scholarly journals Sex differences in the prevalence of genetic mutations in FTD and ALS

Neurology ◽  
2017 ◽  
Vol 89 (15) ◽  
pp. 1633-1642 ◽  
Author(s):  
Ashley F. Curtis ◽  
Mario Masellis ◽  
Ging-Yuek Robin Hsiung ◽  
Rahim Moineddin ◽  
Kathy Zhang ◽  
...  
Keyword(s):  
Sex Differences ◽  
Meta Analysis ◽  
Phenotypic Expression ◽  
Chromosome 9 ◽  
Random Effects Models ◽  
Reading Frame ◽  
Female Patients ◽  
Hexanucleotide Repeat ◽  
Mutation Carriers ◽  
Related Risk

Objective:To conduct a meta-analysis that investigates sex differences in the prevalence of mutations in the 3 most common genes that cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)—chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN), or microtubule-associated protein tau (MAPT)—in patients clinically diagnosed with these conditions.Methods:MEDLINE, EMBASE, and PsycINFO databases were searched (inception to June 30, 2016). Studies of patients with FTD or ALS that reported the number of men and women with and without mutations of interest were selected. Female to male pooled risk ratios (RR) and 95% confidence intervals (CI) for each mutation were calculated using random-effects models.Results:Thirty-two articles reporting 12,784 patients with ALS (including 1,244 C9orf72 mutation carriers) revealed a higher prevalence of female patients with C9orf72-related ALS (RR 1.16, 95% CI 1.04–1.29). Twenty-three articles reporting 5,320 patients with FTD (including 488 C9orf72 mutation carriers) revealed no sex differences in C9orf72-related FTD (RR 0.95, 95% CI 0.81–1.12). Thirty-six articles reporting 3,857 patients with FTD (including 369 GRN mutation carriers) revealed a higher prevalence of female patients with GRN-related FTD (RR 1.33, 95% CI 1.09–1.62). Finally, 21 articles reporting 2,377 patients with FTD (including 215 MAPT mutation carriers) revealed no sex difference in MAPT-related FTD (RR 1.21, 95% CI 0.95–1.55).Conclusions:Higher female prevalence of C9orf72 hexanucleotide repeat expansions in ALS and GRN mutations in FTD suggest that sex-related risk factors might moderate C9orf72 and GRN-mediated phenotypic expression.

scholarly journals Novel Optineurin Frameshift Insertion in a Family With Frontotemporal Dementia and Parkinsonism Without Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Jacqueline Dominguez ◽  
Jeryl Tan Yu ◽  
Yi Jayne Tan ◽  
Arlene Ng ◽  
Ma Fe De Guzman ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Frontotemporal Dementia ◽  
Positive Family History ◽  
Clinical Manifestations ◽  
The Philippines ◽  
Chromosome 9 ◽  
Genetic Modifiers ◽  
Reading Frame ◽  
Hexanucleotide Repeat ◽  
Lateral Sclerosis

Frontotemporal Dementia (FTD) is a common cause of Young Onset Dementia and has diverse clinical manifestations involving behavior, executive function, language and motor function, including parkinsonism. Up to 50% of FTD patients report a positive family history, supporting a strong genetic basis, particularly in cases with both FTD and amyotrophic lateral sclerosis (FTD-ALS). Mutations in three genes are associated with the majority of familial FTD (fFTD) cases - microtubule associated protein tau gene (MAPT), granulin precursor (GRN), and hexanucleotide repeat expansions in chromosome 9 open reading frame 72- SMCR8complex subunit (C9orf72) while mutations in other genes such as optineurin (OPTN) have rarely been reported. Mutations in OPTN have been reported mostly in familial and sporadic cases of ALS, or in rare cases of FTD-ALS, but not in association with pure or predominant FTD and/or parkinsonian phenotype. Here, we report for the first time, a family from the Philippines with four members harboring a novel frameshift insertion at OPTN (Chr 10:13166090 G>GA) p.Lys328GluTer11, three of whom presented with FTD-related phenotypes. Additionally, one sibling heterozygous for the frameshift insertion had a predominantly parkinsonian phenotype resembling corticobasal syndrome, but it remains to be determined if this phenotype is related to the frameshift insertion. Notably, none of the affected members showed any evidence of motor neuron disease or ALS at the time of writing, both clinically and on electrophysiological testing, expanding the phenotypic spectrum of OPTN mutations. Close follow-up of mutation carriers for the development of new clinical features and wider investigation of additional family members with further genetic analyses will be conducted to investigate the possibility of other genetic modifiers in this family which could explain phenotypic heterogeneity.

scholarly journals Genetics and Sex in the Pathogenesis of Amyotrophic Lateral Sclerosis (ALS): Is There a Link?

