Familial cases presenting very early onset autosomal dominant Alzheimer’s disease with I143T in presenilin-1 gene: implication for genotype–phenotype correlation

Arai, Noritoshi; Kishino, Atsushi; Takahashi, Yūji; Morita, Daiji; Nakamura, Koichiro; Yokoyama, Takahiro; Watanabe, Toshi; M, Ida; Goto, Jun; Tsuji, Shoji

doi:10.1007/s10048-007-0104-2

Cited by 16 publications

(11 citation statements)

References 8 publications

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“…Abeta accumulation was also high, which suggests that the mutation correlates with PSEN1 dysfunction, leading to disease progression. 55 The clinical phenotype of Japanese patients with the Ile143Thr mutation was similar to that of the Belgian patients. Codon 143 might be an important locus in PSEN1, given that the following additional mutations have been described: Ile143Met, Ile143Phe, Ile143Asn, and Ile143Val, and all of them have been confirmed as pathogenic mutations.…”

Section: App Psen1 and Psenmentioning

confidence: 63%

“… 22 , 47 , 53 , 69 Additional mutations, such as Leu226Phe, Thr116Ile, Met233Thr (Korea), Ile143Thr, and Arg269His (Japan), were also reported in Korea and Japan. 16 , 17 , 27 , 28 , 55 , 66 – 68 In the People’s Republic of China, most of the PSEN1 variants, such as Ile167del, Ser169del, and Leu248Pro, were newly discovered. 12 , 43 , 44 PSEN2 mutation was rare in Asian countries; however, novel Val214Leu, His169Asn, and Asn141Tyr mutations were found.…”

Section: Discussionmentioning

confidence: 99%

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Mutations, associated with early-onset Alzheimer’s disease, discovered in Asian countries

Bagyinszky

Youn

et al. 2016

CIA

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Alzheimer’s disease (AD), the most common form of senile dementia, is a genetically complex disorder. In most Asian countries, the population and the number of AD patients are growing rapidly, and the genetics of AD has been extensively studied, except in Japan. However, recent studies have been started to investigate the genes and mutations associated with AD in Korea, the People’s Republic of China, and Malaysia. This review describes all of the known mutations in three early-onset AD (EOAD) causative genes (APP, PSEN1, and PSEN2) that were discovered in Asian countries. Most of the EOAD-associated mutations have been detected in PSEN1, and several novel PSEN1 mutations were recently identified in patients from various parts of the world, including Asia. Until 2014, no PSEN2 mutations were found in Asian patients; however, emerging studies from Korea and the People’s Republic of China discovered probably pathogenic PSEN2 mutations. Since several novel mutations were discovered in these three genes, we also discuss the predictions on their pathogenic nature. This review briefly summarizes genome-wide association studies of late-onset AD and the genes that might be associated with AD in Asian countries. Standard sequencing is a widely used method, but it has limitations in terms of time, cost, and efficacy. Next-generation sequencing strategies could facilitate genetic analysis and association studies. Genetic testing is important for the accurate diagnosis and for understanding disease-associated pathways and might also improve disease therapy and prevention.

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Section: App Psen1 and Psenmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Mutations, associated with early-onset Alzheimer’s disease, discovered in Asian countries

Bagyinszky

Youn

et al. 2016

CIA

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“…This mutation has previously been reported to cause EOAD both in single unrelated cases, related cases and in two families in which segregation was proven, but clinical, neuropathological, and biochemical details have been lacking. [16][17][18][19][20][21][22][23] The form of EOAD recurring in this family is severe and its mean onset age is reported to be 34 years, whereas the mean age of death is 41.2 years (http://www.molgen.ua.ac.be/ADMutations). Our clinical investigation revealed an aggressive form of AD with rapid progression and extensive myoclonia.…”

Section: Discussionmentioning

confidence: 99%

The PSEN1 I143T mutation in a Swedish family with Alzheimer's disease: clinical report and quantification of Aβ in different brain regions

et al. 2010

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Early-onset dominantly inherited forms of Alzheimer's disease (AD) are rare, but studies of such cases have revealed important information about the disease mechanisms. Importantly, mutations in amyloid precursor protein (APP), presenilin 1 (PSEN1) and PSEN2, alter the APP processing and lead to an increased amyloid b-peptide (Ab) 42/40 ratio. This, together with other studies on pathogenic mechanisms, show that Ab42 is a major player in the etiology of AD. Here, we present a clinical and neuropathological description of a Swedish family with an I143T mutation in the PSEN1 gene, which gives rise to a severe form of AD. We also performed an extensive investigation on the concentration and distribution of Ab species of different lengths in six brain regions from two mutation carriers. Our study showed that Ab42 and a longer peptide, Ab43, were present both in plaque cores and in total amyloid preparations, and were each clearly more frequent than Ab40 in all examined regions, as shown by both mass spectrometry and immunohistochemistry.

