Targeted Screening of the C9orf72 Gene in Bulgarian Amyotrophic Lateral Sclerosis Patients
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Abstract:
Abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, characterized by progressive degeneration of the upper and lower motor neurons, leading to muscle weakness, hypotrophy, swallowing and respiratory failure. The cause of ALS is not yet fully elucidated, but there are 35 associated genes and 2 gene loci with an unidentified gene. The most common are C9orf72, SOD1, TARDBP and FUS found in approximately 10% of patients. Variants in the C9orf72 gene are the main cause of fALS – 25-40% of cases (and a small percentage of sALS). The goal of the present study was to evaluate the significance of the C9orf72 hexanucleotide repeat expansion in Bulgarian patients with ALS, through the means of in house and triplet repeat-primed PCR assay (TP-PCR). From 171 patients diagnosed with ALS and included in the current study, we have identified the repeat expansion with more than 145 GGGGCC repeats in 7 (4,1%). Short expansions or borderline values (24 to 30 repeats) were not detected. Due to absence of sufficient data, we have established an ALS-focused research for the association of the C9orf72 gene in clinically well-characterized Bulgarian ALS patients. Published data show variable percentage ratios for genetically verified cases (4-40%), which is mainly due to small sample counts and sALS-fALS ratios. Our patients’ group also contains sALS and fALS cases, which explains the low percentage of genetic verification. The obtained results enrich the worldwide database and shed light onto genetically characterized Bulgarian ALS patients. Affected patients and their families can receive adequate medical-genetic consultation and prenatal diagnostic testing.Keywords:
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Bulgarian
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Objective
To further assess the presence of a large hexanucleotide repeat expansion in the first intron of the C9orf72 gene identified as the genetic cause of chromosome 9p21–linked amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD) in 4 unrelated families with a conclusive linkage to c9ALS/FTD.Design
A repeat-primed polymerase chain reaction assay.Setting
Academic research.Participants
Affected and unaffected individuals from 4 ALS/FTD families.Main Outcome Measure
The amplified C9orf72 repeat expansion.Results
We show that the repeat is expanded in and segregated perfectly with the disease in these 4 pedigrees.Conclusion
Our findings further confirm the C9orf72 hexanucleotide repeat expansion as the causative mutation for c9ALS/FTD and strengthen the hypothesis that ALS and FTD belong to the same disease spectrum.C9ORF72
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Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) have a strong clinical, genetic and pathological overlap. This review focuses on the current understanding of structural, functional and molecular neuroimaging signatures of genetic FTD and ALS. We overview quantitative neuroimaging studies on the most common genes associated with FTD (MAPT, GRN), ALS (SOD1), and both (C9orf72), and summarize visual observations of images reported in the rarer genes (CHMP2B, TARDBP, FUS, OPTN, VCP, UBQLN2, SQSTM1, TREM2, CHCHD10, TBK1).
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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) were independently described in clinical and pathological details more than a century ago. Recent breakthrough discoveries identifying common genes that are causal to either ALS or FTD or an overlapping ALS-FTD syndrome have dramatically transformed our view regarding their pathogenesis. Most recently, a massive hexanucleotide (GGGGCC) repeat expansion mutation in C9orf72 gene has been linked to the majority of familial ALS, FTD and mixed ALS-FTD cases. C9orf72 and other genes causal to ALS and FTD are consistently associated with the formation of cellular RNA inclusions and protein aggregates. This article summarizes the recently reported ALS-FTD-linked genes and the emerging common unifying mechanism in the pathogenesis of ALS-FTD spectrum disorders along with a comment on the potential new therapeutic targets in these hitherto incurable diseases.
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Objective: To recognize the variable presentation of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) due to C9ORF72 mutation. Background FTD and ALS are closely related syndromes with common pathological substrates. Recent identification of mutations in the C9ORF72 gene as a cause of both familial FTD and ALS further highlights their relationships. In this study we analyzed the clinical presentation from 16 unrelated families with proven mutation in the C9ORF72 gene. Design/Methods: Subjects were recruited from families with proven FTLD-TDP pathology for longitudinal assessment. Clinical charts were also retrospectively reviewed in deceased subjects. The GGGGCC hexanucleotide repeats were detected by repeat-primed PCR reaction and RNA-FISH confirmation. Clinical diagnosis of FTD was based on Neary criteria and ALS diagnosis was based on El Escorial criteria. The presence of clinical features was scored using a semiquantitative grading system (0, absent; 1, mild; 2, moderate; 3, severe). Results: Thirty subjects (70% male) from 16 unrelated families with proven C9ORF72 mutation were identified. Age of onset ranged from 34 to 74. Initial diagnoses included 15 bvFTD, 9 ALS, 1 FTD-ALS, 2 alcoholic dementia, 1 mild cognitive impairment, 1 psychosis/schizophrenia, and 1 atypical Alzheimer disease. The common presenting symptoms are behavioural (47%) and language (47%), followed by executive dysfunction (40%), affective changes (40%), motor weakness (33%), memory problems (30%), and extrapyramidal symptoms (10%). ALS increased to 50% of the subjects in longitudinal follow up, and had a negative impact on survival (2.8 yrs +/- 1.5 with ALS vs. 8.4 +/- 3.8 without ALS). Conclusions: While patients with FTD and ALS associated with C9ORF72 hexanucleotide expansion have a common molecular mechanism and typical pathology, their initial clinical presentations can be quite variable and may overlap with other clinical syndromes. Early recognition requires a high clinical acumen. Other genetic or environmental factors may influence the presentation of clinical phenotype. Supported by: Canadian Institutes of Health Research [operating grants #179009, #74580] and the Pacific Alzheimer Research Foundation [center grant C06-01]. Disclosure: Dr. Hsiung has nothing to disclose. Dr. DeJesus-Hernandez has nothing to disclose. Dr. Feldman has received personal compensation for activities with Bristol-Myers Squibb Company as an employee. Dr. Feldman holds stock and/or stock options in Bristol-Myers Squibb Company. Dr. Sengdy has nothing to disclose. Dr. Bouchard-Kerr has nothing to disclose. Dr. Dwosh has nothing to disclose. Dr. Leung has nothing to disclose. Dr. Fok has nothing to disclose. Dr. Rutherford has nothing to disclose. Dr. Baker has nothing to disclose. Dr. Rademakers has nothing to disclose. Dr. Mackenzie has nothing to disclose.
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There is a close association between frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) on a clinical, pathological and genetic level. Three causative genes are responsible for over 80% of cases of FTD in families with a clear autosomal dominant family history: MAPT, GRN, and C9ORF72. Rarer genetic causes of FTD include mutations in the VCP, FUS, and CHMP2B genes. In this chapter, we discuss the genetic background of FTD-ALS overlap syndromes with a focus on when to suspect a mutation in the C9ORF72 is responsible. It has been recently established that an expanded hexanucleotide repeat in this gene is the most common cause of familial FTD and ALS.The presence of psychiatric symptoms in the context of FTD-ALS should alert clinicians to the possibility of a C9ORF72 expansion.
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The Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) consortia are two closely connected studies, involving multiple North American centers that evaluate both sporadic and familial frontotemporal dementia (FTD) participants and study longitudinal changes.
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