Novel mutations and repeated findings of mutations in familial Alzheimer disease

Finckh, Ulrich; Kuschel, Christian; Anagnostouli, Maria; Patsouris, Efstratios; Pantes, George V.; Gatzonis, Stylianos; Kapaki, Elisabeth; Davaki, Panagiota; Lamszus, Katrin; Stavrou, D; Gal, Andreas

doi:10.1007/s10048-005-0211-x

Cited by 72 publications

(42 citation statements)

References 31 publications

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“…The neurological examination was normal. A brain MRI did not show focal atrophy or other alterations, whereas a slight hypometabolism in bilateral temporal regions was present in an 18 FDG-PET study. EEG standard showed diffuse theta waves mostly represented in temporal regions.…”

Section: Resultsmentioning

confidence: 96%

The London APP Mutation (Val717Ile) Associated with Early Shifting Abilities and Behavioral Changes in Two Italian Families with Early-Onset Alzheimer’s Disease

Talarico

Gasparini

Salati

et al. 2010

Dement Geriatr Cogn Disord

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Background/Aims: Mutations in the amyloid precursor protein gene were the first to be recognized as a cause of Alzheimer’s disease (AD). Methods: We describe 2 Italian families showing the missense mutation in exon 17 of the amyloid precursor protein gene on chromosome 21 (Val717Ile), known as London mutation. Results: In 1 family, this mutation was responsible for AD in 3 out of 7 siblings and it is also present in a fourth sibling who has only shown signs of executive dysfunction so far. Two subjects of the other family with AD diagnosis were carriers of the same mutation. Conclusion: All AD subjects showed a cognitive profile characterized by early impairment in long-term memory, shifting abilities and affective symptoms beginning in the fifth decade of life.

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Section: Resultsmentioning

confidence: 96%

The London APP Mutation (Val717Ile) Associated with Early Shifting Abilities and Behavioral Changes in Two Italian Families with Early-Onset Alzheimer’s Disease

Talarico

Gasparini

Salati

et al. 2010

Dement Geriatr Cogn Disord

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“…There are well-documented cases of Alzheimer disease with proven pathogenic mutations in which symptoms first appeared after 65 years of age in some familial pedigrees of early-onset disease. [27][28][29][30] Early-onset Alzheimer disease and familial Alzheimer disease are not synonymous. Sporadic cases of early-onset Alzheimer disease can occur with no family history and no genetic mutations, and familial late-onset pedigrees can occur with no responsible genes identified.…”

mentioning

confidence: 99%

Diagnosis and treatment of dementia: 1. Risk assessment and primary prevention of Alzheimer disease

Patterson¹,

Feightner²,

García³

et al. 2008

Canadian Medical Association Journal

217

136

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Mr. A, a 45-year-old professional, presents for a routine health check-up, during which he states "I am quite worried about getting Alzheimer disease, just like my mother." He goes on to say "As you know, our family has been caring for her while she slowly deteriorated. A month ago, we had to move her to a long-term care facility. It is really taking a toll on our family. So I want to know what my chances are of escaping this terrible disease. I want to do everything I can to avoid my mother's fate." Mr. A then goes on to say that his mother, who is alive, had her first symptoms of dementia at the age of 74 years. To his knowledge, no other family members, including aunts and uncles, have been affected by dementia. Mr. A is relatively healthy. He has never smoked and rarely drinks alcohol. However, he has been taking medication for hypertension for over a year and has hyperlipi- Methods:We developed evidence-based guidelines using systematic literature searches, with specific criteria for study selection and quality assessment, and a clear and transparent decision-making process. We selected studies published from January 1996 to December 2005 that met the following criteria: dementia (all-cause, Alzheimer disease or vascular dementia) as the outcome; longitudinal cohort study; study population broadly reflective of Canadian demographics; and genetic risk factors and general risk factors (e.g., hypertension, education, occupation and chemical exposure) identified. We graded the strength of evidence using the criteria of the Canadian Task Force on Preventive Health Care.Results: Of 3424 articles on potentially modifiable risk factors for dementia, 1719 met our inclusion criteria; 60 were deemed to be of good or fair quality. Of 1721 articles on genetic risk factors, 62 that met our inclusion criteria were deemed to be of good or fair quality. On the basis of evidence from these articles, we made recommendations for the risk assessment and primary prevention of Alzheimer disease. For the primary prevention of Alzheimer's disease, there is good evidence for controlling vascular risk factors, especially hypertension (grade A), and weak or insufficient evidence for manipulation of lifestyle factors and prescribing of medications (grade C). There is good evidence to avoid estrogens and high-dose (> 400 IU/d) of vitamin E for this purpose (grade E). Genetic counselling and testing may be offered to at-risk individuals with an apparent autosomal dominant inheritance (grade B). Screening for the apolipoprotein E genotype in asymptomatic individuals in the general population is not recommended (grade E).

