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1.
CNS Neurosci Ther ; 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34551193

RESUMO

AIM: The role of vascular dementia (VaD)-associated genes in Alzheimer's disease (AD) remains elusive despite similar clinical and pathological features. We aimed to explore the relationship between these genes and AD in the Chinese population. METHODS: Eight VaD-associated genes were screened by a targeted sequencing panel in a sample of 3604 individuals comprising 1192 AD patients and 2412 cognitively normal controls. Variants were categorized into common variants and rare variants according to minor allele frequency (MAF). Common variant (MAF ≥ 0.01)-based association analysis was conducted by PLINK 1.9. Rare variant (MAF < 0.01) association study and gene-based aggregation testing of rare variants were performed by PLINK 1.9 and Sequence Kernel Association Test-Optimal (SKAT-O test), respectively. Age at onset (AAO) and Mini-Mental State Examination (MMSE) association studies were performed with PLINK 1.9. Analyses were adjusted for age, gender, and APOE ε4 status. RESULTS: Four common COL4A1 variants, including rs874203, rs874204, rs16975492, and rs1373744, exhibited suggestive associations with AD. Five rare variants, NOTCH3 rs201436750, COL4A1 rs747972545, COL4A1 rs201481886, CST3 rs765692764, and CST3 rs140837441, showed nominal association with AD risk. Gene-based aggregation testing revealed that HTRA1 was nominally associated with AD. In the AAO and MMSE association studies, variants in GSN, ITM2B, and COL4A1 reached suggestive significance. CONCLUSION: Common variants in COL4A1 and rare variants in HTRA1, NOTCH3, COL4A1, and CST3 may be implicated in AD pathogenesis. Besides, GSN, ITM2B, and COL4A1 are probably involved in the development of AD endophenotypes.

2.
NPJ Genom Med ; 6(1): 69, 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34389718

RESUMO

Neurodegenerative dementias are a group of diseases with highly heterogeneous pathology and complicated etiology. There exist potential genetic component overlaps between different neurodegenerative dementias. Here, 1795 patients with neurodegenerative dementias from South China were enrolled, including 1592 with Alzheimer's disease (AD), 110 with frontotemporal dementia (FTD), and 93 with dementia with Lewy bodies (DLB). Genes targeted sequencing analysis were performed. According to the American College of Medical Genetics (ACMG) guidelines, 39 pathogenic/likely pathogenic (P/LP) variants were identified in 47 unrelated patients in 14 different genes, including PSEN1, PSEN2, APP, MAPT, GRN, CHCHD10, TBK1, VCP, HTRA1, OPTN, SQSTM1, SIGMAR1, and abnormal repeat expansions in C9orf72 and HTT. Overall, 33.3% (13/39) of the variants were novel, the identified P/LP variants were seen in 2.2% (35/1592) and 10.9% (12/110) of AD and FTD cases, respectively. The overall molecular diagnostic rate was 2.6%. Among them, PSEN1 was the most frequently mutated gene (46.8%, 22/47), followed by PSEN2 and APP. Additionally, the age at onset of patients with P/LP variants (51.4 years), ranging from 30 to 83 years, was ~10 years earlier than those without P/LP variants (p < 0.05). This study sheds insight into the genetic spectrum and clinical manifestations of neurodegenerative dementias in South China, further expands the existing repertoire of P/LP variants involved in known dementia-associated genes. It provides a new perspective for basic research on genetic pathogenesis and novel guiding for clinical practice of neurodegenerative dementia.

