阿茲海默氏症的基因檢測與遺傳諮詢

Genetic Testing and Counseling for Alzheimer's Disease

阿茲海默氏症是最常見的失智症，其病理上的特徵是腦組織出現老化斑。老化斑的基本成分β-amyloid protein-42（簡稱Aβ42）來自amyloid precursor protein（APP）；科學家在1987年找出APP的基因，接著發現一小部份的家族性失智症起因於APP基因的點突變；後來以基因連鎖分析所找到的presenilin-1基因，不僅實驗上可以證明其突變會造成Aβ42的聚積，也有一半的家族性阿茲海默氏症被證實起因於presenilin-1基因的突變；隨後又被找到的presenilin-2基因，其突變也會造成阿茲海默氏症。另外，apolipoprotein E的ε4對偶子雖然不是此病的直接病因，卻會增加罹病的機率。除此之外，還有好幾個可疑的基因已經在科學家的實驗桌上等待檢驗，這些基因的發現已經使阿茲海默氏症的病理機轉逐漸明朗。傳統上認為遺傳了阿茲海默氏症的突變基因就註定要罹患失智症的迷思已經因為APPβ-secretase （BACE 與Asp2）的發現而被打破。BACE與Asp2是產生Aβ42的關鍵酵素，一旦開發出抑制BACE或Asp2的藥物，預防或治療阿茲海默氏症將不再是夢想，而預測阿茲海默氏症的基因診斷也將因此變得重要。美國法院在1995與1996年分別判決二位醫師業務過失，因為他們沒有對患者的子女提出甲狀腺髓狀癌或多發性息肉大腸直腸癌會遺傳的警告。這二個案例與阿茲海默氏症即將可以預防或治療的展望，提醒現代的醫療人員，面對這個曾經「什麼事也不能做」的世紀大病，別忘了詢問患者的家族史，必要時還得安排基因檢測，並提供適當的遺傳諮詢。

Alzheimer’s disease is a chronic, degenerative, dementing illness which involves a progressive, multifaceted loss of cognitive and intellectual abilities. Mutations in the amyloid precursor protein (APP) gene or the presenilin 1 and presenilin 2 (PS1 and PS2) genes can directly lead to the disease; ε4 allele of apolipoprotein (ApoE) increases the risk of the disease. The cognate proteins of these pathogenic loci have direct relations to the pathology of the relevant diseases, molecular testing has been able to make accurate diagnosis and to predict some of these diseases, while clonings of enzymes metabolizing APP has facilitated the possibility of treating or preventing Alzheimer's disease. In order to initiate a program of molecular diagnosis and genetic counseling for dementia, we have setup methods to genotype ApoE and screen mutations in APP, PS1 and PS2 genes in patients with family history of dementia. Although the rate of familial AD with identifiable mutations is still too low to obtain the physicians' attention in Taiwan, the verdicts announcing physicians’ duty to warn third parties about genetically inherited diseases from the courts of the United States deserves our concern. We believe frequent open discussions may help preventing unnecessary conflicts and aggregating consensus on the practice of molecular testing and genetic counseling for AD and other late onset inherited diseases.