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...

Full description

Saved in:
Bibliographic Details
Published in:Journal of the neurological sciences 2013-03, Vol.326 (1), p.75-82
Main Authors: Ehling, Rainer, Nosková, Lenka, Stránecký, Viktor, Hartmannová, Hana, Přistoupilová, Anna, Hodaňová, Kateřina, Benke, Thomas, Kovacs, Gabor G, Ströbel, Thomas, Niedermüller, Ulrike, Wagner, Michaela, Nachbauer, Wolfgang, Janecke, Andreas, Budka, Herbert, Boesch, Sylvia, Kmoch, Stanislav
Format: Article
Language:English
Subjects:
Adult
Adult neuronal ceroid lipofuscinosis
Alzheimer Disease - diagnosis
Alzheimer Disease - genetics
Alzheimer's disease
Ataxia
Cathepsin D
Cathepsin D - genetics
Cerebellar Diseases - diagnosis
Cerebellar Diseases - genetics
Early onset Alzheimer's disease
Exome sequencing
Female
Genetic Variation - genetics
Humans
Male
Mutation - genetics
Neurology
Pedigree
Presenilin-1 - genetics
Presenilin1
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0022-510X
1878-5883
DOI:10.1016/j.jns.2013.01.017