The Presenilin 1 P264L Mutation Presenting as non-Fluent/Agrammatic Primary Progressive Aphasia

Mahoney, Colin; Downey, Laura; Beck, Jon; Liang, Yuying; Mead, Simon; Perry, Richard; Warren, Jason D.

doi:10.3233/jad-122092

Cited by 15 publications

(5 citation statements)

References 24 publications

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“…Although pathogenic variants in PSEN1 are the main genetic causes of AD, there are a few reports of PSEN1 variants linked to FTD phenotypes (Bernardi et al, 2009;Mahoney et al, 2013;Riudavets et al, 2013;Robles et al, 2009). We identified one bvFTD case with a missense variant (p.Tyr115Cys) in the PSEN1 gene (Table 2, case 13).…”

Section: Pathogenic and Likely Pathogenic Variants In Common Ftd And mentioning

confidence: 97%

“…Recently, two new genes have been associated with FTD: TANK-binding kinase 1 (TBK1) (Freischmidt et al, 2015) and RNA-binding protein T cell-restricted intracellular antigen-1 (TIA1) (Mackenzie et al, 2017). In addition, while presenilin 1 (PSEN1) is one of the main genetic causes of Alzheimer's disease (AD), there are a few reports of PSEN1 variants associated with FTD phenotypes (Bernardi et al, 2009;Mahoney et al, 2013;Riudavets et al, 2013;Robles et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Frontotemporal dementia spectrum: first genetic screen in a Greek cohort

Ramos

Koros

Dokuru

et al. 2019

Neurobiology of Aging

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Frontotemporal dementia (FTD) is a heterogeneous group of neurodegenerative syndromes associated with several causative and susceptibility genes. Herein, we aimed to determine the incidence of the most common causative dementia genes in a cohort of 118 unrelated Greek FTD spectrum patients. We also screened for novel possible disease-associated variants in additional 21 genes associated with FTD or amyotrophic lateral sclerosis. Pathogenic or likely pathogenic *

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Section: Pathogenic and Likely Pathogenic Variants In Common Ftd And mentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Frontotemporal dementia spectrum: first genetic screen in a Greek cohort

Ramos

Koros

Dokuru

et al. 2019

Neurobiology of Aging

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“…All the PSEN1 c.791C>T (p.Pro264Leu) carrier haplotypes shared an IBD segment of 2.79 cM around the PSEN1 locus, supporting the hypothesis of a common ancestor for all three families originating at about the same time (Additional file 1: Figure S17). PSEN1 c.791C>T (p.Pro264Leu) has been described in multiple populations (France [89,[96][97][98][99], UK [100,101], Turkey [102], and Japan [103]) suggesting that PSEN1 c.791C>T (p.Pro264Leu) is a recurring mutation. While the European carriers of this variant often present SP [104], this phenotype was not observed in the Colombian carriers of the variant.…”

Section: Neurodegenerative Disease Variants In the Tangl Cohort Ad-as...mentioning

confidence: 99%

A neurodegenerative disease landscape of rare mutations in Colombia due to founder effects

et al. 2022

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Background The Colombian population, as well as those in other Latin American regions, arose from a recent tri-continental admixture among Native Americans, Spanish invaders, and enslaved Africans, all of whom passed through a population bottleneck due to widespread infectious diseases that left small isolated local settlements. As a result, the current population reflects multiple founder effects derived from diverse ancestries. Methods We characterized the role of admixture and founder effects on the origination of the mutational landscape that led to neurodegenerative disorders under these historical circumstances. Genomes from 900 Colombian individuals with Alzheimer’s disease (AD) [n = 376], frontotemporal lobar degeneration-motor neuron disease continuum (FTLD-MND) [n = 197], early-onset dementia not otherwise specified (EOD) [n = 73], and healthy participants [n = 254] were analyzed. We examined their global and local ancestry proportions and screened this cohort for deleterious variants in disease-causing and risk-conferring genes. Results We identified 21 pathogenic variants in AD-FTLD related genes, and PSEN1 harbored the majority (11 pathogenic variants). Variants were identified from all three continental ancestries. TREM2 heterozygous and homozygous variants were the most common among AD risk genes (102 carriers), a point of interest because the disease risk conferred by these variants differed according to ancestry. Several gene variants that have a known association with MND in European populations had FTLD phenotypes on a Native American haplotype. Consistent with founder effects, identity by descent among carriers of the same variant was frequent. Conclusions Colombian demography with multiple mini-bottlenecks probably enhanced the detection of founder events and left a proportionally higher frequency of rare variants derived from the ancestral populations. These findings demonstrate the role of genomically defined ancestry in phenotypic disease expression, a phenotypic range of different rare mutations in the same gene, and further emphasize the importance of inclusiveness in genetic studies.

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“…Pathogenic variants in PSEN1 are the main genetic causes of AD; however, they have occasionally been linked in the literature to FTD phenotypes. [25][26][27][28] We identified two related individuals with a missense variant (p.H163R) in the PSEN1 gene (Table 2). This variant is absent from gnomAD, is predicted to be damaging, and has been associated with multiple cases of AD, warranting classification as likely pathogenic.…”

Section: Overall Genetic Findingsmentioning

confidence: 99%

Genetic screening of a large series of North American sporadic and familial frontotemporal dementia cases

Ramos

Dokuru

Berlo

et al. 2020

Alzheimer's & Dementia

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Introduction: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. Methods:We screened the major dementia-associated genes in 302 sporadic and 390 familial (symptomatic or at-risk) participants enrolled in these studies.Results: Among the sporadic patients, 16 (5.3%) carried chromosome 9 open reading frame 72 (C9orf72), microtubule-associated protein tau (MAPT), and progranulin (GRN) pathogenic variants, whereas in the familial series we identified 207 carriers from 146 families. Of interest, one patient was found to carry a homozygous C9orf72 expansion, while another carried both a C9orf72 expansion and a GRN pathogenic variant. We also identified likely pathogenic variants in the TAR DNA binding protein (TARDBP), presenilin 1 (PSEN1), and valosin containing protein (VCP) genes, and a subset of variants of unknown significance in other rare FTD genes.Discussion: Our study reports the genetic characterization of a large FTD series and supports an unbiased sequencing screen, irrespective of clinical presentation or family history.

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The Presenilin 1 P264L Mutation Presenting as non-Fluent/Agrammatic Primary Progressive Aphasia

Cited by 15 publications

References 24 publications

Frontotemporal dementia spectrum: first genetic screen in a Greek cohort

Frontotemporal dementia spectrum: first genetic screen in a Greek cohort

A neurodegenerative disease landscape of rare mutations in Colombia due to founder effects

Genetic screening of a large series of North American sporadic and familial frontotemporal dementia cases

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