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“…Evidence for the cosegregation of the mutations with the disease was not proven in all families because no additional patients in the same family were available for DNA analyses. However, the pathological nature of these PSEN1 mutations is supported by the following findings: (1) these mutations were observed in FAD patients of different ethnic backgrounds [12][13][14][15][16] ; (2) these mutations were not found in 100 Japanese normal chromosomes; (3) the mutated amino acids were conserved in human PSEN2 and PSEN1 of other species; (4) expression of these PSEN1 mutants results in an increased production of pathological A ␤ 42 polypeptides in cultured cells. Mutations in MAPT cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) [22] .…”

Section: Discussionmentioning

confidence: 54%

“…The frequency of the PSEN1 mutations was highest in our study, confirming prior reports [1][2][3][19][20][21] . We found 4 different missense PSEN1 mutations: L286V, G378E, L381V, and L392V, all of which were previously reported in other ethnic populations [12][13][14][15][16] . This finding raises the question of whether these mutations in the Japanese pop- Western blotting using ␤ -actin as loading control was also performed (lower panel).…”

Section: Discussionmentioning

confidence: 67%

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Mutational Analysis in Early-Onset Familial Dementia in the Japanese Population

Ikeuchi¹,

Kaneko²,

Miyashita³

et al. 2008

Dement Geriatr Cogn Disord

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Background: Three major causative genes have been implicated as the cause of early-onset familial Alzheimer’s disease (AD): the amyloid precursor protein gene (APP), presenilin-1 (PSEN1) and PSEN2. Although rare, a tau-related dementia with mutations in the microtubule-associated protein tau gene (MAPT) has been identified in patients showing clinical presentations similar to those of AD. Methods: We performed mutational analysis of APP, PSEN1, PSEN2, and MAPT in 10 Japanese families with early-onset dementia clinically diagnosed as probable Alzheimer’s disease. Results: In 4 index patients, we identified 4 missense PSEN1 mutations, namely, L286V, G378E, L381V, and L392V. The mean age at onset in the patients with PSEN1 mutations was 39 years. In 2 families, we found the R406W mutation in MAPT. The mean age at onset of the patients carrying the R406W mutation was 52 years, and they presented with the peculiar AD-like phenotype without apparent behavioral or language problems. Conclusion: These observations suggest that although PSEN1 mutations are the most frequent cause, the MAPT R406W mutation is an important cause of early-onset familial dementia clinically diagnosed as AD. Differentiation of patients with the MAPT mutation from AD patients by genetic testing would be meaningful, considering that a different therapeutic approach should be applied.

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Novel mutations and repeated findings of mutations in familial Alzheimer disease

Cited by 72 publications

References 31 publications

The London APP Mutation (Val717Ile) Associated with Early Shifting Abilities and Behavioral Changes in Two Italian Families with Early-Onset Alzheimer’s Disease

The London APP Mutation (Val717Ile) Associated with Early Shifting Abilities and Behavioral Changes in Two Italian Families with Early-Onset Alzheimer’s Disease

Diagnosis and treatment of dementia: 1. Risk assessment and primary prevention of Alzheimer disease

Mutational Analysis in Early-Onset Familial Dementia in the Japanese Population

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