3.
Neurobiol Aging ; 2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34172279

RESUMO

Alzheimer's disease (AD) and frontotemporal dementia (FTD) overlap clinically and pathologically. However, the role of FTD-associated genes in patients with AD remained unclear. To explore the relationship between FTD-associated genes and AD risk, we investigated 14 FTD-associated genes via targeted next-generation sequencing panel or whole-genome sequencing in a total of 721 AD patients and 1391 controls. Common variant-based association analysis and gene-based association test of rare variants were performed by PLINK 1.9 and Sequence Kernel Association Test-Optimal (SKAT-O test) respectively. As a result, 2 common variants, UBQLN1 rs1044175 (p value = 2.76 × 10-4) and MAPT rs2258689 (p value = 5.71 × 10-4), differed significantly between AD patients and controls. Additionally, gene-based analysis aggregating rare variants demonstrated that HNRNPA1 reached statistical significance in the SKAT-O test (p value = 2.24 × 10-3). Protein-protein interaction analysis showed that UBQLN1, MAPT, and HNRNPA1 interacted with proteins encoded by well-recognized AD-associated genes. Our study indicated that UBQLN1, MAPT, and HNRNPA1 are implicated in the pathogenesis of AD in the mainland Chinese population.

4.
CNS Neurosci Ther ; 27(8): 930-940, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33942994

RESUMO

AIMS: NOTCH3 gene mutations predominantly cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, a common etiology of subcortical vascular dementia (SVaD). Besides, there may be a pathogenic link between NOTCH3 variants and Alzheimer's disease (AD). We aimed to study the role of NOTCH3 variants in AD and SVaD patients. METHODS: We recruited 763 patients with dementia (667 AD and 96 SVaD) and 365 healthy controls from the Southern Han Chinese population. Targeted capture sequencing was performed on NOTCH3 coding and adjacent intron regions to detect the pathogenic variants in AD and SVaD. The relationship between common or rare NOTCH3 variants and AD was further analyzed using Plink1.9. RESULTS: Five known pathogenic variants (p.R182C, p.C201S, p.R544C, p.R607C, and p.R1006C) and two novel likely pathogenic variants (p.C201F and p.C1061F) were detected in 16 SVaD patients. Additionally, no pathogenic or likely pathogenic variants were found in AD patients. NOTCH3 was not associated with AD in either single-variant association analysis or gene-based association analysis. CONCLUSION: Our findings broaden the mutational spectrum of NOTCH3 and validate the pathogenic role of NOTCH3 mutations in SVaD, but do not support the notion that NOTCH3 variation influences the risk of AD.

5.
Aging (Albany NY) ; 13(8): 11352-11362, 2021 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-33833133

RESUMO

BACKGROUND: Three polymorphisms in the Methylenetetrahydrofolate reductase (MTHFR) gene (C677T, A1298C, and A1793G) were reported associated with AD. However, their genotype distributions and associations with age at onset (AAO), homocysteine, and white matter lesions (WML) were unclear in the Chinese AD population. METHOD: We determined the presence of C677T, A1298C, and A1793G polymorphisms in the MTHFR gene using Sanger sequencing in a Chinese cohort comprising 721 AD patients (318 early-onset AD patients (EOAD) and 403 late-onset AD patients (LOAD)) and 365 elderly controls. Additionally, the homocysteine level and WML were evaluated in 121 AD patients. RESULTS: The frequency of allele T of C677T polymorphism was significantly higher in AD patients than in controls (P = 0.040), while no statistical difference was observed in A1298C and A1793G (P > 0.05). Besides, genotype distributions of C677T and A1298C polymorphisms statistically varied between AD patients and controls (P = 0.021, P = 0.012). Moreover, the AAO was significantly lower in CT/TT (C677T) genotypes carriers (P = 0.042) and higher in AC/CC (A1298C) and AG/GG (A1793G) genotypes carriers (P = 0.034, P = 0.009) in patients with LOAD. We also found that patients with CT/TT (C677T) genotypes were prone to present an increased homocysteine level (P = 0.036) and higher Fazekas score (P = 0.024). In comparison, patients with AG/GG genotypes (A1793G) had a significantly lower Fazekas score (P = 0.013). CONCLUSIONS: The genotype distributions of C677T and A1298C polymorphisms are associated with AD in the Chinese population. Moreover, AD patients with C677T polymorphism are prone to present an earlier onset, higher homocysteine level, and more severe WML.


