C9ORF72 repeat expansion in a large Italian ALS cohort: evidence of a founder effect

Ratti, Antonia; Corrado, Lucia; Castellotti, Barbara; Bo, Roberto Del; Fogh, Isabella; Cereda, Cristina; Tiloca, Cinzia; D’Ascenzo, Carla; Bagarotti, Alessandra; Pensato, Viviana; Ranieri, Michela; Gagliardi, Stella; Calini, Daniela; Mazzini, Letizia; Taroni, Franco; Corti, Stefania; Ceroni, Mauro; Oggioni, Gaia Donata; Lin, Kuang; Powell, John; Sorarù, Gian Domenico; Ticozzi, Nicola; Comi, Giacomo P.; D’Alfonso, Sandra; Gellera, Cinzia; Silani, Vincenzo

doi:10.1016/j.neurobiolaging.2012.06.008

Cited by 79 publications

(66 citation statements)

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“…Additionally, the pathologic expansion has been identified in 5%-10% of patients with ALS designated as sporadic, though these analyses have excluded family histories of nonmotor manifestations that are seen in people with the C9 expansion, specifically frontotemporal dementia (FTD). 1,9,11 There are practical advantages in defining the clinical similarities and differences between C9Pos and C9Neg patients, including whether mechanistic findings from C9 models can be generalized to C9Neg ALS, and whether ALS clinical trials should focus specifically on the C9Pos population. The Emory ALS Center maintains a large collection of DNA samples from patients with ALS along with their demographic and clinical characteristics.…”

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confidence: 99%

Comparative analysis of C9orf72 and sporadic disease in an ALS clinic population

Umoh

Fournier

et al. 2016

Neurology

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Objective: We investigated whether the C9orf72 expansion mutation in patients with amyotrophic lateral sclerosis (ALS) is associated with unique demographic and clinical features.Methods: Between 2001 and, approximately half of all patients attending the Emory ALS Clinic agreed to donate DNA for research. This research cohort of 781 patients was screened for the C9orf72 expansion, and demographic and clinical data were compared between those with and without the C9orf72 mutation. For mutation carriers without a family history of ALS, we sought further family history of dementia and other non-ALS neurodegenerative diseases in first-degree relatives.Results: The C9orf72 expansion was identified in 61 patients (7.8%). Compared to those without the expansion mutation, these patients did not differ in race, age, or site of onset. As expected, C9orf72 patients were more likely to have a family history of ALS (59% vs 7.9%) and to present with comorbid frontotemporal dementia (FTD) (14.8% vs 1.7%). Survival was shorter in patients with the expansion (log-rank x 2 [1] 5 45.323, p , 0.001). Further investigation in 28 patients initially categorized as having no known family history of ALS identified a family history of dementia in 16 cases; 6 of these had characteristics suggestive of FTD. Conclusions:Comparing the C9orf72 ALS population to the general ALS population, there were no differences in race, age at onset, or proportion of patients with bulbar onset disease. Differences identified in patients with the C9orf72 mutation included shortened survival and an equal proportion of men and women. In addition, we found that assessing family history for dementia may identify other family members likely to be carrying the C9orf72 expansion, reduce the number of sporadic cases, and thus increase our understanding of disease penetrance.

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confidence: 99%

Comparative analysis of C9orf72 and sporadic disease in an ALS clinic population

Umoh

Fournier

et al. 2016

Neurology

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“…At present, the most common mutation in ALS involves an intronic hexanucleotide repeat expansion in C9ORF72 gene (Ratti et al, 2012;Renton et al, 2014). Although its pathogenetic mechanism is still unclear, it is remarkable that the protein encoded by C9ORF72 localizes with autophagosomes and its function is related to endocytic trafficking (Farg et al, 2014).…”

Section: Accumulation Of Als Pathogenetic Proteins and Autophagymentioning

confidence: 99%

Autophagy in motor neuron disease: Key pathogenetic mechanisms and therapeutic targets

