Different Clinical Phenotypes in Siblings with a Presenilin-1 P264L Mutation

Ishizuka, Takanori; Nakamura, Masayuki; Ichiba, Mio; Fujita, Seigo; Takeuchi, Kouzo; Fujimoto, Toshiro; Sano, Akira

doi:10.1159/000338394

Cited by 9 publications

(3 citation statements)

References 89 publications

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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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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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“…Second, other genetic factors may modify the disease, perhaps interacting with the different mutations. A recent report describes different clinical phenotypes in siblings carrying the same PSEN1 mutation [57]. Previous studies have also suggested greater medial temporal atrophy in AD subjects carrying the APOE ε4 allele compared with non-carriers [58, 59], while the APOE ε2 allele may have a protective effect regarding time of disease onset.…”

Section: Discussionmentioning

confidence: 99%

Genetic Influences on Atrophy Patterns in Familial Alzheimer's Disease: A Comparison of APP and PSEN1 Mutations

Scahill

Ridgway

Bartlett

et al. 2013

JAD

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Mutations in the presenilin1 (PSEN1) and amyloid β-protein precursor (APP) genes account for the majority of cases of autosomal dominantly inherited Alzheimer's disease (AD). We wished to assess and compare the patterns of cerebral loss produced by these two groups of mutations. Volumetric magnetic resonance imaging and neuropsychological assessments were performed in individuals with clinical AD carrying mutations in the APP (n = 10) and PSEN1 (n = 18) genes and in healthy controls (n = 18). Voxel-based morphometry (VBM), cortical thickness, and region of interest analyses were performed. Mini-Mental State Examination scores were similar in the two disease groups suggesting similar levels of disease severity. There was evidence that APP subjects have smaller hippocampal volume compared with PSEN1 subjects (p = 0.007), and weak evidence that they have larger whole-brain and grey matter volumes (both p = 0.07). Although there was no evidence of statistically significant differences between APP and PSEN1 in VBM or cortical thickness analyses, effect-maps were suggestive of APP subjects having more medial temporal lobe atrophy and conversely PSEN1 subjects showing more neocortical loss. Neuropsychological data were consistent with these regional differences and suggested greater memory deficits in the APP patients and greater impairment in non-memory domains in the PSEN1 group, although these differences were not statistically significant. We conclude that the mechanisms by which APP and PSEN1 mutations cause neuronal loss may differ which furthers our understanding of the neuropathology underlying AD and may inform future therapeutic strategies and trial designs.

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“…This is evident both in relation to previously published cases (Table 1[7–15,20]), and reported clinical phenotypes within the patient’s family: whilst detailed clinical information about the previous generation is lacking, the substantially later age of the patient’s father at clinical onset and his clinical phenotype (a memory/behavioural led syndrome) suggests that if (as is plausible) he also carried the P264L mutation, then the clinical phenotype of the mutation varied within this family. Indeed, a recent report has highlighted the potential heterogeneity of this mutation among members of a single family; one member had word comprehension deficits, whilst another had more typical features of AD with poor episodic memory and apraxia [14].…”

Section: Discussionmentioning

confidence: 99%

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

Mahoney

Downey

Beck

et al. 2013

JAD

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Primary progressive aphasia (PPA) represents a diverse group of language-led dementias most often due to frontotemporal lobar degeneration. We report clinical, neuropsychological, and neuroimaging data in the case of a 47-year-old woman presenting with non-fluent PPA due to a genetically confirmed pathogenic Presenilin 1 P264L mutation. This case highlights an unusual clinical presentation of familial Alzheimer's disease and a novel presentation of the P264L mutation. The case adds to accumulating evidence that particular mutations can promote specific brain network degeneration, with wider implications for understanding the sporadic forms of Alzheimer's disease and PPA.

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Different Clinical Phenotypes in Siblings with a Presenilin-1 P264L Mutation

Cited by 9 publications

References 89 publications

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

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

Genetic Influences on Atrophy Patterns in Familial Alzheimer's Disease: A Comparison of APP and PSEN1 Mutations

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

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