Assuntos
Doença de Alzheimer/genética , Predisposição Genética para Doença , Homocisteína/sangue , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Substância Branca/patologia , Idade de Início , Idoso , Alelos , Doença de Alzheimer/sangue , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/patologia , Apolipoproteínas E/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China/epidemiologia , Feminino , Homocisteína/metabolismo , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
6.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 46(2): 189-194, 2021 Feb 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-33678657

RESUMO

Alzheimer's disease (AD) is the most common senile neurodegenerative disease characterized by progressive cognitive dysfunction, psychological and behavioral abnormalities, and impaired ability of activities of daily living. A family with a total of 3 patients were admitted to the Department of Neurology of Xiangya Hospital, Central South University in 2018. The proband showed memory decline as the presenting symptoms, and subsequently showed psychological and behavioral abnormalities, personality changes, seizures, and motor retardation. Definite diagnosis of early-onset familial AD (EOFAD) with missense mutation of presenilin 2 (PSEN2) (c.715A>G p.M239V) was established by whole exome sequencing (WES) technology. We reported the mutation in Chinese Han population for the first time, which expanded the mutation spectrum ofPSEN2 gene and aid to enrich the characterization of clinical phenotype in EOFAD associated to PSEN2 mutations. Patients with early onset age and complex clinical manifestations of AD can be diagnosed with the help of genetic testing to avoid misdiagnosis.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Atividades Cotidianas , Doença de Alzheimer/genética , Humanos , Mutação , Presenilina-1/genética , Presenilina-2/genética
7.
Artigo em Inglês | MEDLINE | ID: mdl-33538206

RESUMO

Backgbround: Frontotemporal dementia (FTD) is the second most common presenile dementia, characterized by prominent behavioral, language, and cognitive impairment, which has a strong genetic component contributing to its pathogenesis. Due to geographical and ethnic variability, the prevalence of the causative genes of FTD may be different. Methods: To explore the genetics of FTD in the Chinese population, we reviewed 97 closely related studies that were searched in PubMed and Web of Science. In this review, we summarized the characteristics of each FTD gene. We also reassessed their pathogenicity and revised some mutations from pathogenic to uncertain significance according to the American College of Medical Genetics and Genomics (ACMG). Results: Thirty-two rare variants in genes of MAPT, GRN, C9orf72, CHCHD10, VCP, and TBK1 were identified in Chinese FTD populations, including 25 pathogenic mutations and seven variants of uncertain significance (VUS). Among them, the frequency of rare variants in the CHCHD10 gene was the highest. Surprisingly, twelve variants reported as pathogenic mutations were revised as VUS by ACMG. The correlations between genes and clinical manifestations were MAPT and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), GRN and frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP), C9orf72/CHCHD10/TBK1 and amyotrophic lateral sclerosis (ALS)-FTD spectrum, and VCP corresponds inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD). Conclusions: It is necessary to strictly interpret the contributions of genes to diseases by ACMG. MAPT is the most common pathogenic gene for FTD in China.


Assuntos
Esclerose Amiotrófica Lateral , Demência Frontotemporal , Degeneração Lobar Frontotemporal , China/epidemiologia , Demência Frontotemporal/epidemiologia , Demência Frontotemporal/genética , Humanos , Mutação/genética
8.
Front Neurol ; 11: 565088, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33281701

