mutation characteristics of a family of early - onset familial Alzheimer's disease (EOFAD) type 3 with spastic paraplegia as the first symptom. Methods and Results: A 29 - year - old male patient with spastic paraplegia as the first symptom was admitted to Xuanwu Hospital, Capital Medical University on March 30, 2021. Head MRI showed multiple ischemic foci in bilateral subfrontal cortex and bilateral temporal lobes. Thoracic MRI showed mild atrophic changes. Follow - up medical history showed the first symptom of the his father were similar and progressed rapidly, including spastic paralysis, speech disorders, dementia, and mental and behavioral abnormalities. The duration from onset to death was 7 years, showing a relatively malignant course. Whole exome sequencing (WES) revealed a missense mutation of PSEN1 gene exon 7 c.668A ＞ G (p.Gln223Arg) in the patient. The results of Sanger sequencing showed the mother and sister of the patient did not carry this mutation, and it was speculated the mutation came from the father of the patient. According to the guidelines of the American College of Medical Genetics and Genomics (ACMG), the above mutation was classified as likely pathogenic (PS3 + PM2 + PS4_Moderate). The patient was diagnosed with spastic paraplegia, and the family was diagnosed with EOFAD3. Conclusions: A missense mutation of PSEN1 gene exon 7 c. 668A ＞ G (p. Gln223Arg) was identified, which was the pathogenic variant of this family, resulting in a rare EOFAD3 with spastic paraplegia as the first symptom, detailed family investigation combined with WES would help improve the efficiency of early diagnosis.

Key words: Alzheimer disease, Paraplegia, Genes, Mutation, missense, Pedigree