Conidi Maria E, Bernardi Livia, Puccio Gianfranco, Smirne Nicoletta, Muraca Maria G, Curcio Sabrina A M, Colao Rosanna, Piscopo Paola, Gallo Maura, Anfossi Maria, Frangipane Francesca, Clodomiro Alessandra, Mirabelli Maria, Vasso Franca, Cupidi Chiara, Torchia Giusi, Di Lorenzo Raffaele, Mandich Paola, Confaloni Annamaria, Maletta Raffaele G, Bruni Amalia C
From the Regional Neurogenetic Centre (M.E.C., L.B., G.P., N.S., M.G.M., S.A.M.C., R.C., M.G., M.A., F.F., A. Clodomiro, M.M., F.V., C.C., G.T., R.D.L., R.G.M., A.C.B.), ASP Catanzaro, Lamezia Terme; Department of Cell Biology and Neurosciences (P.P., A. Confaloni), National Institute of Health, Rome; and DINOGMI (P.M.), Università degli studi di Genova, Italy.
Neurology. 2015 Jun 2;84(22):2266-73. doi: 10.1212/WNL.0000000000001648. Epub 2015 May 6.
To report, for the first time, a large autosomal dominant Alzheimer disease (AD) family in which the APP A713T mutation is present in the homozygous and heterozygous state. To date, the mutation has been reported as dominant, and in the heterozygous state associated with familial AD and cerebrovascular lesions.
The family described here has been genealogically reconstructed over 6 generations dating back to the 19th century. Plasma β-amyloid peptide was measured. Sequencing of causative AD genes was performed.
Twenty-one individuals, all but 1 born from 2 consanguineous unions, were studied: 8 were described as affected through history, 5 were studied clinically and genetically, and 8 were asymptomatic at-risk subjects. The A713T mutation was detected in the homozygous state in 3 patients and in the heterozygous state in 8 subjects (6 asymptomatic and 2 affected).
Our findings, also supported by the β-amyloid plasma assay, confirm (1) the pathogenic role of the APP A713T mutation, (2) the specific phenotype (AD with cerebrovascular lesions) associated with this mutation, and (3) the large span of age at onset, not influenced by APOE, TOMM40, and TREM2 genes. No substantial differences concerning clinical phenotype were evidenced between heterozygous and homozygous patients, in line with the classic definition of dominance. Therefore, in this study, AD followed the classic definition of a dominant disease, contrary to that reported in a previously described AD family with recessive APP mutation. This confirms that genetic AD may be considered a disease with dominant and recessive traits of inheritance.
首次报告一个大型常染色体显性阿尔茨海默病（AD）家系，其中APP A713T突变以纯合子和杂合子状态存在。迄今为止，该突变被报告为显性，且杂合子状态与家族性AD和脑血管病变相关。
本文所描述的家系已追溯重建至19世纪的6代人。检测了血浆β-淀粉样肽。对导致AD的基因进行了测序。
共研究了21人，除1人外均来自2次近亲联姻：8人经病史描述为患病，5人进行了临床和基因研究，8人为无症状高危受试者。在3例患者中检测到A713T突变的纯合子状态，8名受试者（6名无症状，2名患病）中检测到杂合子状态。
我们的发现也得到血浆β-淀粉样肽检测的支持，证实了（1）APP A713T突变的致病作用，（2）与该突变相关的特定表型（伴有脑血管病变的AD），以及（3）发病年龄范围广，不受APOE、TOMM40和TREM2基因影响。杂合子和纯合子患者在临床表型上无显著差异，符合显性的经典定义。因此，在本研究中，AD遵循显性疾病的经典定义，这与先前描述的具有隐性APP突变的AD家系的报告相反。这证实了遗传性AD可被视为一种具有显性和隐性遗传特征的疾病。