RESUMO

Aims: To investigate the causes, clinical characteristics, imaging features, and therapeutic implications of hypertrophic pachymeningitis (HP) in a southern Chinese population. Methods: We retrospectively analyzed 48 patients with HP with different causes from 1 January 2006 to 31 December 2018. Clinical manifestation, laboratory findings, and neuroimaging results were evaluated in all HP patients. Results: The mean age at onset was 50 ± 12 years. The most common diagnosis was idiopathic HP (67%), followed by antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (15%), tuberculous meningitis (8%), viral meningitis (6%), and bacterial meningitis (4%). Headache was the most common symptom. The most frequently changed laboratory finding was elevated erythrocyte sedimentation rate (ESR). Imaging was characterized by cerebral or spinal dura mater enhancement in MRI scan with contrast. Enhancements were mainly located in the posterior fossa for idiopathic HP; frontal, parietal, and occipital lobes for ANCA-related HP; and posterior fossa for tuberculous-associated HP. Diffuse enhancement was found in most cases, except for tuberculous-associated HP. Glucocorticoid or immunosuppressive treatment was applied in most cases. Conclusions: The etiology of HP varied among patients, with idiopathic HP being the most common. MRI showed enhancement of the dura mater, which differed according to different etiologies. Glucocorticoid or immunosuppressive agents were the primary drugs for treatment.

9.
Front Aging Neurosci ; 12: 581524, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33192475

RESUMO

Amyloid protein deposition is a common mechanism of hereditary amyloidosis (HA) and Alzheimer's disease (AD). Mutations of gelsolin (GSN), cystatin C (CST3), transthyretin (TTR), and integral membrane protein 2B (ITM2B) genes can lead to HA. But the relationship is unclear between these genes and AD. Genes targeted sequencing (GTS), including GSN, CST3, TTR, and ITM2B, was performed in a total of 636 patients with clinical AD and 365 normal controls from China. As a result, according to American College of Medical Genetics and Genomics (ACMG) guidelines, two novel likely pathogenic frame-shift mutations (GSN:c.1036delA:p.K346fs and GSN:c.8_35del:p.P3fs) were detected in five patients with AD, whose initial symptom was memory decline, accompanied with psychological and behavioral abnormalities later. Interestingly, the patient with K346fs mutation, presented cerebral ß-amyloid protein deposition, had an early onset (48 years) and experienced rapid progression, while the other four patients with P3fs mutation had a late onset [(Mean ± SD): 69.50 ± 5.20 years] and a long course of illness [(Mean ± SD): 9.24 ± 4.86 years]. Besides, we also discovered 17 variants of uncertain significance (VUS) in these four genes. To our knowledge, we are the first to report AD phenotype with GSN mutations in patients with AD in the Chinese cohort. Although mutations in the GSN gene are rare, it may explain a small portion of clinically diagnosed AD.

10.
Front Neurol ; 11: 538301, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33178099

RESUMO

Objective: This review summarizes recent findings on the epigenetics of Alzheimer's disease (AD) and provides therapeutic strategies for AD. Methods: We searched the following keywords: "genetics," "epigenetics," "Alzheimer's disease," "DNA methylation," "DNA hydroxymethylation," "histone modifications," "non-coding RNAs," and "therapeutic strategies" in PubMed. Results: In this review, we summarizes recent studies of epigenetics in AD, including DNA methylation/hydroxymethylation, histone modifications, and non-coding RNAs. There are no consistent results of global DNA methylation/hydroxymethylation in AD. Epigenetic genome-wide association studies show that many differentially methylated sites exist in AD. Several studies investigate the role of histone modifications in AD; for example, histone acetylation decreases, whereas H3 phosphorylation increases significantly in AD. In addition, non-coding RNAs, such as microRNA-16 and BACE1-antisense transcript (BACE1-AS), are associated with the pathology of AD. These epigenetic changes provide us with novel insights into the pathogenesis of AD and may be potential therapeutic strategies for AD. Conclusion: Epigenetics is associated with the pathogenesis of AD, including DNA methylation/hydroxymethylation, histone modifications, and non-coding RNAs, which provide potential therapeutic strategies for AD.