2020 ◽  
Vol 21 (10) ◽  
pp. 3647 ◽  
Author(s):  
Francesca Trojsi ◽  
Giulia D’Alvano ◽  
Simona Bonavita ◽  
Gioacchino Tedeschi
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Disease Risk ◽  
Genetic Mutation ◽  
Chromosome 9 ◽  
Patient Specific ◽  
Reading Frame ◽  
Hexanucleotide Repeat ◽  
Sporadic Als ◽  
Als Patients ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no known cure. Approximately 90% of ALS cases are sporadic, although multiple genetic risk factors have been recently revealed also in sporadic ALS (SALS). The pathological expansion of a hexanucleotide repeat in chromosome 9 open reading frame 72 (C9orf72) is the most common genetic mutation identified in familial ALS, detected also in 5–10% of SALS patients. C9orf72-related ALS phenotype appears to be dependent on several modifiers, including demographic factors. Sex has been reported as an independent factor influencing ALS development, with men found to be more susceptible than women. Exposure to both female and male sex hormones have been shown to influence disease risk or progression. Moreover, interplay between genetics and sex has been widely investigated in ALS preclinical models and in large populations of ALS patients carrying C9orf72 repeat expansion. In light of the current need for reclassifying ALS patients into pathologically homogenous subgroups potentially responsive to targeted personalized therapies, we aimed to review the recent literature on the role of genetics and sex as both independent and synergic factors, in the pathophysiology, clinical presentation, and prognosis of ALS. Sex-dependent outcomes may lead to optimizing clinical trials for developing patient-specific therapies for ALS.

scholarly journals Downregulation of exosomal miR-204-5p and miR-632 as a biomarker for FTD: a GENFI study

2018 ◽  
Vol 89 (8) ◽  
pp. 851-858 ◽  
Author(s):  
Raphael Schneider ◽  
Paul McKeever ◽  
TaeHyung Kim ◽  
Caroline Graff ◽  
John Cornelis van Swieten ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Pathogenic Mutation ◽  
Chromosome 9 ◽  
Degree Relative ◽  
Sporadic Alzheimer’S Disease ◽  
Diagnostic Biomarkers ◽  
Reading Frame ◽  
Protein Tau ◽  
Mutation Carriers ◽  
Receiver Operator Characteristics

ObjectiveTo determine whether exosomal microRNAs (miRNAs) in cerebrospinal fluid (CSF) of patients with frontotemporal dementia (FTD) can serve as diagnostic biomarkers, we assessed miRNA expression in the Genetic Frontotemporal Dementia Initiative (GENFI) cohort and in sporadic FTD.MethodsGENFI participants were either carriers of a pathogenic mutation in progranulin, chromosome 9 open reading frame 72 or microtubule-associated protein tau or were at risk of carrying a mutation because a first-degree relative was a known symptomatic mutation carrier. Exosomes were isolated from CSF of 23 presymptomatic and 15 symptomatic mutation carriers and 11 healthy non-mutation carriers. Expression of 752 miRNAs was measured using quantitative PCR (qPCR) arrays and validated by qPCR using individual primers. MiRNAs found differentially expressed in symptomatic compared with presymptomatic mutation carriers were further evaluated in a cohort of 17 patients with sporadic FTD, 13 patients with sporadic Alzheimer’s disease (AD) and 10 healthy controls (HCs) of similar age.ResultsIn the GENFI cohort, miR-204-5p and miR-632 were significantly decreased in symptomatic compared with presymptomatic mutation carriers. Decrease of miR-204-5p and miR-632 revealed receiver operator characteristics with an area of 0.89 (90% CI 0.79 to 0.98) and 0.81 (90% CI 0.68 to 0.93), respectively, and when combined an area of 0.93 (90% CI 0.87 to 0.99). In sporadic FTD, only miR-632 was significantly decreased compared with AD and HCs. Decrease of miR-632 revealed an area of 0.90 (90% CI 0.81 to 0.98).ConclusionsExosomal miR-204-5p and miR-632 have potential as diagnostic biomarkers for genetic FTD and miR-632 also for sporadic FTD.

Screening for C9orf72 Expansion Mutation in Serbian Patients with Early-Onset Dementia

2015 ◽  
Vol 40 (5-6) ◽  
pp. 358-365 ◽  
Author(s):  
Gorana Mandic-Stojmenovic ◽  
Elka Stefanova ◽  
Valerija Dobricic ◽  
Ivana Novakovic ◽  
Tanja Stojkovic ◽  
...  
Keyword(s):  
Early Onset ◽  
Lewy Bodies ◽  
Chromosome 9 ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Reading Frame ◽  
Early Onset Dementia ◽  
Hexanucleotide Repeat ◽  
Disease Spectrum ◽  
Hexanucleotide Repeat Expansion ◽  
Expansion Mutation

