A novel p.leu(381)phe mutation in presenilin 1 is associated with very early onset and unusually fast progressing dementia as well as lysosomal inclusions typically seen in kufs disease

Whole exome sequencing in a family with suspected dominant Kufs disease identified a novel Presenilin 1 mutation p.Leu(381)Phe in three brothers who, along with their father, developed progressive dementia and motor deficits in their early 30 s. All affected relatives had unusually rapid disease progression (on average 3.6 years from disease onset to death). In silico analysis of mutation p.Leu(381)Phe predicted more detrimental effects when compared to the common Presenilin 1 mutation p.Glu(280)Ala. Electron microscopy study of peripheral fibroblast cells of the proband showed lysosomal inclusions typical for Kufs disease. However, brain autopsy demonstrated typical changes of Alzheimer's disease. Supplementary Material. JAD131340-Suppl.pdf Supplementary Figure 1. A) The superimposed 20 NMR structures of the large domain 1 are shown. The residue Leu(381) is displayed in red; (B) the model of the 3D structure of the small domain 2. The residue Leu(381) is shown in red. JAD131340-Figure S1.TIF