11.
Front Aging Neurosci ; 12: 584801, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33240075

RESUMO

The genes involved in the metabolic pathways of amyloid-ß (Aß) and tau proteins significantly influence the etiology of Alzheimer's disease (AD). Various studies have explored the associations between some of these genes and AD in the Caucasian population; however, researches regarding these associations remain limited in the Chinese population. To systematically evaluate the associations of these genes with AD, we investigated 19 genes involved in the metabolism of Aß and tau based on previous studies selected using the PubMed database. This study included 372 patients with sporadic late-onset AD (sLOAD) and 345 cognitively healthy individuals from southern China. The results were replicated in the International Genomics of Alzheimer's Project (IGAP). Protein-protein interactions were determined using the STRING v11 database. We found that a single-nucleotide polymorphism, rs11682128, of BIN1 conferred susceptibility to sLOAD after adjusting for age, sex, and APOE ε4 status and performing the Bonferroni correction {corrected P = 0.000153, odds ratio (OR) [95% confidence interval (CI)] = 1.403 (1.079-1.824)}, which was replicated in the IGAP. Protein-protein interactions indicated that BIN1 was correlated with MAPT. Moreover, rare variants of NEP and FERMT2 (0.0026 < corrected P < 0.05), and the Aß degradation, tau pathology, and tau phosphatase pathways (0.01 < corrected P < 0.05), were nominally significantly associated with sLOAD. This study suggested that the genes involved in the metabolic pathways of Aß and tau contributed to the etiology of sLOAD in the southern Han Chinese population.

12.
Ann Clin Transl Neurol ; 7(10): 1985-1995, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32941707

RESUMO

OBJECTIVE: To investigate the impact of rare variants underlying neurodegenerative-related genes to familial Alzheimer's disease (AD). METHODS: We performed targeted sequencing of 277 neurodegenerative-related genes on probands from 75 Chinese AD families non-carrying causative mutation of dementia genes. Rare coding variants segregated in families were tested for association in an independent cohort of 506 patients with sporadic AD and 498 cognitively normal controls. East Asians data from the Exome Aggregation Consortium (ExAC) were used as a reference control. RESULTS: A novel rare variant, P410S of PLD3 was found in an early-onset AD family. LRRK2 I2012T, a causative mutation of Parkinson's disease, was identified in another early-onset AD family. Missense variants in ABCA7 (P143S and A1507T) and CR1(T239M) were significantly associated with familial AD (P = 0.005437, 0.001383, 0.000549), a missense variant in TREM2(S183C) was significantly associated with AD (P = 0.000396) when compared with the East Asian controls in ExAC database. A non-frameshift variant in FUS (G223del) was frequent in AD cases and significantly associated with familial AD (P = 0.008). INTERPRETATION: Multiple rare coding variants of causal and risk neurodegenerative genes were presented in clinically diagnosed AD families that may confer risk of AD. Our data supported that the clinical, pathological, and genetic architectures of AD, PD, and FTD/ALS may overlapping. We propose that targeted sequencing on neurodegenerative-related genes is necessary for genetically unclear AD families.

13.
Eur J Neurosci ; 52(8): 4009-4017, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32506655

RESUMO

Recently, functional studies have demonstrated that legumain (LGMN) cleaves both amyloid ß-protein precursor and tau, promoting senile plaques and formation of neurofibrillary tangles, which may play a crucial role in the pathogenesis of Alzheimer's disease (AD). However, the genetic role of LGMN in AD has not been clearly elucidated. Here, we used Sanger sequencing to investigate the single independent (single-variant association test) and cumulative (gene-based association test) effects of variants in the LGMN gene as potential susceptibility factors for AD, in a cohort comprising 676 AD cases and 365 elderly controls from the Han population of South China. In single-variant association analysis, none of the common variants in LGMN were statistically significant. In gene-based analysis, the LGMN gene also showed no association with AD. The results of our replication study in the Alzheimer's Disease Neuroimaging Initiative cohort also showed no association between LGMN and AD. These findings suggest that the LGMN gene may not be a critical factor for AD development.


