Summary
The vast majority of families with presenilin (PSEN) mutations have the clinical phenotype of Alzheimer's disease. However, there are reports of patients who carry PSEN mutations and have Alzheimer's disease with a variety of other clinical phenotypes including spastic paraplegia, seizures, myoclonus, parkinsonism, epilepsy and amyloid angiopathy. Remarkably, three of the studied families have frontotemporal dementia (FTD). The mutations associated with FTD are L113P (Raux et al. 2000), Ins R362 (Tang-Wai et al. 2002) and G183V (Dermaut et al. 2004). Raux and colleagues (2000) reported six members from four generations of the SAL family who had early onset FTD. Tang-Wai and colleagues (2002) reported three patients from three generations who had FTD in their 50s and 60s. Dermaut and colleagues (2004) reported a large family from two generations. Three were definitely affected and a total of 12 members were evaluated. Again the disease was of early onset. In all three families, the clinical phenotype was convincingly FTD in nature. In the first two families (L113P and Ins R362), no autopsy was available, but in the third family (G183V), one case had an autopsy and the pathology showed Pick's disease with Pick bodies and no Alzheimer pathology. Usually PSEN1 mutations enhance the γ-secretase effect on the amyloid precursor protein (APP), increasing Aβ42 protein, but a study by Amtul and colleagues (2002) found that the InsR 362 (but not L113P, which they also tested) caused a “dominant negative” effect on the metabolism of APP (and NOTCH), decreasing Aβ42 production. The G183V mutation does not have the same effect. In this family, there are two siblings without the mutation (II-3 age 67 and II-4 age 66) who had abnormal SPECT scans and mild dysexecutive function, and II-3 had anomia and mild MRI atrophy. All of these findings raise the possibility that FTD might not be linked to the G183V mutation. In conclusion, in the families described so far, there is suggestive but not conclusive evidence that PSEN1 mutations can cause FTD.
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Graff-Radford, N.R. (2005). Presenilin Mutations: Variations in the Behavioral Phenotype with an Emphasis on the Frontotemporal Dementia Phenotype. In: Cummings, J.L., Poncet, M., Hardy, J., Christen, Y. (eds) Genotype — Proteotype — Phenotype Relationships in Neurodegenerative Diseases. Research and Perspectives in Alzheimer's Disease. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-26522-8_8
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DOI: https://doi.org/10.1007/3-540-26522-8_8
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