Analysis of Heritability Across the Clinical Phenotypes of Frontotemporal Dementia and the Frequency of the C9ORF72 in a Colombian Population

Frontotemporal dementia (FTD) is a highly heritable condition. Up to 40% of FTD is familial and an estimated 15% to 40% is due to single-gene mutations. It has been estimated that the G4C2 hexanucleotide repeat expansions in the C9ORF72 gene can explain up to 37.5% of the familial cases of FTD, especially in populations of Caucasian origin. The purpose of this paper is to evaluate hereditary risk across the clinical phenotypes of FTD and the frequency of the G4C2 expansion in a Colombian cohort diagnosed with FTD.Methods: A total of 132 FTD patients were diagnosed according to established criteria in the behavioral variant FTD, logopenic variant PPA, non-fluent agrammatic PPA, and semantic variant PPA. Hereditary risk across the clinical phenotypes was established in four categories that indicate the pathogenic relationship of the mutation: high, medium, low, and apparently sporadic, based on those proposed by Wood and collaborators. All subjects were also examined for C9ORF72 hexanucleotide expansion (defined as >30 repetitions).Results: There were no significant differences in the demographic characteristics of the patients between the clinical phenotypes of FTD. The higher rate phenotype was bvFTD (62.12%). In accordance with the risk classification, we found that 72 (54.4%) complied with the criteria for the sporadic cases; for the familial cases, 23 (17.4%) fulfilled the high-risk criteria, 23 (17.4%) fulfilled the low risk criteria, and 14 (10.6%) fulfilled the criteria to be classified as subject to medium risk. C9ORF72 expansion frequency was 0.76% (1/132).Conclusion: The FTD heritability presented in this research was very similar to the results reported in the literature. The C9ORF72 expansion frequency was low. Colombia is a triethnic country, with a high frequency of genetic Amerindian markers; this shows consistency with the present results of a low repetition frequency. This study provides an initial report of the frequency for the hexanucleotide repeat expansions in C9ORF72 in patients with FTD in a Colombian population and paves the way for further study of the possible genetic causes of FTD in Colombia.

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The Frequency of Genetic Mutations Associated With Behavioral Variant Frontotemporal Dementia in Chinese Han Patients

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.699836 ◽

2021 ◽

Vol 13 ◽

Author(s):

Li Liu ◽

Bo Cui ◽

Min Chu ◽

Yue Cui ◽

Donglai Jing ◽

...

Keyword(s):

Frontotemporal Dementia ◽

Genetic Variants ◽

Genetic Mutations ◽

Chinese Han ◽

Behavioral Variant Frontotemporal Dementia ◽

Pathogenic Variants ◽

Hexanucleotide Repeat ◽

Mapt Gene ◽

Repeat Expansions ◽

Expansion Mutation

BackgroundBehavioral variant frontotemporal dementia (bvFTD) is a clinically heterogeneous syndrome with high heredity. However, the frequencies of mutations associated with bvFTD have yet to be determined. The aim of the current study was to investigate the frequency of Chinese Han patients harboring genetic bvFTD variants.MethodsA total of 49 bvFTD patients selected from our frontotemporal lobar degeneration database, including 14 familial cases belonging to eight families and 35 sporadic cases were consecutively recruited from July 2014 to December 2019 at Xuanwu Hospital (Beijing, China). Whole-exome sequencing (WES) was performed and repeat-primed PCR was used to test samples for the C9orf72 hexanucleotide repeat expansion mutation. The frequency of genetic variants and the pathogenicity of the novel variants were analyzed.ResultsTen pathogenic or likely pathogenic variants were identified in 17 bvFTD patients, including C9orf72 repeat expansions, six previously reported mutations and three novel mutations (MAPT p. R5C, p. D54N, GRN p. P451L). Genetic mutations accounted for 27.9% (12/43) of total cases, 87.5% (7/8) of patients with familial bvFTD, and 14.3% (5/35) with sporadic bvFTD. Pathogenic variants mostly occurred in MAPT gene (20.9%, 9/43), followed by C9orf72 repeat expansions (2.3%, 1/43), GRN gene (2.3%, 1/43) and FUS gene (2.3%, 1/43).ConclusionThere was a high prevalence of genetic variants in Chinese bvFTD patients, highlighting the necessity of genetic testing for bvFTD.