Assuntos
Doença de Alzheimer , Idoso , Doença de Alzheimer/genética , Peptídeos beta-Amiloides , China , Cisteína Endopeptidases , Humanos , Polimorfismo de Nucleotídeo Único
14.
Gene ; 743: 144604, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32213297

RESUMO

AIM: Colon adenocarcinoma (COAD) is the third most common cancer in the world. We aimed to explore the functional mechanism of LINC00342 in COAD. METHODS: The LINC00342 expressions in COAD tissues were detected via qRT-PCR and in situ hybridization analysis. Statistical analysis was performed to analyze the relationship between LINC00342 expression and COAD clinical features. Small interfering LINC00342 (siLINC00342)/siCtrl were synthesized and then transfected into COAD cells. Cell apoptosis and proliferation were respectively assessed by flow cytometry and cell counting kit-8 assay. Cell migration and invasion were both measured using transwell assay. The target miRNA of LINC00342 were predicted and verified by online bioinformatics tools and luciferase reporter assay and RNA pull-down assay. Mice COAD models were constructed to explore the effects of LINC00342 on COAD in vivo. RESULTS: LINC00342 was over-expressed in COAD tissues and LINC00342 overexpression was related to the poor prognosis of COAD patients. LINC00342 knockdown inhibited cell proliferation, migration and invasion and promoted apoptosis of COAD cells. LINC00342 targeted to miR-545-5p/murine double minute 2 (MDM2) in COAD. In COAD tissues and cell lines, LINC00342 expression was positively correlated to MDM2 expression, while it was negatively correlated to miR-545-5p expression. Both miR-545-5p-mimic and siMDM2 transfection could recover the changes of cell biological activities which were induced by LINC00342 overexpression. LINC00342 knockdown suppressed COAD tumor growth in vivo. CONCLUSION: LINC00342 affected cell biological activities of COAD in vivo and in vitro via regulating miR-545-5p/MDM2. It might a novel target in COAD therapy.


Assuntos
Adenocarcinoma/genética , Neoplasias do Colo/genética , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-mdm2/genética , RNA Longo não Codificante/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Animais , Apoptose/genética , Movimento Celular/genética , Proliferação de Células/genética , Colo/patologia , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Conjuntos de Dados como Assunto , Feminino , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Células HEK293 , Humanos , Masculino , Camundongos , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Prognóstico , Taxa de Sobrevida , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Neurobiol Aging ; 89: 142.e1-142.e7, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32081467

RESUMO

Recently, the (GGC)n repeat expansion in the NOTCH2NLC gene has been identified to be associated with neuronal intranuclear inclusion disease (NIID). Given the clinical overlap of dementia-dominant NIID with neurodegenerative dementia, we therefore hypothesized that the NOTCH2NLC repeat expansion might also contribute to these diseases. In the present study, repeat primed polymerase chain reaction (RP-PCR) and GC-rich PCR were conducted to detect the repeats of NOTCH2NLC in a cohort of 1004 patients with neurodegenerative dementias from mainland China. As a result, 4 sporadic patients were found to carry the NOTCH2NLC repeats expansion, totally accounting for 0.4% of all dementia individuals, and the accurate repeated sizes were 110, 133,120 and 76 respectively. Of 4 mutation carriers, three and one were clinically diagnosed Alzheimer's disease (AD) and frontotemporal dementia (FTD) respectively. In addition, 3 out of them revealed leukoencephalopathy in T2-Flair imaging. This study revealed that although rare, the NOTCH2NLC repeat expansions may be associated with AD or FTD-like phenotype as well as leukoencephalopathy.


