Frequency Of C9orf72 Repeat Expansion Research Articles

Impact of C9orf72 on Japanese Patients with Amytrophic Lateral Sclerosis (ALS)/Frontotemporal Dementia (FTD)

In 2011, C9orf72 hexanucleotide (GGGGCC) repeat expansion (HRE) in intron 1 was reported as the most common cause of sporadic and familial amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) in the Caucasian population. In the Japanese population, the C9orf72 repeat expansion was found to account for 0.2% cases of sporadic ALS and 2.6% of familial ALS. Notably, among individuals in the Kii peninsula which has recorded high incidence of ALS or ALS/PDC (parkinsonism-dementia complex), the frequency of C9orf72 repeat expansion was 20% (3/15) indicating high prevalence. It is important to obtain detailed family history of ALS and FTD to understand the cause of the diseases including the C9orf72 mutation.

The role of C9orf72 in neurodegenerative disorders: a systematic review, an updated meta-analysis, and the creation of an online database

A pathologic expansion of a noncoding GGGGCC hexanucleotide repeat of the C9orf72 gene has been strongly associated with familial amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) cases predominantly in Caucasian populations. In the last decade, scientific interest had been drawn to this gene and many studies conducted have shown a possible correlation with other neurodegenerative diseases as well. We performed an extensive literature search for C9orf72 mutation and its frequency in various neurological and psychiatric diseases. In addition, we performed a meta-analysis of the data related to ALS and familial ALS. An online cloud-based database and an interactive map were developed. The overall mutation frequency of C9orf72 is 20% for familial FTD, 16% for familial ALS and around 6%–8% for sporadic ALS and FTD. The updated meta-analysis that we performed showed that the pooled frequency of C9orf72 repeat expansion in patients with familial ALS was 23% (CI: 18%–28%) and in patients with sporadic ALS 3% (CI: 3%–4%). The subgroup analysis regarding the origin of the population revealed significant differences between Caucasian and Asian patients. Our analysis supports the direct causal relation of the C9orf72 expansion in ALS and FTD. On the contrary, the role of C9orf72 in other neurodegenerative disorders remains controversial. The system that we developed—the online database and the interactive map—is hopefully a stepping stone for an ever-growing platform that will aid scientists from all over the world in contributing to the meta-analysis of C9orf72-related publications.

Phenotypic variability and neuropsychological findings associated with C9orf72 repeat expansions in a Bulgarian dementia cohort.

BackgroundThe GGGGCC repeat expansion in the C9orf72 gene was recently identified as a major cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in several European populations. The objective of this study was to determine the frequency of C9orf72 repeat expansions in a Bulgarian dementia cohort and to delineate the associated clinical features.Methods and findingsPCR-based assessments of the C9orf72 hexanucleotide repeat expansion in all study samples (including 82 FTD, 37 Alzheimer’s disease (AD), and 16 other neurodegenerative/dementia disorder cases) were performed. We report the clinical, neuropsychological, and neuroimaging findings obtained for the C9orf72 repeat expansion carriers. Of the 135 cases screened, 3/82 (3.7%) of all FTD cases and 1/37 (2.7%) of all clinical AD cases had a C9orf72 repeat expansion. In this cohort, the C9orf72 pathological expansion was found in clinical diagnoses bridging the FTD, parkinsonism, ALS and AD spectrum. Interestingly, we showed early writing errors without aphasia in two subjects with C9orf72 expansions.ConclusionsThis study represents the first genetic screening for C9orf72 repeat expansions in a Bulgarian dementia cohort. The C9orf72 repeat expansion does not appear to be a common cause of FTD and related disorders. This report confirms the notion that C9orf72 repeat expansions underlie a broad spectrum of neurodegenerative phenotypes. Relatively isolated agraphia in two cases with C9orf72 repeat expansions is a strong motivation to provide detailed and sophisticated oral and written language assessments that can be used to more precisely characterize early cognitive deficits in these heterogeneous conditions.