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C9orf72 Hexanucleotide Repeat Expansions as the Causative Mutation for Chromosome 9p21–Linked Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Archives of Neurology ◽

10.1001/archneurol.2012.377 ◽

2012 ◽

Vol 69 (9) ◽

Cited By ~ 13

Author(s):

Hussein Daoud ◽

Hamid Suhail ◽

Mike Sabbagh ◽

Veronique Belzil ◽

Anna Szuto ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Frontotemporal Dementia ◽

Causative Mutation ◽

Chromosome 9P21 ◽

Hexanucleotide Repeat ◽

Repeat Expansions ◽

Lateral Sclerosis

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C9orf72 Repeat Expansions in Rapid Eye Movement Sleep Behaviour Disorder

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2014.39 ◽

2014 ◽

Vol 41 (6) ◽

pp. 759-762 ◽

Cited By ~ 12

Author(s):

Hussein Daoud ◽

Ronald B. Postuma ◽

Cynthia V. Bourassa ◽

Daniel Rochefort ◽

Maude Turcotte Gauthier ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Frontotemporal Dementia ◽

Eye Movement ◽

Repeat Expansion ◽

Risk Haplotype ◽

Rapid Eye Movement ◽

Rapid Eye Movement Sleep ◽

Hexanucleotide Repeat ◽

Repeat Expansions ◽

Lateral Sclerosis

AbstractBackground: A large hexanucleotide repeat expansion in C9orf72 has been identified as the most common genetic cause in familial amyotrophic lateral sclerosis and frontotemporal dementia. Rapid Eye Movement Sleep Behavior Disorder (RBD) is a sleep disorder that has been strongly linked to synuclein-mediated neurodegeneration. The aim of this study was to evaluate the role of the C9orf72 expansions in the pathogenesis of RBD. Methods: We amplified the C9orf72 repeat expansion in 344 patients with RBD by a repeat-primed polymerase chain reaction assay. Results: We identified two RBD patients carrying the C9orf72 repeat expansion. Most interestingly, these patients have the same C9orf72 associated-risk haplotype identified in 9p21-linked amyotrophic lateral sclerosis and frontotemporal dementia families. Conclusions: Our study enlarges the phenotypic spectrum associated with the C9orf72 hexanucleotide repeat expansions and suggests that, although rare, this expansion may play a role in the pathogenesis of RBD.

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Frequency of common genetic forms of frontotemporal dementia in a Russian cohort of patients

Nauchno-prakticheskii zhurnal «Medicinskaia genetika» ◽

10.25557/2073-7998.2020.04.30-32 ◽

2020 ◽

pp. 30-32

Author(s):

Ю.А. Шпилюкова ◽

Е.Ю. Федотова ◽

Н.Ю. Абрамычева ◽

С.Н. Иллариошкин

Keyword(s):

Frontotemporal Dementia ◽

Clinical Phenotypes ◽

Mapt Gene ◽

First Time

Впервые в российской популяции на когорте пациентов с клиническим диагнозом ЛВД исследована частота встречаемости мутаций в наиболее частых генах, ассоциированных с данным заболеванием. Наибольшая часто мутирующими являются гены C9orf72 и GRN. Реже всего встречаются мутации в гене MAPT, что возможно связано с неравномерным представительством клинических фенотипов в нашей выборке. For the first time in the Russian cohort of FTD patients the frequency of mutations in the most common genes associated with this disease was studied. The most frequently mutating are the genes C9orf72 and GRN. Mutations in the MAPT gene are least likely to occur, which is probably due to the uneven representation of clinical phenotypes in our sample.

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Screening for novel hexanucleotide repeat expansions at ALS- and FTD-associated loci

Neurology Genetics ◽

10.1212/nxg.0000000000000071 ◽

2016 ◽

Vol 2 (3) ◽

pp. e71 ◽

Cited By ~ 3

Author(s):

Fang He ◽

Julie M. Jones ◽

Claudia Figueroa-Romero ◽

Dapeng Zhang ◽

Eva L. Feldman ◽

...

