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Objective:To summarize and analyze the clinical data of Chinese patients with colony-stimulating factor 1 receptor (CSF1R)-related leukoencephalopathy, and clarify the phenotypic and genetic characteristics of Chinese patients.Methods:Medical history of patients with CSF1R-related leukoencephalopathy diagnosed from April 1, 2018 to January 31, 2021 in the department of neurology of 22 hospitals in China was collected, and scores of Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment Scale (MoCA), magnetic resonance severity scale were evaluated. Group comparison was performed between male and female patients.Results:A total of 62 patients were included, and the male-female ratio was 1∶1.95. The age of onset was (40.35±8.42) years. Cognitive impairment (82.3%, 51/62) and motor symptoms (77.4%,48/62) were the most common symptoms. The MMSE and MoCA scores were 18.79±7.16 and 13.96±7.23, respectively, and the scores of two scales in male patients (22.06±5.31 and 18.08±5.60) were significantly higher than those in females (15.53±7.41 , t=2.954, P=0.006; 10.15±6.26, t=3.328 , P=0.003). The most common radiographic feature was bilateral asymmetric white matter changes (100.0%), and the magnetic resonance imaging severity scale score was 27.42±11.40, while the white matter lesion score of females (22.94±8.39) was significantly higher than that of males (17.62±8.74 , t=-2.221, P<0.05). A total of 36 CSF1R gene mutations were found in this study, among which c.2381T>C/p.I794T was the hotspot mutation that carried by 17.9% (10/56) of the probands. Conclusions:The core phenotypic characteristics of CSF1R-related leukoencephalopathy in China are progressive motor and cognitive impairment, with bilateral asymmetrical white matter changes. In addition, there exist gender differences clinically, with severer cognitive impairment and imaging changes in female patients. Thirty-six CSF1R gene mutations were found in this study, and c.2381T>C/p. I794T was the hotspot mutation.
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Objective:To investigate the clinical and genetic features of early-onset Alzheimer's disease(EOAD)and the characteristics of pathogenic mutations in probands and their families.Methods:Clinical and genetic features of three EOAD probands and their family members China were analyzed and summarized.Peripheral blood of three probands and their relatives was collected and the genes were detected by second generation sequencing(Next Generation Sequencing, NGS). Pathogenic mutations carried by the probands were identified by whole exome sequencing and then verified by Sanger sequencing in the probands and their families.Furthermore, the clinical and genetic characteristics of EOAD were discussed.Results:The first case was familial EOAD, with the heterozygous mutation c. 851C>T(p.P284L)in exon 8 of PSEN1.The second was also a case of familial EOAD, involving the heterozygous deletion mutation c. 497_499del(p.Ile167del)in exon 6 of PSEN1.In the third proband, there was no family history and the c. 626G>A(G209E)mutation was found in exon 7 of the PSEN1 gene.All three patients had memory loss as their first symptom, accompanied by clinical manifestations of slow movement, abnormal gait, unclear speech, bladder and bowel incontinence, psychiatric and other symptoms.Conclusions:These mutations represent additional mutation types and clinical manifestations in EOAD patients.Examining the genetic characteristics of PSEN1 in EOAD may contribute to the understanding of the pathogenesis, genetic classification and clinical diagnosis of EOAD.
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Objective To investigate the toxic effect of the carboxyl-terminal peptide of β-amyloid precursor protein (APPC31) on Neuro2a cells as well as its role in the toxic process in Neuro2a cells induced by Aβ42 in vitro.Methods The plasmid vector and the APPC31 construct were transiently transfected into Neuro2a cells respectively by lipofectamine 2000.The viability of the cells was measured by the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay at 48 h after transfection,and their morphocytology was observed by 4', 6-diamidino-2-phenylindole (DAPI) nucleus staining.Afterword different constructs including vector, WTAPP695, APP( D664A), the amino-terminal peptide of β-amyloid precursor protein (APP△C31) and APPC31 were transiently transfected into Neuro2a cells respectively via the same method.At 24 h after transfection Aβ42 was added into the culture medium of Neuro2a cells with the desired concentration for another 24 h for cell studies.The viabihty and morphocytology of the cells were measured by using the MTT assay and DAPI nucleus staining, respectively.Results When incubated in the absence of Aβ42, the viability of cells transfected with vector and APPC31construct were 0.81 ±0.10 and 0.88 ±0.12 respectively, and accordingly there was no significant difference between the these two groups (t = - 0.78, P = 0.48 ); meanwhile no obvious cell nuclear morphological changes of apoptosis or death occurred.However when incubated in the presence of Aβ42, the viability of cells transfected with vector, WTAPP695, APP( D664A), APP△C31 and APPC31 constructs were 0.82 ±0.01, 0.78 ±0.03, 0.55 ±0.04, 0.81 ±0.04, 0.78 ±0.02 and 0.54 ±0.02 respectively.The viability of cells transfected with WTAPP construct and APPC31 construct decreased significantly ( F = 47.53, P ＜0.05) compared with the control group, meanwhile cells displayed condensed nuclear and even nuclear fragmentation.Conclusions In vitro, over-expression of a certain level of APPC31 in Neuro2a cells fails in causing cell death, but this short peptide enhances cytotoxicity induced by Aβ42 in Neuro2a cells.Thus,these results provide the experimental basis for the further explication of the pathogenesis of Alzheimer's disease.
