Cognitive Deficits in Familial Alzheimer’s Disease Associated with M239V Mutation of Presenilin 2

Giovagnoli, Anna Rita; Marcon, Gabriella; Giaccone, Giorgio; Confaloni, Annamaria; Tagliavini, Fabrizio

doi:10.1159/000094972

Cited by 10 publications

(5 citation statements)

References 30 publications

(27 reference statements)

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“…In addition, the clinical phenotypes of carriers of the M239V mutation varied widely. Our findings, together with previous reports, further suggest that phenotypic heterogeneity exists even at the same codon site because of different amino acid transversions 30 , 32 , 33 .…”

Section: Discussionsupporting

confidence: 86%

The role of genetics in neurodegenerative dementia: a large cohort study in South China

et al. 2021

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Neurodegenerative dementias are a group of diseases with highly heterogeneous pathology and complicated etiology. There exist potential genetic component overlaps between different neurodegenerative dementias. Here, 1795 patients with neurodegenerative dementias from South China were enrolled, including 1592 with Alzheimer’s disease (AD), 110 with frontotemporal dementia (FTD), and 93 with dementia with Lewy bodies (DLB). Genes targeted sequencing analysis were performed. According to the American College of Medical Genetics (ACMG) guidelines, 39 pathogenic/likely pathogenic (P/LP) variants were identified in 47 unrelated patients in 14 different genes, including PSEN1, PSEN2, APP, MAPT, GRN, CHCHD10, TBK1, VCP, HTRA1, OPTN, SQSTM1, SIGMAR1, and abnormal repeat expansions in C9orf72 and HTT. Overall, 33.3% (13/39) of the variants were novel, the identified P/LP variants were seen in 2.2% (35/1592) and 10.9% (12/110) of AD and FTD cases, respectively. The overall molecular diagnostic rate was 2.6%. Among them, PSEN1 was the most frequently mutated gene (46.8%, 22/47), followed by PSEN2 and APP. Additionally, the age at onset of patients with P/LP variants (51.4 years), ranging from 30 to 83 years, was ~10 years earlier than those without P/LP variants (p < 0.05). This study sheds insight into the genetic spectrum and clinical manifestations of neurodegenerative dementias in South China, further expands the existing repertoire of P/LP variants involved in known dementia-associated genes. It provides a new perspective for basic research on genetic pathogenesis and novel guiding for clinical practice of neurodegenerative dementia.

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Section: Discussionsupporting

confidence: 86%

The role of genetics in neurodegenerative dementia: a large cohort study in South China

et al. 2021

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“…Memory was relatively spared. Only one study found anosognosia, severe visuospatial impairment, apraxia and fluent aphasia, with relative sparing of memory function in a patient with a known preseniline 2 mutation (M239V) 35 . More clinicopathological studies are necessary to determine whether this combination of symptoms represents a clinical subtype of AD or whether other underlying pathology is responsible for this syndrome.…”

Section: Discussionmentioning

confidence: 99%

Early-Versus Late-Onset Alzheimer's Disease: More than Age Alone

Koedam

Lauffer

Vlies

et al. 2010

JAD

381

303

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Alzheimer's disease (AD) is the most common cause of dementia at older age. Although less prevalent before the age of 65 years, it is still the most frequent cause of early-onset dementia followed by frontotemporal dementia. The typical presentation of AD is memory dysfunction, however, presentations with prominent cognitive impairment in other domains besides memory, like prominent apraxia, language problems, or executive dysfunction, may occur and are relatively more common in early-onset AD. In this retrospective descriptive study, we determined the prevalence of non-memory presentations in a large sample of early-onset AD patients compared to late-onset AD. The clinical files of 270 patients with AD starting before the age of 65 years and 90 patients with late-onset AD ( 65 years) were reviewed to assess clinical characteristics. Patients were classified as memory presentation and non-memory presentation according to their clinical presentation. The mean age of the early-onset group was 56 +/- 5 years and 74 +/- 6 years for the late-onset group. A third of the early-onset AD group presented with non-memory symptoms compared to only 6% in the late-onset group (p < 0.001). Within the group with non-memory presentations, apraxia/visuospatial dysfunction was the most prevalent presenting symptom (12%). Patients with early-onset AD often present with a non-memory phenotype, of which apraxia/visuospatial dysfunction is the most common presenting symptom. Atypical presentations of AD should be considered in the clinical differential diagnosis of early-onset dementia.

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“…Only 7 of these mutations are well documented to be pathogenic, although pathogenicity in several others remains possible. A previous study in an Italian family has identified a distinctive pattern of visuospatial, praxis and language impairments in AD associated with the M239V mutation of the PSEN2 gene [18]. In Japanese patients, epidemiologic and genetic studies of Alzheimer's dementia did not find any mutations in PSEN2 and PSEN1 [19].…”

Section: Discussionmentioning

confidence: 99%

Clinical and Neuroimaging Characterization of Chinese Dementia Patients with PSEN1 and PSEN2 Mutations

Shi

Wang

Liu

et al. 2014

Dement Geriatr Cogn Disord

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Background: Alzheimer's disease (AD) and frontotemporal dementia (FTD) are two common forms of primary neurodegenerative dementia. Mutations in 3 genes (PSEN1, PSEN2, and APP) have been identified in patients with early-onset AD. Methods: We performed gene sequencing in PSEN1, PSEN2, and APP in 61 AD and 35 FTD Chinese patients. Amyloid load using ¹¹C-labeled Pittsburgh compound B (¹¹C-PIB) positron emission tomography (PET) and cerebral glucose metabolism using ¹⁸F-fludeoxyglucose PET were evaluated in patients carrying mutations. Results: We identified 1 known pathogenic PSEN1 (p.His163Arg, c.488A>G) mutation and 3 novel PSEN2 mutations in 6 patients. The novel mutation PSEN2 (p.His169Asn, c.505C>A) was identified in 1 patient with familial late-onset AD and in 1 sporadic FTD patient. The PSEN2 (p.Val214Leu, c.640G>T; p.Lys82Arg, c.245A>G) mutations were identified in 2 early-onset AD patients and 1 early-onset AD patient, respectively. Three patients with PSEN2 mutations were observed to have PIB retention on the cortex and striatum. One patient with the FTD phenotype was not observed to have PIB retention. Conclusion: PSEN2 mutations are common in the Chinese Han population with a history of AD and FTD. Pathogenic mutations or risk variants in the PSEN2 gene can influence both FTD and AD phenotypic traits and show variations in neuroimaging characterization. © 2014 S. Karger AG, Basel

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Cognitive Deficits in Familial Alzheimer’s Disease Associated with M239V Mutation of Presenilin 2

Cited by 10 publications

References 30 publications

The role of genetics in neurodegenerative dementia: a large cohort study in South China

The role of genetics in neurodegenerative dementia: a large cohort study in South China

Early-Versus Late-Onset Alzheimer's Disease: More than Age Alone

Clinical and Neuroimaging Characterization of Chinese Dementia Patients with <b><i>PSEN1</i></b> and <b><i>PSEN2</i></b> Mutations

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