Polymerase chain reaction and Southern blot-based analysis of the C9orf72 hexanucleotide repeat in different motor neuron diseases

The GGGGCC-hexanucleotide repeat expansion in C9orf72 is the most common genetic cause of familial amyotrophic lateral sclerosis and frontotemporal dementia. This study determined the frequency of C9orf72 repeat expansions in different motor neuron diseases (amyotrophic lateral sclerosis (ALS), motor neuron diseases affecting primarily the first or the second motor neuron and hereditary spastic paraplegia). Whereas most studies on C9orf72 repeat expansions published so far rely on a polymerase chain reaction-based screening, we applied both polymerase chain reaction-based techniques and Southern blotting. Furthermore, we determined the sensitivity and specificity of Southern blotting of the C9orf72 hexanucleotide repeat in DNA derived from lymphoblastoid cell lines. C9orf72 repeat expansions were found in 27.1% out of 166 familial ALS patients, only once in 68 sporadic ALS patients, and not in 61 hereditary spastic paraplegia patients or 52 patients with motor neuron diseases affecting clinically primarily either the first or the second motor neuron. We found hints for a correlation between C9orf72 repeat length and the age of onset. Somatic instability of the C9orf72 repeat was observed in lymphoblastoid cell lines compared with DNA derived from whole blood from the same patient and therefore caution is warranted for repeat length determination in immortalized cell lines.

Frequency of C9orf72 repeat expansions in amyotrophic lateral sclerosis: a Belgian cohort study

We determined the frequency of C9orf72 repeat expansions in a large cohort of Belgian patients with familial (fALS) and sporadic (sALS) amyotrophic lateral sclerosis (ALS). In total, 119 patients with fALS from 62 kindreds, 471 patients with sALS, and 384 control subjects were included. A C9orf72 repeat expansion was found in 32 of 62 fALS pedigrees (51.6%), in 45 of 471 patients with sALS (9.6%), but in none of the control subjects. Compared with fALS of unknown etiology or fALS caused by mutations in other ALS-causing genes, C9orf72 repeat expansion carriers had a later age at onset (57.3 vs. 51.4 years; p = 0.0061), a higher proportion of bulbar onset (31.9% vs. 12.5%, p < 0.0001), and a reduced survival (29.4 vs. 67.7 months, p = 0.0003). In the sALS cohort, there were no significant differences in these disease characteristics between the C9orf72 repeat expansion carriers and the noncarriers. C9orf72 repeat expansions are a frequent cause of ALS in Belgium, and also in sALS patients. These results might justify genetic testing of C9orf72 in all ALS patients.

C9orf72 Hexanucleotide Repeat Expansions in Clinical Alzheimer Disease

Hexanucleotide repeat expansions in the chromosome 9 open reading frame 72 (C9orf72) gene underlie a significant fraction of frontotemporal dementia and amyotrophic lateral sclerosis. To investigate the frequency of C9orf72 repeat expansions in clinically diagnosed late-onset Alzheimer disease (AD). This case-control study genotyped the C9orf72 repeat expansion in 872 unrelated familial AD cases and 888 control subjects recruited as part of the National Institute on Aging Late-Onset Alzheimer Disease Family Study cohort, a multisite collaboration studying 1000 families with 2 or more individuals clinically diagnosed as having late-onset AD. We determined the presence or absence of the C9orf72 repeat expansion by repeat-primed polymerase chain reaction, the length of the longest nonexpanded allele, segregation of the genotype with disease, and clinical features of repeat expansion carriers. RESULTS Three families showed large C9orf72 hexanucleotide repeat expansions. Two additional families carried more than 30 repeats. Segregation with disease could be demonstrated in 3 families. One affected expansion carrier had neuropathology compatible with AD. In the National Institute on Aging Late-Onset Alzheimer Disease Family Study series, the C9orf72 repeat expansions constituted the second most common pathogenic mutation, just behind the PSEN1 A79V mutation, highlighting the heterogeneity of clinical presentations associated with repeat expansions. C9orf72 repeat expansions explain a small proportion of patients with a clinical presentation indistinguishable from AD, and they highlight the necessity of screening frontotemporal dementia genes in clinical AD cases with strong family history.

