Frontal behavioral changes may be the presenting features of single-photon emission tomography (presenilin-1 [PS-1]) mutations, the most common cause of familial Alzheimer's disease (AD). The authors describe a PS-1 (M233L) mutation with the features of frontotemporal dementia (FTD) and review the literature. PS-1 mutations may produce FTD-like phenotypes with the neuropathology of AD. Some PS-1 mutations have additional Pick's bodies, a neuropathological marker of FTD, and a report of a PS-1 (G183V) mutation found Pick's bodies without amyloid plaques. The patient and the literature suggest that PS-1 mutations result in an overlapping continuum of the clinical and neuropathological features of AD and FTD. In PS-1 mutations, the expression of AD or FTD may depend on the degree of loss of function of the PS-1 gene and the resultant tau pathophysiology.
"A large proportion (~20–50%) of FTD cases have a familial component, and mutations in microtubule-associated protein tau and progranulin genes are the most frequent genetic causes (Galimberti and Scarpini, 2010). Interestingly, mutations in the presenilin-1 (PSEN1) and presenilin-2 (PSEN2) genes, which are the major cause of familial AD, have also been implicated in FTD (Mendez and McMurtray, 2006). Since the first identification of the PSEN1 c.338T>C mutation in cases of familial dementia with prominent clinical frontotemporal features (Raux et al., 2000), more than 10 mutations in the PSEN genes have been associated with clinical diagnoses of FTD, in some cases accompanied by frontotemporal atrophy and frontotemporal hypoperfusion on neuroimaging studies (Rippon et al., 2003; Dermaut et al., 2004; Halliday et al., 2005; Zekanowski et al., 2006; Bernardi et al., 2009; de Bot et al., 2009; Marcon et al., 2009; Gallo et al., 2010; Borroni et al., 2011). "
[Show abstract][Hide abstract] ABSTRACT: Mutations in the presenilin-1 (PSEN1) gene are associated with familial Alzheimer's disease and frontotemporal dementia (FTD). Interestingly, neuropathological analysis of a Belgian FTD family carrying a PSEN1 c.548G>T mutation confirmed neurodegeneration in the absence of amyloid plaques. To investigate the impact of the c.548G>T mutation on presenilin-1 (PS1) function in vivo, we introduced this mutation into the genomic Psen1 locus. The resulting c.548G>T knock-in (KI) mice are viable but express markedly lower levels of Psen1 mRNA and protein in the brain. This reduction is due to production of aberrantly spliced transcripts lacking either exon 6 or exons 6 and 7 and their subsequent degradation via non-sense-mediated decay (NMD); inhibition of NMD by cycloheximide treatment stabilized these transcripts and restored the level of Psen1 mRNA in KI/KI brains. Interestingly, the reduction of Psen1 mRNA expression and the degradation of aberrant Psen1 splice products occur exclusively in the brain but not in other tissues. Consistent with decreased Psen1 expression, γ-secretase activity was strongly reduced in the cerebral cortex of KI mice, as measured by de novo γ-secretase-mediated cleavage of APP and Notch. Moreover, PS1 expressed from Psen1 cDNA carrying the c.548G>T mutation displayed normal γ-secretase activity in cultured cells, indicating that the corresponding p.183G>V amino acid substitution does not affect γ-secretase activity. Finally, Psen1 c.548G>T(KI/KI);Psen2(-/-) mice exhibited mild spatial memory deficits in the Morris water maze task. Together, our findings demonstrate that the c.548G>T mutation results in a brain-specific loss of presenilin function due to decreased Psen1 mRNA expression.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 04/2012; 32(15):5085-96. DOI:10.1523/JNEUROSCI.0317-12.2012 · 6.34 Impact Factor
"D'autres mutations, moins fréquentes se situent sur le chromosome 3, gène de CHMP2B (Chromatin Modifying Protein 2B , sur le chromosome 9, gène de VCP (valosin-containing protein) responsable aussi d'une myopathie à inclusions et d'une maladie de Paget osseuse , sur le chromosome 1, gène de TARDBP (transactive response (TAR)-DNA-binding protein) à l'origine de la protéine TDP-43   voire sur le chromosome 16, gène de FUS (Fused in sarcoma) plutôt impliqué dans la SLA . À noter que des phénotypes de DFT ont été décrits dans le cas de mutations PS1 (chromosome 14) à l'origine de maladie d'Alzheimer . "
[Show abstract][Hide abstract] ABSTRACT: Frontotemporal dementias (FTD) are defined by a gradual change in social conduct, behavior and language, associated with frontal and anterior temporal lobe degeneration. The clinicalfeatures depend on the location of the degenerative process. In the last 20 years, increasingly specific and sensitive operational criteria have been established. Ongoing neuropathological and genetic studies have highlighted overlaps between FTD, motor neuron disease, and atypical parkinsonian syndromes (supranuclear palsy, corticobasal degeneration). They have also provided a better knowledge of the pathophysiology of FTD, and new specific therapeutic targets. These dementias, which usually occur before the age of 65 years, are now better recognized but are still underdiagnosed and often initially mistaken for psychiatric illnesses. Healthcare professionals managing these patients must therefore be better informed Serotonergic agents provide a symptomatic improvement, but environmental adaptation, prevention of language and swallowing difficulties, and information and support for the family and caregivers remain essential.
Bulletin de l'Académie nationale de médecine 02/2012; 196(2):431-42; discussion 442-3. · 0.22 Impact Factor
"The family history was unclear. This mutation has been reported several times before (Kwok et al., 1997; Campion et al., 1999; Raux et al., 2005), as other mutations in the same residue (M233L, M233V and M233I) (Aldudo et al., 1999; Houlden et al., 2001; Rogaeva et al., 2001; Mendez and McMurtray, 2006). It alters a conserved residue between PSEN1 and PSEN2 located in the fifth transmembrane domain. "
[Show abstract][Hide abstract] ABSTRACT: Mutations in three genes (PSEN1, PSEN2, and APP) have been identified in patients with early-onset (<65 years) Alzheimer's disease (AD). We performed a screening for mutations in the coding regions of presenilins, as well as exons 16 and 17 of the APP gene in a total of 231 patients from the Iberian peninsular with a clinical diagnosis of early-onset AD (mean age at onset of 52.9 years; range 31-64). We found three novel mutations in PSEN1, one novel mutation in PSEN2, and a novel mutation in the APP gene. Four previously described mutations in PSEN1 were also found. The same analysis was carried in 121 elderly healthy controls from the Iberian peninsular, and a set of 130 individuals from seven African populations belonging to the Centre d'Etude du Polymorphisme Humain-Human Genome Diversity Panel (CEPH-HGDP), in order to determine the extent of normal variability in these genes. Interestingly, in the latter series, we found five new non-synonymous changes in all three genes and a presenilin 2 variant (R62H) that has been previously related to AD. In some of these mutations, the pathologic consequence is uncertain and needs further investigation. To address this question we propose and use a systematic algorithm to classify the putative pathology of AD mutations.
Neurobiology of aging 08/2008; 31(5):725-31. DOI:10.1016/j.neurobiolaging.2008.06.012 · 5.01 Impact Factor
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