title: Cerebellar dysfunction in a family harboring the PSEN1 mutation co-segregating with a cathepsin D variant p.A58V.
abstract: Presenile dementia may be caused by a variety of different genetic conditions such as familial Alzheimer's disease, prion disease as well as several hereditary metabolic disorders including adult onset neuronal ceroid lipofuscinosis. We report a multigenerational family with autosomal dominant presenile dementia harboring a cerebellar phenotype. Longitudinal clinical work-up in affected family members revealed ataxia accompanied by progressive cognitive decline, rapid loss of global cognition, memory, visuospatial and frontal-executive functions accompanied by progressive motor deterioration and early death. Linkage analysis and exome sequencing identified the p.S170F mutation of Presenilin 1 in all affected individuals, which is known to be associated with very early onset Alzheimer's disease. Additional search for potentially modifying variants revealed in all affected individuals of the third generation a paternally inherited variant p.A58V (rs17571) of Cathepsin D which is considered an independent risk factor for Alzheimer's disease. Involvement of cerebellar and brainstem structures leading to functional decortication in addition to rapid progressive presenile dementia in this PSEN1 family may therefore indicate an epistatic effect of the p.A58V Cathepsin D variant on the deleterious course of this disease.
authors: Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
authors: Rainer
authors: R
authors: Ehling
authors: Lenka
authors: L
authors: Nosková
authors: Viktor
authors: V
authors: Stránecký
authors: Hana
authors: H
authors: Hartmannová
authors: Anna
authors: A
authors: Přistoupilová
authors: Kateřina
authors: K
authors: Hodaňová
authors: Thomas
authors: T
authors: Benke
authors: Gabor G
authors: GG
authors: Kovacs
authors: Thomas
authors: T
authors: Ströbel
authors: Ulrike
authors: U
authors: Niedermüller
authors: Michaela
authors: M
authors: Wagner
authors: Wolfgang
authors: W
authors: Nachbauer
authors: Andreas
authors: A
authors: Janecke
authors: Herbert
authors: H
authors: Budka
authors: Sylvia
authors: S
authors: Boesch
authors: Stanislav
authors: S
authors: Kmoch
mesh_terms: D000328:Adult; D000544:Alzheimer Disease / Q000175:diagnosis / Q000235:genetics; D002402:Cathepsin D / Q000235:genetics*; D002526:Cerebellar Diseases / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D053764:Presenilin-1 / Q000235:genetics*
chemical_list: C508853:PSEN1 protein, human; D053764:Presenilin-1; C533922:CTSD protein, human; D002402:Cathepsin D