Keyword(s):

Hexanucleotide Repeat ◽

Repeat Expansions

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[18 F]AV-1451 binding is increased in frontotemporal dementia due to C9orf72 expansion

Annals of Clinical and Translational Neurology ◽

10.1002/acn3.631 ◽

2018 ◽

Vol 5 (10) ◽

pp. 1292-1296 ◽

Cited By ~ 11

Author(s):

Richard W. Bevan-Jones ◽

Thomas E. Cope ◽

Simon P. Jones ◽

Luca Passamonti ◽

Young T. Hong ◽

...

Keyword(s):

Frontotemporal Dementia ◽

C9orf72 Expansion

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Concomitant gain and loss of function pathomechanisms in C9ORF72 amyotrophic lateral sclerosis

Life Science Alliance ◽

10.26508/lsa.202000764 ◽

2021 ◽

Vol 4 (4) ◽

pp. e202000764

Author(s):

Arun Pal ◽

Benedikt Kretner ◽

Masin Abo-Rady ◽

Hannes Glaβ ◽

Banaja P Dash ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Loss Of Function ◽

Dna Double Strand Breaks ◽

Hexanucleotide Repeat ◽

Rna Foci ◽

Repeat Expansions ◽

Organelle Motility ◽

Trafficking Defects ◽

Induced Pluripotent ◽

Lateral Sclerosis

Intronic hexanucleotide repeat expansions (HREs) in C9ORF72 are the most frequent genetic cause of amyotrophic lateral sclerosis, a devastating, incurable motoneuron (MN) disease. The mechanism by which HREs trigger pathogenesis remains elusive. The discovery of repeat-associated non-ATG (RAN) translation of dipeptide repeat proteins (DPRs) from HREs along with reduced exonic C9ORF72 expression suggests gain of toxic functions (GOFs) through DPRs versus loss of C9ORF72 functions (LOFs). Through multiparametric high-content (HC) live profiling in spinal MNs from induced pluripotent stem cells and comparison to mutant FUS and TDP43, we show that HRE C9ORF72 caused a distinct, later spatiotemporal appearance of mainly proximal axonal organelle motility deficits concomitant to augmented DNA double-strand breaks (DSBs), RNA foci, DPRs, and apoptosis. We show that both GOFs and LOFs were necessary to yield the overall C9ORF72 pathology. Increased RNA foci and DPRs concurred with onset of axon trafficking defects, DSBs, and cell death, although DSB induction itself did not phenocopy C9ORF72 mutants. Interestingly, the majority of LOF-specific DEGs were shared with HRE-mediated GOF DEGs. Finally, C9ORF72 LOF was sufficient—albeit to a smaller extent—to induce premature distal axonal trafficking deficits and increased DSBs.

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C9orf72-derived arginine-containing dipeptide repeats associate with axonal transport machinery and impede microtubule-based motility

10.1101/835082 ◽

2019 ◽

Cited By ~ 4

Author(s):

Laura Fumagalli ◽

Florence L. Young ◽

Steven Boeynaems ◽

Mathias De Decker ◽

Arpan R. Mehta ◽

...

Keyword(s):

Axonal Transport ◽

Motor Neurons ◽

Single Molecule ◽

Induced Pluripotent Stem Cell ◽

Cytoplasmic Dynein ◽

Inhibitory Interaction ◽

Hexanucleotide Repeat ◽

Repeat Expansions

ABSTRACTHexanucleotide repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How this mutation leads to these neurodegenerative diseases remains unclear. Here, we use human induced pluripotent stem cell-derived motor neurons to show that C9orf72 repeat expansions impair microtubule-based transport of mitochondria, a process critical for maintenance of neuronal function. Cargo transport defects are recapitulated by treating healthy neurons with the arginine-rich dipeptide repeat proteins (DPRs) that are produced by the hexanucleotide repeat expansions. Single-molecule imaging shows that these DPRs perturb motility of purified kinesin-1 and cytoplasmic dynein-1 motors along microtubules in vitro. Additional in vitro and in vivo data indicate that the DPRs impair transport by interacting with both microtubules and the motor complexes. We also show that kinesin-1 is enriched in DPR inclusions in patient brains and that increasing the level of this motor strongly suppresses the toxic effects of arginine-rich DPR expression in a Drosophila model. Collectively, our study implicates an inhibitory interaction of arginine-rich DPRs with the axonal transport machinery in C9orf72-associated ALS/FTD and thereby points to novel potential therapeutic strategies.

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