Background: Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia (EOD), characterized by behavioral changes (behavioral variant; bvFTD) or language deficits. A hexanucleotide repeat expansion in a noncoding region of chromosome 9 open reading frame 72 (C9orf72) has been proved to be a major cause of both familial and sporadic amyotrophic lateral sclerosis or FTD, with or without concomitant motor neuron disease (MND). Methods: The aim of this study was to assess the frequency of the C9orf72 hexanucleotide expansion in a cohort of 117 Serbian patients with EOD and to report phenotypic features of identified carriers. Results: We identified 4 of 117 (3.4%) patients with EOD to have C9orf72 hexanucleotide expansions. All patients were classified in the FTD disease spectrum group (8.2%): 3 patients fulfilled the criteria for bvFTD, and 1 patient had FTD-MND. None of the patients with the C9orf72 hexanucleotide expansion fulfilled the diagnostic criteria for language variants of FTD, FTD-progressive supranuclear palsy overlap syndrome, dementia with Lewy bodies or Alzheimer's dementia. Conclusion: In a cohort of consecutive patients with EOD, 3.4% had the C9orf72 hexanucleotide expansion with clinical phenotypes of bvFTD or an overlap of bvFTD and MND.

scholarly journals Early symptoms in symptomatic and preclinical genetic frontotemporal lobar degeneration

2020 ◽  
Vol 91 (9) ◽  
pp. 975-984 ◽  
Author(s):  
Tamara Paulo Tavares ◽  
Derek G V Mitchell ◽  
Kristy KL Coleman ◽  
Brenda L Coleman ◽  
Christen L Shoesmith ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Neuropsychiatric Symptoms ◽  
Family Members ◽  
Pathogenic Mutation ◽  
Chromosome 9 ◽  
Reading Frame ◽  
Memory Impairments ◽  
Mutation Carriers ◽  
Composite Indices ◽  
Initial Symptoms

ObjectivesThe clinical heterogeneity of frontotemporal dementia (FTD) complicates identification of biomarkers for clinical trials that may be sensitive during the prediagnostic stage. It is not known whether cognitive or behavioural changes during the preclinical period are predictive of genetic status or conversion to clinical FTD. The first objective was to evaluate the most frequent initial symptoms in patients with genetic FTD. The second objective was to evaluate whether preclinical mutation carriers demonstrate unique FTD-related symptoms relative to familial mutation non-carriers.MethodsThe current study used data from the Genetic Frontotemporal Dementia Initiative multicentre cohort study collected between 2012 and 2018. Participants included symptomatic carriers (n=185) of a pathogenic mutation in chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN) or microtubule-associated protein tau (MAPT) and their first-degree biological family members (n=588). Symptom endorsement was documented using informant and clinician-rated scales.ResultsThe most frequently endorsed initial symptoms among symptomatic patients were apathy (23%), disinhibition (18%), memory impairments (12%), decreased fluency (8%) and impaired articulation (5%). Predominant first symptoms were usually discordant between family members. Relative to biologically related non-carriers, preclinical MAPT carriers endorsed worse mood and sleep symptoms, and C9orf72 carriers endorsed marginally greater abnormal behaviours. Preclinical GRN carriers endorsed less mood symptoms compared with non-carriers, and worse everyday skills.ConclusionPreclinical mutation carriers exhibited neuropsychiatric symptoms compared with non-carriers that may be considered as future clinical trial outcomes. Given the heterogeneity in symptoms, the detection of clinical transition to symptomatic FTD may be best captured by composite indices integrating the most common initial symptoms for each genetic group.

scholarly journals A C9ORF72/SMCR8-containing complex regulates ULK1 and plays a dual role in autophagy

2016 ◽  
Vol 2 (9) ◽  
pp. e1601167 ◽  
Author(s):  
Mei Yang ◽  
Chen Liang ◽  
Kunchithapadam Swaminathan ◽  
Stephanie Herrlinger ◽  
Fan Lai ◽  
...  
Keyword(s):  
Chromosome 9 ◽  
Autophagic Flux ◽  
Reading Frame ◽  
Guanosine Diphosphate ◽  
Hexanucleotide Repeat ◽  
Autophagy Induction ◽  
Important Regulator ◽  
Hexanucleotide Repeat Expansion ◽  
Guanosine Triphosphatase ◽  
Mutant Cells

