Neurobiology of aging
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Neurobiology of aging · Dec 2015
Novel TBK1 truncating mutation in a familial amyotrophic lateral sclerosis patient of Chinese origin.
Missense and frameshift mutations in TRAF family member-associated NF-kappa-B activator (TANK)-binding kinase 1 (TBK1) have been reported in European sporadic and familial amyotrophic lateral sclerosis (ALS) cohorts. To assess the role of TBK1 in ALS patient cohorts of wider ancestry, we have analyzed whole-exome sequence data from an Australian cohort of familial ALS (FALS) patients and controls. We identified a novel TBK1 deletion (c.1197delC) in a FALS patient of Chinese origin. ⋯ L399fs) likely results in a truncated protein that lacks functional domains required for adapter protein binding, as well as protein activation and structural integrity. No novel or reported TBK1 mutations were identified in FALS patients of European ancestry. This is the first report of a TBK1 mutation in an ALS patient of Asian origin and indicates that sequence variations in TBK1 are a rare cause of FALS in Australia.
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Neurobiology of aging · Nov 2015
Mutation analysis of CHCHD2 gene in Chinese familial Parkinson's disease.
Funayama et al. recently identified mutations in the CHCHD2 gene in Japanese families with autosomal dominant Parkinson's disease, increasing our knowledge about the monogenic cause of this disorder. However, there is no report regarding the association between CHCHD2 and Parkinson's disease (PD) in the Chinese Han population. ⋯ Genetic analysis of mutations in CHCHD2 gene was conducted in a cohort of 92 families with autosomal dominant Parkinson's disease from mainland China. No mutations in CHCHD2 gene were identified, suggesting that CHCHD2 mutations might not be a common cause of PD in Chinese familial cases.
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Neurobiology of aging · Nov 2015
TBK1 mutation frequencies in French frontotemporal dementia and amyotrophic lateral sclerosis cohorts.
TANK1-binding kinase 1 (TBK1) has been recently identified as a new amyotrophic lateral sclerosis (ALS) gene. Loss-of-function (LoF) mutations in TBK1 could be responsible for 0.4%-4% of ALS. Considering the strong genetic overlap existing between frontotemporal dementia (FTD) and ALS, we have evaluated the frequencies of TBK1 mutations in a cohort of French FTD and of ALS patients. ⋯ We also identified 5 heterozygous missense variants, predicted to be deleterious, in 1 isolated FTD, 1 FTD-ALS, and 3 ALS cases. Our results demonstrate that TBK1 loss-of-function mutations are more frequent in patients with FTD-ALS (10.8%) than in isolated ALS. TBK1 should thus also be sequenced, after exclusion of C9orf72 mutation, in patients presenting FTD, particularly in cases secondarily associated with ALS.
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Neurobiology of aging · Nov 2015
De novo FUS mutations are the most frequent genetic cause in early-onset German ALS patients.
In amyotrophic lateral sclerosis (ALS) patients with known genetic cause, mutations in chromosome 9 open reading frame 72 (C9orf72) and superoxide dismutase 1 (SOD1) account for most familial and late-onset sporadic cases, whereas mutations in fused in sarcoma (FUS) can be identified in just around 5% of familial and 1% of overall sporadic cases. There are only few reports on de novo FUS mutations in juvenile ALS patients. To date, no systematic evaluation on the frequency of de novo FUS mutations in early-onset ALS patients has been conducted. ⋯ Three of the 6 identified patients presented with initial bulbar symptoms. Our study identifies FUS mutations as the most frequent genetic cause in early-onset ALS. Genetic testing of FUS thus seems indicated in sporadic early-onset ALS patients especially if showing predominant bulbar symptoms and an aggressive disease course.
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Neurobiology of aging · Oct 2015
Role of brain infarcts in behavioral variant frontotemporal dementia: Clinicopathological characterization in the National Alzheimer's Coordinating Center database.
Diagnosing behavioral variant frontotemporal dementia (bvFTD) in patients with prior history of stroke or with silent brain infarcts on neuroimaging studies can be challenging. Vascular changes in patients with bvFTD are not unusual, but bvFTD tends to be ruled out in the presence of cerebrovascular disease. We aimed to identify the clinical, cognitive, and risk factor profile of bvFTD with coexistent cerebrovascular disease (V-bvFTD). ⋯ V-bvFTD was often underdiagnosed, affected elderly patients, and had a similar cognitive profile as NV-bvFTD despite the presence of brain infarcts. In the whole cohort, we observed enhanced cognitive performance with increasing age quintiles despite larger proportions of cerebrovascular disease pathology, likely meaning that frontotemporal lobe degeneration-related primary neurodegeneration exerts a stronger impact on cognition than cerebrovascular disease. Coexisting cerebrovascular disease should not preclude the diagnosis of bvFTD.