Assuntos
Doença de Alzheimer/genética , Expansão das Repetições de DNA , Demência Frontotemporal/genética , Leucoencefalopatias/genética , Doenças Neurodegenerativas/genética , Receptor Notch2/genética , Idoso , China , Estudos de Coortes , Feminino , Estudos de Associação Genética , Humanos , Corpos de Inclusão Intranuclear/genética , Masculino , Pessoa de Meia-Idade
16.
J Clin Neurosci ; 73: 311-313, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31987637

RESUMO

Charcot-Marie-Tooth (CMT) disease is the most common hereditary peripheral neuropathy. X-linked Charcot-Marie-Tooth disease in the GJB1 gene is known as CMTX1. We report a 14 years-old young man with walked unstably, bilateral strephenopodia, severe alopecia and paroxysmal bilateral upper limbs tremor without obvious muscle atrophy. Diagnostic whole-exome sequencing revealed a hemizygote missense mutation c.278 T > A in exon 2 of the GJB1 gene, with lysine at position 93 of the mature protein (p.M93K). This is the first CMT case with alopecia areata reported in the world.


Assuntos
Doença de Charcot-Marie-Tooth/diagnóstico , Conexinas/genética , Fenótipo , Adolescente , Doença de Charcot-Marie-Tooth/genética , Testes Genéticos , Humanos , Masculino , Mutação de Sentido Incorreto , Sequenciamento Completo do Exoma
17.
J Alzheimers Dis ; 72(2): 633-640, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31594229

RESUMO

Recent studies found that poor oral hygiene was associated with increased risk of dementia, and the number of oral bacteria significantly increased in the brain tissues of patients with Alzheimer's disease (AD), suggesting that the oral microbiota may play an important role in the pathogenesis of AD. However, the actual composition of oral bacteria communities in patients with AD and whether these oral bacteria are associated with disease severity remain largely unknown. Also, the APOEɛ4 polymorphism is a strong risk factor for sporadic AD, and it would be pertinent to see if the bacterial flora was different in those patients who were APOEɛ4 positive. A total of 78 subjects were recruited in this study, including 39 patients with AD and 39 healthy controls. Saliva was collected from each subject. 16S ribosomal RNA (16S rRNA) sequencing was conducted to analyze the salivary microbiota, and Sanger sequencing was performed to analyze the APOE genotype. There was a significantly lower richness and diversity of saliva microbiota detected in AD patients than healthy controls. The relative abundance of Moraxella, Leptotrichia, and Sphaerochaeta in the saliva of AD patients greatly increased, whereas that of Rothia was significantly reduced. Compared with APOEɛ4 (-) patients, the level of Abiotrophia and Desulfomicrobium was comparatively abundant, while Actinobacillus and Actinomyces decreased significantly in patients carrying the APOEɛ4. No bacteria were found to be associated with the severity of AD. This is the first study to analyze the salivary microorganisms in patients with AD, and we discovered that the composition of salivary microbiome was altered in AD, providing further support for the role of the oral microbiome in AD development.


Assuntos
Doença de Alzheimer/microbiologia , Microbiota , Saliva/microbiologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Doença de Alzheimer/psicologia , Apolipoproteína E4/genética , DNA/química , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , RNA Ribossômico 16S/análise
18.
Neuroreport ; 30(16): 1068-1073, 2019 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-31568198

RESUMO

OBJECTIVE: Translocase of outer mitochondrial membrane 40 (TOMM40) encodes translocase of the outer mitochondrial membrane (TOM), which is associated with mitochondrial dysfunction in Alzheimer's disease (AD). TOMM40 rs157581-G has been reported to increase susceptibility to AD. However, the effect of TOMM40 rs157581-G in resting-state functional MRI (rs-fMRI) on AD has not been studied. Therefore, we aimed to investigate the role of TOMM40 rs157581-G on rs-fMRI results in AD patients. METHODS: Twenty-four AD patients were divided into two groups based on TOMM40 rs157581-G status, and clinical and imaging data were compared between the groups. RESULTS: TOMM40 rs157581-G carriers of AD showed decreased regional homogeneity in the left precuneus and decreased amplitude of low-frequency fluctuations in the bilateral temporal poles compared with noncarriers of AD. TOMM40 rs157581-G carriers of AD also showed increased functional connectivity between the right middle occipital gyrus and the left supramarginal gyrus and decreased connectivity between the left superior occipital gyrus and the right transverse temporal gyrus in comparison with TOMM40 rs157581-G noncarriers. CONCLUSION: We analyzed rs-fMRI characteristics of TOMM40 rs157581-G carriers of AD for the first time, which suggest that TOMM40 rs157581-G plays a harmful role in AD patients.