Parkinson disease is not associated with C9ORF72 repeat expansions

Hexanucleotide expansions in the C9ORF72 gene are frequently found in patients with amyotrophic lateral sclerosis, frontotemporal dementia or both, some of whom exhibit concurrent extrapyramidal symptoms. To determine if repeat expansions are a cause of Parkinson's disease (PD), we used repeat-primed polymerase chain reaction to investigate the frequency of C9ORF72 repeat expansions in a cohort of 478 patients with PD and 662 control subjects. Three control subjects were found to be expansion carriers, and no expansions were found among patients, suggesting that C9ORF72 expansions are not a common cause of PD.

Frequency and Phenotypes Associated with C9ORF72 Repeat Expansion in French FTLD and FTLD-ALS Patients (S54.003)

Objective: To evaluate the frequency of c9ORF72 repeat expansion in french FTLD and FTLD-ALS patients and to describe the associated clinical phenotypes, imaging and brain pathological characteristics. Background c9ORF72 was recently identified as a major gene implicated in FTLD/ALS spectrum of disease. Its genetic contribution remains to be established in different geographic populations. Design/Methods: c9ORF72 repeat expansion was searched for by repeat-primed PCR in 600 french probands with frontal variant FTD (fvFTD, n=330), FTLD with amyotrophic lateral scelrosis (FTLD-ALS, n=210), primary progressive aphasia (PPA, n=40) and progressive supranuclear palsy (PSP, n=20). Half patients had a family history of FTLD or ALS, half were sporadic cases. Brain post-mortem examination was performed in 18 patients. Results: A GGGGCC repeat expansion was identified in 140 unrelated probands. The frequency of the expansion was 15% in the patients with bvFTD (8% in sporadic cases, 20% in familial bvFTD)and 43% in the patients with FTLD-ALS (15% in sporadic cases; 64% in familial forms). No expansion was identified in the PPA patients. Most patients had a bvFTD; only two patients presented with semantic dementia or progressive non fluent aphasia both associated with ALS at onset. The detailed clinical phenotypes, SPECT imaging characteristics and pathology of 60 c9ORF72 expansion carriers will be presented. Conclusions: c9ORF gene is the most frequent cause of familial FTLD before PGRN gene. The frequency of mutation is much higher in the population with FTLD-ALS. Less than 30% of familial FTLD/FTLD-ALS are unexplained by the eight known FTLD genes. Disclosure: Dr. Le Ber has nothing to disclose. Dr. Camuzat has nothing to disclose. Dr. Guillot-Noel has nothing to disclose. Dr. Guedj has nothing to disclose. Dr. Hannequin has nothing to disclose. Dr. Wargon has nothing to disclose. Dr. Couratier has nothing to disclose. Dr. Deramecourt has nothing to disclose. Dr. Berger has nothing to disclose. Dr. Viennet has nothing to disclose. Dr. Pasquier has nothing to disclose. Dr. Lacomblez Aurousseau has nothing to disclose. Dr. Salachas has nothing to disclose. Dr. Martinaud has nothing to disclose. Dr. Golfier has nothing to disclose. Dr. Puel has nothing to disclose. Dr. Vercelletto has nothing to disclose. Dr. Didic has nothing to disclose. Dr. Sauvee has nothing to disclose. Dr. Sellal has nothing to disclose. Dr. Thomas-Anterion has nothing to disclose. Dr. Campion has nothing to disclose. Dr. Michel has nothing to disclose. Dr. Dubois has received personal compensation for activities with Bristol-Myers Squibb, Roche, Elan, Eli Lilly, Eisai, and Janssen as a consultantDr. Dubois has received personal compensation for serving on the advisory board of Bristol-Myers Squibb, Roche, Elan, Eli Lilly, Eisai, and Janssen.Dr. Dubois has received research support from Novartis and Sanofi-Aventis. Dr. Camu has nothing to disclose. Dr. Seilhean has nothing to disclose. Dr. Meininger has received personal compensation for activities with Servier and GlaxoSmithKline. Dr. Habert has nothing to disclose. Dr. Duyckaerts has nothing to disclose. Dr. Brice has nothing to disclose.