Lopergolo Diego, Bianchi Silvia, Gallus Gian Nicola, Locci Sara, Pucci Barbara, Leoni Valerio, Gasparini Daniele, Tardelli Elisa, Chincarini Andrea, Sestini Stelvio, Santorelli Filippo Maria, Zetterberg Henrik, De Stefano Nicola, Mignarri Andrea
Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.
UOC Neurologia e Malattie Neurometaboliche, Azienda Ospedaliero-Universitaria Senese, Siena, Italy.
J Med Genet. 2024 Mar 21;61(4):332-339. doi: 10.1136/jmg-2023-109219.
mutations are responsible for Niemann-Pick disease type C (NPC), a rare autosomal recessive neurodegenerative disease. Patients harbouring heterozygous mutations may rarely show parkinsonism or dementia. Here, we describe for the first time a large family with an apparently autosomal dominant late-onset Alzheimer's disease (AD) harbouring a novel heterozygous mutation.
All the five living siblings belonging to the family were evaluated. We performed clinical evaluation, neuropsychological tests, assessment of cerebrospinal fluid markers of amyloid deposition, tau pathology and neurodegeneration (ATN), structural neuroimaging and brain amyloid-positron emission tomography. Oxysterol serum levels were also tested. A wide next-generation sequencing panel of genes associated with neurodegenerative diseases and a whole exome sequencing analysis were performed.
We detected the novel heterozygous c.3034G>T (p.Gly1012Cys) mutation in , shared by all the siblings. No other point mutations or deletions in or were found. In four siblings, a diagnosis of late-onset AD was defined according to clinical characterisation and ATN biomarkers (A+, T+, N+) and serum oxysterol analysis showed increased 7-ketocholesterol and cholestane-3β,5α,6β-triol.
We describe a novel heterozygous mutation harboured by different members of a family with autosomal dominant late-onset amnesic AD without NPC-associated features. A missense mutation in homozygous state in the same aminoacidic position has been previously reported in a patient with NPC with severe phenotype. The alteration of serum oxysterols in our family corroborates the pathogenic role of our mutation. Our work, illustrating clinical and biochemical disease hallmarks associated with heterozygosity in patients affected by AD, provides relevant insights into the pathogenetic mechanisms underlying this possible novel association.
突变是尼曼-匹克病C型（NPC）的病因，这是一种罕见的常染色体隐性神经退行性疾病。携带杂合突变的患者可能很少表现出帕金森症或痴呆症状。在此，我们首次描述了一个患有明显常染色体显性晚发性阿尔茨海默病（AD）的大家族，该家族携带一种新的杂合突变。
对该家族中所有在世的五名兄弟姐妹进行了评估。我们进行了临床评估、神经心理学测试、脑脊液淀粉样蛋白沉积、tau病理和神经退行性变（ATN）标志物评估、结构神经影像学检查以及脑淀粉样蛋白正电子发射断层扫描。还检测了血清氧化甾醇水平。对与神经退行性疾病相关的基因进行了广泛的二代测序，并进行了全外显子组测序分析。
我们在所有兄弟姐妹中均检测到新的杂合c.3034G>T（p.Gly1012Cys）突变。在或中未发现其他点突变或缺失。根据临床表现和ATN生物标志物（A+、T+、N+），四名兄弟姐妹被诊断为晚发性AD，血清氧化甾醇分析显示7-酮胆固醇和胆甾烷-3β,5α,6β-三醇增加。
我们描述了一个常染色体显性晚发性遗忘型AD家族的不同成员所携带的一种新的杂合突变，该家族无NPC相关特征。先前在一名具有严重表型的NPC患者中报道了同一氨基酸位置的纯合状态的错义突变。我们家族中血清氧化甾醇的改变证实了我们突变的致病作用。我们的研究展示了与AD患者杂合性相关的临床和生化疾病特征，为这种可能的新关联的潜在致病机制提供了相关见解。