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“…64 A literature review disclosed a total of 101 cases of VEOAD from 1934 to 2007 64 , with all for whom conclusive genetic analysis have been done showing PS1 mutations. 42,[64][65][66][67] Very little has been published on the neuropsychological profile in EOFAD with PS1 mutations. 63,68 Although a subcortical pattern of neuropsychological deficits has been noted in some case reports, the cognitive profile has so far predominantly shown amnestic and involved multiple domains.…”

Section: Clinical Spectrum Of Ps1 Mutationsmentioning

confidence: 99%

Early-Onset Familial Alzheimer's Disease (EOFAD)

Rosa‐Neto

Hsiung

et al. 2012

Can. J. Neurol. Sci.

174

135

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436Early-onset familial Alzheimer's disease (EOFAD) is a condition characterized by dementia onset at a relatively young age (before 65 years of age) and a positive family history for dementia. Multiple terminologies such as familial Alzheimer's disease (FAD) 1 , early-onset AD (EOAD) 2 , autosomal dominant AD (ADAD), and autosomal dominant forms of early-onset AD (ADEOAD) 3 have been used to describe similar but overlapping entities. We summarize the complex nosology in Figure 1.Diagnostic criteria have a tremendous impact on the EOFAD epidemiology. If we use the stringent criteria of EOAD as onset of disease at age＜61 years, and ADEOAD as occurrence of EOAD in at least three generations, the prevalence of EOAD and ADEOAD are 41.2 and 5.3 per 100,000 persons, respectively. 3This variable nosology poses a substantive challenge in identifying cases that should undergo predictive genetic testing in asymptomatic individuals for mutations in one of the three identified Alzheimer's disease (AD)-related causal genes, since ABSTRACT: Early-onset familial Alzheimer's disease (EOFAD) is a condition characterized by early onset dementia (age at onset < 65 years) and a positive family history for dementia. To date, 230 mutations in presenilin (PS1, PS2) and amyloid precursor protein (APP) genes have been identified in EOFAD. The mutations within these three genes (PS1/PS2/APP) affect a common pathogenic pathway in APP synthesis and proteolysis, which lead to excessive production of amyloid β. Compared with sporadic Alzheimer's disease (AD), EOFAD has some distinctive features including early age at onset, positive familial history, a variety of non-cognitive neurological symptoms and signs, and a more aggressive course. There is marked phenotypic heterogeneity among different mutations of EOFAD. Studies in presymptomatic mutation carriers reveal biomarkers abnormalities. EOFAD diagnosis is based on clinical and family history, neurological symptoms and examination, biomarker features, as well as genotyping in some cases. New therapeutic agents targeting amyloid formation may benefit EOFAD individuals. RÉSUMÉ: La maladie d'Alzheimer familiale à début précoce. La maladie d'Alzheimer familiale à début précoce (MAFDP) est une maladie caractérisée par une démence à début précoce (âge de début < 65 ans) et une histoire familiale de démence. À ce jour, 230 mutations dans les gènes des présélinines (PS1, PS2) et du précurseur de la protéine amyloïde (APP) ont été identifiées dans la MAFDP. Des mutations de ces 3 gènes (PS1, PS2, APP) touchent une voie pathogène commune dans la synthèse et la protéolyse de l'APP, ce qui entraîne la production excessive de protéine β-amyloïde. La MAFDP comporte des caractéristiques distinctes de la MA sporadique, dont un âge de début précoce, une histoire familiale positive, des symptômes et des signes neurologiques non cognitifs variés et une évolution plus rapide de la maladie. Il existe beaucoup d'hétérogénéité phénotypique parmi les différentes mutations dans la MAFDP. Des études effectuées ch...

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Familial cases presenting very early onset autosomal dominant Alzheimer’s disease with I143T in presenilin-1 gene: implication for genotype–phenotype correlation

Cited by 16 publications

References 8 publications

Mutations, associated with early-onset Alzheimer’s disease, discovered in Asian countries

Mutations, associated with early-onset Alzheimer’s disease, discovered in Asian countries

The PSEN1 I143T mutation in a Swedish family with Alzheimer's disease: clinical report and quantification of Aβ in different brain regions

Early-Onset Familial Alzheimer's Disease (EOFAD)

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Familial cases presenting very early onset autosomal dominant Alzheimer’s disease with I143T in presenilin-1 gene: implication for genotype–phenotype correlation

Cited by 16 publications

References 8 publications

Mutations, associated with early-onset Alzheimer&rsquo;s disease, discovered in Asian countries

Mutations, associated with early-onset Alzheimer&rsquo;s disease, discovered in Asian countries

The PSEN1 I143T mutation in a Swedish family with Alzheimer's disease: clinical report and quantification of Aβ in different brain regions

Early-Onset Familial Alzheimer's Disease (EOFAD)

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Mutations, associated with early-onset Alzheimer’s disease, discovered in Asian countries

Mutations, associated with early-onset Alzheimer’s disease, discovered in Asian countries