Assuntos
Doença de Alzheimer/genética , Encéfalo/fisiopatologia , Proteínas de Membrana Transportadoras/genética , Doença de Alzheimer/fisiopatologia , Mapeamento Encefálico/métodos , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Descanso
19.
Medicine (Baltimore) ; 98(27): e16284, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31277157

RESUMO

RATIONALE: Propylthiouracil (PTU) is a common antithyroid drug which can treat hyperthyroidism effectively. PTU is, however, associated to multiple adverse effects. In rare case, PTU can cause interstitial pneumonia. PATIENT CONCERNS: A 40-year-old woman presented with dyspnea and was diagnosed with pulmonary infection at the first time. After the treatment with moxifloxacin, her symptoms still got worse. DIAGNOSIS: The lung tissues biopsy confirmed the diagnosis of organizing pneumonia (OP) and the administration of PTU suggested the diagnosis of PTU-induced OP. INTERVENTION: Withdrawal of PTU and the administration of methylprednisolone. OUTCOMES: The patient's symptoms relieved significantly 1 month later and lung computed tomography (CT) scan also demonstrated significant reduction of lung lesions. LESSONS: Here we report the first case of histologically confirmed OP induced by PTU and conduct a literature review of the cases of PTU-induced interstitial pneumonia. The awareness of PTU-induced OP can help physicians reduce the possibility of misdiagnosis.


Assuntos
Doenças Pulmonares Intersticiais/induzido quimicamente , Propiltiouracila/efeitos adversos , Adulto , Antitireóideos/efeitos adversos , Antitireóideos/uso terapêutico , Feminino , Humanos , Hipertireoidismo/tratamento farmacológico , Doenças Pulmonares Intersticiais/diagnóstico , Propiltiouracila/uso terapêutico , Tomografia Computadorizada por Raios X
20.
World J Clin Cases ; 7(11): 1358-1366, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31236401

RESUMO

BACKGROUND: Hereditary spastic paraplegias (HSPs) refer to a group of heterogeneous neurodegenerative diseases characterized by lower limbs spasticity and weakness. So far, over 72 genes have been found to cause HSP (SPG1-SPG72). Among autosomal dominant HSP patients, spastic paraplegia 4 (SPG4/SPAST) gene is the most common pathogenic gene, and atlastin-1 (ATL1) is the second most common one. Here we reported a novel ATL1 mutation in a Chinese spastic paraplegia 3A (SPG3A) family, which expands the clinical and genetic spectrum of ATL1 mutations. CASE SUMMARY: A 9-year-old boy with progressive spastic paraplegia accompanied by right hearing loss and mental retardation for five years was admitted to our hospital. Past history was unremarkable. The family history was positive, and his grandfather and mother had similar symptoms. Neurological examinations revealed hypermyotonia in his lower limbs, hyperreflexia in knee reflex, bilateral positive Babinski signs and scissors gait. The results of blood routine test, liver function test, blood glucose test, ceruloplasmin test and vitamin test were all normal. The serum lactic acid level was significantly increased. The testing for brainstem auditory evoked potential demonstrated that the right side hearing was impaired while the left was normal. Magnetic resonance imaging showed mild atrophy of the spinal cord. The gene panel test revealed that the proband carried an ATL1 c.752A>G p.Gln251Arg (p.Q251R) mutation, and Sanger sequencing confirmed the existence of family co-segregation. CONCLUSION: We reported a novel ATL1 Q251R mutation and a novel clinical phenotype of hearing loss in a Chinese SPG3A family.

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