Cupidi Chiara, Frangipane Francesca, Gallo Maura, Clodomiro Alessandra, Colao Rosanna, Bernardi Livia, Anfossi Maria, Conidi Maria Elena, Vasso Franca, Curcio Sabrina Anna Maria, Mirabelli Maria, Smirne Nicoletta, Torchia Giusi, Muraca Maria Gabriella, Puccio Gianfranco, Di Lorenzo Raffaele, Zampieri Stefania, Romanello Milena, Dardis Andrea, Maletta Raffaele Giovanni, Bruni Amalia Cecilia
Regional Neurogenetic Centre (CRN), ASP Catanzaro, Lamezia Terme, Italy.
Regional Coordinator Centre for Rare Diseases, University Hospital Santa Maria della Misericordia, Udine, Italy.
J Alzheimers Dis. 2017;55(3):1249-1259. doi: 10.3233/JAD-160214.
Several neurological and systemic diseases can cause dementia, beyond Alzheimer's disease. Rare genetic causes are often responsible for dementia with atypical features. Recently, mutations causative for Niemann-Pick type C disease (NPC) have also been implicated in neurodegenerative diseases. NPC is an autosomal recessive lipid storage disorder caused by mutations in NPC1 and NPC2 genes. In adults, clinical presentation mimicking other neurodegenerative diseases makes diagnosis difficult. Recent evidence suggests that heterozygous mutations in NPC genes may take on etiological significance.
To investigate the presence of NPC1 and NPC2 mutations in adults affected by neurodegenerative dementia plus.
We performed a genetic screening on 50 patients using a wide clinical and biochemical approach to characterize the phenotype of mutated patients.
Sequencing analysis revealed four different and known heterozygous mutations in NPC1 and NPC2 genes. Patient 1 carried the p. F284LfsX26 in NPC1 and was affected by progressive supranuclear palsy-like syndrome. The remaining three patients showed a corticobasal syndrome and harbored the c.441+1G>A variant of NPC2 (patient 2), the missense p.N222 S mutation associated with the c.1947+8G>C variant in the splice region of intron 12 in NPC1 (patient 3), and the p.V30M mutation in NPC2 (patient 4), respectively. Filipin staining was abnormal in patients 1 and 2. mRNA analysis revealed an altered splicing of the NPC2 gene in patient 2.
Heterozygous mutations of NPC1 and NPC2 genes could contribute to dementia plus, at least in a subset of patients. We highlight the occurrence of NPC1 and NPC2 heterozygous variants in dementia-plus as pathological event.
除阿尔茨海默病外，多种神经系统和全身性疾病均可导致痴呆。罕见的遗传因素常导致具有非典型特征的痴呆。最近，尼曼-匹克C型病（NPC）的致病突变也与神经退行性疾病有关。NPC是一种常染色体隐性脂质贮积病，由NPC1和NPC2基因突变引起。在成年人中，临床表现与其他神经退行性疾病相似，这使得诊断困难。最近的证据表明，NPC基因的杂合突变可能具有病因学意义。
研究神经退行性痴呆叠加型成年患者中NPC1和NPC2基因突变的情况。
我们采用广泛的临床和生化方法对50例患者进行基因筛查，以明确突变患者的表型。
测序分析在NPC1和NPC2基因中发现了四种不同的已知杂合突变。患者1在NPC1基因中携带p.F284LfsX26突变，患有进行性核上性麻痹样综合征。其余三名患者表现为皮质基底节综合征，分别携带NPC2基因的c.441+1G>A变异（患者2）、与NPC1基因第12内含子剪接区域的c.1947+8G>C变异相关的错义p.N222 S突变（患者3）以及NPC2基因的p.V30M突变（患者4）。患者1和患者2的荧光素染色异常。mRNA分析显示患者2的NPC2基因剪接改变。
NPC1和NPC2基因的杂合突变可能至少在部分患者中导致痴呆叠加型。我们强调痴呆叠加型中NPC1和NPC2杂合变异的发生是一种病理事件。
