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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.
AuthorsRainer Ehling, Lenka Nosková, Viktor Stránecký, Hana Hartmannová, Anna Přistoupilová, Kateřina Hodaňová, Thomas Benke, Gabor G Kovacs, Thomas Ströbel, Ulrike Niedermüller, Michaela Wagner, Wolfgang Nachbauer, Andreas Janecke, Herbert Budka, Sylvia Boesch, Stanislav Kmoch
JournalJournal of the neurological sciences (J Neurol Sci) Vol. 326 Issue 1-2 Pg. 75-82 (Mar 15 2013) ISSN: 1878-5883 [Electronic] Netherlands
PMID23415546 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2013 Elsevier B.V. All rights reserved.
Chemical References
  • PSEN1 protein, human
  • Presenilin-1
  • CTSD protein, human
  • Cathepsin D
Topics
  • Adult
  • Alzheimer Disease (diagnosis, genetics)
  • Cathepsin D (genetics)
  • Cerebellar Diseases (diagnosis, genetics)
  • Female
  • Genetic Variation (genetics)
  • Humans
  • Male
  • Mutation (genetics)
  • Pedigree
  • Presenilin-1 (genetics)

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