Mis

Brajkovic

Frattini

et al. 2016

Molecular and Cellular Neuroscience

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a b s t r a c tAutophagy is a lysosome-dependant intracellular degradation process that eliminates long-lived proteins as well as damaged organelles from the cytoplasm. An increasing body of evidence suggests that dysregulation of this system plays a pivotal role in the etiology and/or progression of neurodegenerative diseases including motor neuron disorders. Herein, we review the latest findings that highlight the involvement of autophagy in the pathogenesis of amyotrophic lateral sclerosis (ALS) and the potential role of this pathway as a target of therapeutic purposes. Autophagy promotes the removal of toxic, cytoplasmic aggregate-prone pathogenetic proteins, enhances cell survival, and modulates inflammation. The existence of several drugs targeting this pathway can facilitate the translation of basic research to clinical trials for ALS and other motor neuron diseases..

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“…In contrast, a small study in Taiwanese of Han Chinese ancestry reported higher frequencies of the repeat expansion (18.2% in fALS patients and 2.0% in sALS patients) [75]. The GGGGCC repeat has also been found in neurologically healthy controls (~0.2 %) as well as in Italian geriatric cases without ALS or dementia (1.2%) [71,[76][77][78][79].…”

Section: C9orf72 Gene and Alsmentioning

confidence: 88%

“…The HRE has also been found in neurologically healthy controls (~0.2 %) as well as in Italian geriatric cases without ALS or dementia (1.2%) [71,[76][77][78][79]. The relatively high frequency of the HRE amongst controls (compared with the lifetime risk of ALS) may be explained by the late age of onset of ALS, or due to reduced penetrance of the HRE, which is estimated to be non-penetrant in individuals less than 35 years of age, 50% penetrant by 58 years and almost fully penetrant at 80 years [78].…”

Section: Introductionmentioning

confidence: 86%

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Genetics of amyotrophic lateral sclerosis in the Han Chinese

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Amyotrophic lateral sclerosis is the most frequently occurring neuromuscular degenerative disorders, and has an obscure aetiology. Whilst major progress has been made, the majority of the genetic variation involved in ALS is, as yet, undefined. In this thesis, multiple genetic studies have been conducted to advance our understanding of the genetic architecture of the disease. In the light of the paucity of comprehensive genetic studies performed in Chinese, the presented study focused on advancing our current understanding in genetics of ALS in the Han Chinese population. To identify genetic variants altering risk of ALS, a genome-wide association study (GWAS) was performed.The study included 1,324 Chinese ALS cases and 3,115 controls. After quality control, a number of analyses were performed in a cleaned dataset of 1,243 cases and 2,854 controls that included: a genome-wide association analysis to identify SNPs associated with ALS; a genomic restricted maximum likelihood (GREML) analysis to estimate the proportion of the phenotypic variance in ALS liability due to common SNPs; and a genebased analysis to identify genes associated with ALS. There were no genome-wide significant SNPs or genes associated with ALS. However, it was estimated that 17% (SE: 0.05; P=6×10 -5 ) of the phenotypic variance in ALS liability was due to common SNPs. The top associated SNP was within GNAS (rs4812037; p =7×10 -7 ). GNAS was also the most associated gene from the gene-based study (p =2×10 -5 ). Based on GWAS data, a fragment-length and repeat-primed PCR was performed to determine GGGGCC copy number and expansion within the C9orf72 gene in the cohorts (1,092 sporadic ALS and 1,062 controls) from China.A haplotype analysis of 23 SNPs within and surrounding the C9orf72 gene was performed.The C9orf72 hexanucleotide (GGGGCC)n repeat expansion (HRE) was found in three sALS patients (0.3%) but not in control subjects (p = 0.25, Fisher's exact test). Two cases 2 with HRE did not harbor four risk alleles that have previously been determined to be Contributions by others to the thesis

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C9ORF72 repeat expansion in a large Italian ALS cohort: evidence of a founder effect

Cited by 79 publications

References 31 publications

Comparative analysis of C9orf72 and sporadic disease in an ALS clinic population

Comparative analysis of C9orf72 and sporadic disease in an ALS clinic population

Autophagy in motor neuron disease: Key pathogenetic mechanisms and therapeutic targets

Genetics of amyotrophic lateral sclerosis in the Han Chinese

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