Department of Neurology, University of Washington, 1660 S Columbian Way, 182-GRECC, Seattle, WA 98108, USA.
Brain. 2010 Apr;133(Pt 4):1143-54. doi: 10.1093/brain/awq033.
Mutations in presenilin 2 are rare causes of early onset familial Alzheimer's disease. Eighteen presenilin 2 mutations have been reported, although not all have been confirmed pathogenic. Much remains to be learned about the range of phenotypes associated with these mutations. We have analysed our unique collection of 146 affected cases in 11 Volga German families, 101 who are likely to have the same N141I mutation in presenilin 2 (54 genotyped confirmed). We have also assessed the detailed neuropathologic findings in 18 autopsies from these families and reviewed the world's literature on other presenilin 2 mutations; presenting a novel mutation that is predicted to lead to a premature truncation codon. Seven presenilin 2 mutations reported in the literature have strong evidence for pathogenicity whereas others may be benign polymorphisms. One hundred and one affected persons, with sufficient historical information from the Volga German pedigrees (N141I mutation), had a mean onset age of 53.7 years+/-7.8 (range 39-75) and mean age at death of 64.2 years+/-9.8 (range 43-88). These figures overlap with and generally fall between the results from the subjects in our centre who have late onset familial Alzheimer's disease or mutations in presenilin 1. Seizures were noted in 20 (30%) of 64 subjects with detailed medical records. Two mutation carriers lived beyond age 80 without developing dementia, representing uncommon examples of decreased penetrance. Two persons had severe amyloid angiopathy and haemorrhagic stroke. Eighteen cases had detailed histopathology available and analysed at our institution. Braak stage was five or six, amyloid angiopathy and neuritic plaques were common and more than 75% had Lewy bodies in the amygdala. TAR DNA-binding protein-43 inclusions were uncommon. In addition, a 58-year-old female with a 2 year course of cognitive decline and no family history of dementia has abnormal fludeoxyglucose-positron emission tomography imaging and a novel 2 base pair deletion in presenilin 2 at nucleotide 342/343, predicted to produce a frame-shift and premature termination. We conclude that mutations in presenilin 2 are rare with only seven being well documented in the literature. The best studied N141I mutation produces an Alzheimer's disease phenotype with a wide range of onset ages overlapping both early and late onset Alzheimer's disease, often associated with seizures, high penetrance and typical Alzheimer's disease neuropathology. A novel premature termination mutation supports loss of function or haploinsufficiency as pathogenic mechanisms in presenilin 2 associated Alzheimer's disease.
早发性家族性阿尔茨海默病的罕见病因是早老素 2 基因突变。虽然并非所有突变都被证实具有致病性，但已经报道了 18 种早老素 2 突变。我们还有很多关于这些突变相关表型的知识需要学习。我们分析了我们独特的 11 个伏尔加德意志家族的 146 名受影响病例，其中 101 名可能在早老素 2 中有相同的 N141I 突变（54 名经基因分型证实）。我们还评估了这些家族中 18 例尸检的详细神经病理学发现，并回顾了世界上关于其他早老素 2 突变的文献；提出了一种新的突变，预计会导致过早的截断密码子。文献中报道的 7 种早老素 2 突变具有很强的致病性证据，而其他突变可能是良性多态性。101 名受影响的人，根据伏尔加德意志家族的病史信息（N141I 突变），平均发病年龄为 53.7 岁+/-7.8（范围为 39-75），平均死亡年龄为 64.2 岁+/-9.8（范围为 43-88）。这些数字与我们中心患有晚发性家族性阿尔茨海默病或早老素 1 突变的受试者的结果重叠，且通常在两者之间。有详细病历的 64 名受试者中有 20 名（30%）出现癫痫发作。两名突变携带者的寿命超过 80 岁而没有发展为痴呆，这是少见的低外显率例子。两名患者有严重的血管淀粉样变和出血性中风。18 例有详细的组织病理学可供分析。我们机构的分析表明，Braak 分期为五或六期，血管淀粉样变和神经原纤维缠结很常见，超过 75%的患者在杏仁核中有路易体。TAR DNA 结合蛋白-43 包涵体很少见。此外，一名 58 岁的女性，有 2 年的认知衰退病史，没有痴呆家族史，她的氟脱氧葡萄糖正电子发射断层扫描成像异常，并且在早老素 2 中存在 2 个碱基对的缺失，位于核苷酸 342/343，预计会产生移码和过早终止。我们得出结论，早老素 2 突变是罕见的，只有 7 种在文献中有很好的记录。研究最充分的 N141I 突变产生了阿尔茨海默病表型，发病年龄范围广泛，与早发性和晚发性阿尔茨海默病重叠，常伴有癫痫发作、高外显率和典型的阿尔茨海默病神经病理学。一种新的过早终止突变支持早老素 2 相关阿尔茨海默病的功能丧失或杂合性缺失作为致病机制。