The intronic GGGGCC hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) is a prevalent genetic abnormality identified in both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Smith-Magenis syndrome chromosomal region candidate gene 8 (SMCR8) is a protein with unclear functions. We report that C9ORF72 is a component of a multiprotein complex containing SMCR8, WDR41, and ATG101 (an important regulator of autophagy). The C9ORF72 complex displays guanosine triphosphatase (GTPase) activity and acts as a guanosine diphosphate–guanosine 5′-triphosphate (GDP-GTP) exchange factor (GEF) for RAB39B. We created Smcr8 knockout mice and found that Smcr8 mutant cells exhibit impaired autophagy induction, which is similarly observed in C9orf72 knockdown cells. Mechanistically, SMCR8/C9ORF72 interacts with the key autophagy initiation ULK1 complex and regulates expression and activity of ULK1. The complex has an additional role in regulating later stages of autophagy. Whereas autophagic flux is enhanced in C9orf72 knockdown cells, depletion of Smcr8 results in a reduced flux with an abnormal expression of lysosomal enzymes. Thus, C9ORF72 and SMCR8 have similar functions in modulating autophagy induction by regulating ULK1 and play distinct roles in regulating autophagic flux.

scholarly journals Arginine-rich dipeptide-repeat proteins as phase disruptors in C9-ALS/FTD

2020 ◽  
Vol 4 (3) ◽  
pp. 293-305
Author(s):  
Hana M. Odeh ◽  
James Shorter
Keyword(s):  
Rna Binding ◽  
Rna Binding Proteins ◽  
Low Complexity ◽  
Repeat Expansion ◽  
Chromosome 9 ◽  
Reading Frame ◽  
Hexanucleotide Repeat ◽  
Hexanucleotide Repeat Expansion ◽  
Lateral Sclerosis ◽  
Dipeptide Repeat

A hexanucleotide repeat expansion GGGGCC (G4C2) within chromosome 9 open reading frame 72 (C9orf72) is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). This seminal realization has rapidly focused our attention to the non-canonical translation (RAN translation) of the repeat expansion, which yields dipeptide-repeat protein products (DPRs). The mechanisms by which DPRs might contribute to C9-ALS/FTD are widely studied. Arginine-rich DPRs (R-DPRs) are the most toxic of the five different DPRs produced in neurons, but how do R-DPRs promote C9-ALS/FTD pathogenesis? Proteomic analyses have uncovered potential pathways to explore. For example, the vast majority of the R-DPR interactome is comprised of disease-linked RNA-binding proteins (RBPs) with low-complexity domains (LCDs), strongly suggesting a link between R-DPRs and aberrations in liquid–liquid phase separation (LLPS). In this review, we showcase several potential mechanisms by which R-DPRs disrupt various phase-separated compartments to elicit deleterious neurodegeneration. We also discuss potential therapeutic strategies to counter R-DPR toxicity in C9-ALS/FTD.

Early life involvement in C9orf72 repeat expansion carriers

2021 ◽  
pp. jnnp-2020-325994
Author(s):  
Flora Gossink ◽  
Annemiek Dols ◽  
Max L Stek ◽  
Philip Scheltens ◽  
Bas Nijmeijer ◽  
...  
Keyword(s):  
Repeat Expansion ◽  
Chromosome 9 ◽  
Disease Course ◽  
C9orf72 Repeat Expansion ◽  
Reading Frame ◽  
Professional Career ◽  
Hexanucleotide Repeat ◽  
Behavioural Patterns ◽  
Quantitative Analyses ◽  
Hexanucleotide Repeat Expansion

ObjectivesThe chromosome 9 open reading frame 72 gene (C9orf72) hexanucleotide repeat expansion (C9orf72RE) is the most common genetic cause of behavioural variant frontotemporal dementia (bvFTD). Since the onset of the C9orf72RE-associated disease is sometimes hard to define, we hypothesise that C9orf72RE may cause a lifelong neuropsychiatric vulnerability. The first aim of our study was to explore lifelong behavioural and personality characteristics in C9orf72RE. Second, we aimed to describe distinctive characteristics of C9orf72RE during disease course.MethodsOut of 183 patients from the Amsterdam Dementia Cohort that underwent genetic testing between 2011 and 2018, 20 C9orf72RE bvFTD patients and 23 C9orf72RE negative bvFTD patients were included. Patients and their relatives were interviewed extensively to chart their biography. Data analysis was performed through a mixed-methods approach including qualitative and quantitative analyses.ResultsEducation, type of professional career and number of intimate partners were not different between carriers and non-carriers. Carriers were more often described by their relatives as having ‘fixed behavioural patterns in daily life’ and with limited empathy already years before onset of bvFTD symptoms. In carriers, disease course was more often characterised by excessive buying and obsessive physical exercise than in non-carriers.ConclusionThis is the first study thoroughly exploring biographies of bvFTD patients with C9orf72RE, revealing that subtle personality traits may be present early in life. Our study suggests that C9orf72RE exerts a lifelong neuropsychiatric vulnerability. This may strengthen hypotheses of links between neurodevelopmental and neurodegenerative diseases. Moreover, the presence of a distinct C9orf72RE -associated syndrome within the FTD spectrum opens doors for investigation of vulnerable neuronal networks.

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