Genetic study of familial cases of Alzheimer's disease.

Kowalska, Anna; D, Pruchnik-Wolińska; Florczak, Jolanta; Modestowicz, Renata; Szczech, J; Kozubski, Wojciech; G, Rossa; Wender, M

doi:10.18388/abp.2004_3617

Cited by 29 publications

(10 citation statements)

References 23 publications

(19 reference statements)

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“…The p.L424R (p.Leu424Arg) missense mutation in exon 12 has been described as a pathogenic mutation previously, in one family from Poland [13]. Our patient had a similar age of onset (30-35 years) and his mother had a similar progression to death (4-5 years) as in the described family.…”

Section: Discussionsupporting

confidence: 72%

“…The p.L424R and p.L424H mutations were not present in a panel of 400 Dutch control chromosomes (D. Dooijes, unpublished). P.L424R has been previously described to be completely segregated with FAD in a large Polish family [13]. The PSEN1 p.L424H/F mutations, described in another Polish FAD family, a French family, and a Bulgarian family, affects the same Leucine amino acid residue at position 424 of the PSEN1 protein that is affected by the p.L424R mutation [14][15][16].…”

Section: Discussionmentioning

confidence: 99%

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CSF Studies Facilitate DNA Diagnosis in Familial Alzheimer's Disease Due to a Presenilin-1 Mutation

Bot

Kremer

Dooijes

et al. 2009

JAD

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In sporadic Alzheimer's disease (AD), cerebrospinal fluid (CSF) analysis is becoming increasingly relevant to establish an early diagnosis. We present a case of familial AD due to a presenilin-1 mutation in which CSF studies suggested appropriate DNA diagnostics. A 38 year old Dutch man presented with dementia, spastic paraparesis, and frontal executive function impairments, mimicking familial Creutzfeldt Jakob disease and frontotemporal dementia. CSF studies, revealing increased total tau and phosphorylated-tau levels with decreased amyloid-beta42, distinguished familial AD from Creutzfeldt Jakob disease and frontotemporal dementia. A causative p.L424R PSEN1 mutation was subsequently identified.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

CSF Studies Facilitate DNA Diagnosis in Familial Alzheimer's Disease Due to a Presenilin-1 Mutation

Bot

Kremer

Dooijes

et al. 2009

JAD

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“…The underlying genetic defect remains unknown for the remaining 50% of EOFAD cases, suggesting further genetic and/or etiologic heterogeneity. 19,20 While PS1 mutations are responsible for nearly 75-80 % of genotyped families positive for a mutation, APP and PS2 mutations are responsible for 20-15% and less than 5%, respectively. [3][4][5] The majority of the presenilin mutations are single-nucleotide substitutions, but small deletions and insertions have been described as well (http://www.molgen.…”

Section: Genetic Mutationsmentioning

confidence: 99%

Early-Onset Familial Alzheimer's Disease (EOFAD)

Rosa‐Neto

Hsiung

et al. 2012

Can. J. Neurol. Sci.

176

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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“…Genetic analysis from families has allowed the identification of three genes linked to AD: APP (amyloid precursor protein) [52], located on chromosome 21, PSEN1 (presenilin 1) [53] and PSEN2 [54] located on chromosomes 14 and 1 respectively. Some 85 % of familial EAOD cases correspond to a mutation in the PSEN1 gene, whereas mutations in PSEN2 or APP are much less frequent [55,56] (Figure 6). Today, 157 mutations in PSEN1 and ten in PSEN2 have been described worldwide.…”

Section: Genetics Of Admentioning

confidence: 99%

Mechanisms of neuronal death in disease: defining the models and the players

Ribé

Serrano-Saiz

Akpan

et al. 2008

Biochemical Journal

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Dysregulation of life and death at the cellular level leads to a variety of diseases. In the nervous system, aberrant neuronal death is an outstanding feature of neurodegenerative diseases. Since the discovery of the caspase family of proteases, much effort has been made to determine how caspases function in disease, including neurodegenerative diseases. Although many papers have been published examining caspases in neuronal death and disease, the pathways have not been fully clarified. In the present review, we examine the potential players in the death pathways, the current tools for examining these players and the models for studying neurological disease. Alzheimer's disease, the most common neurodegenerative disorder, and cerebral ischaemia, the most common cause of neurological death, are used to illustrate our current understanding of death signalling in neurodegenerative diseases. A better understanding of the neuronal death pathways would provide targets for the development of therapeutic interventions for these diseases.

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Genetic study of familial cases of Alzheimer's disease.

Cited by 29 publications

References 23 publications

CSF Studies Facilitate DNA Diagnosis in Familial Alzheimer's Disease Due to a Presenilin-1 Mutation

CSF Studies Facilitate DNA Diagnosis in Familial Alzheimer's Disease Due to a Presenilin-1 Mutation

Early-Onset Familial Alzheimer's Disease (EOFAD)

Mechanisms of neuronal death in disease: defining the models and the players

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