PMID- 10631141
OWN - NLM
STAT- MEDLINE
DCOM- 20000309
LR  - 20211203
IS  - 0002-9297 (Print)
IS  - 0002-9297 (Linking)
VI  - 66
IP  - 1
DP  - 2000 Jan
TI  - High prevalence of pathogenic mutations in patients with early-onset dementia
      detected by sequence analyses of four different genes.
PG  - 110-7
AB  - Clinical differential diagnosis of early-onset dementia (EOD) includes familial
      Alzheimer disease (FAD) and hereditary prion disease. In both disease entities,
      postmortem brain histopathological examination is essential for unambiguous
      diagnosis. Mutations in the genes encoding the presenilins (PS1 and PS2) and
      amyloid precursor protein (APP) are associated with FAD, whereas mutations in the
      prion protein (PrP) gene are associated with prion disease. To investigate the
      proportion of EOD attributable to known genes, we prospectively (i.e.,
      antemortem) screened these four genes for mutations by sequencing genomic PCR
      products from patients with EOD before age 60 years. Family history for dementia 
      was positive (PFH) in 16 patients, negative (NFH) in 17 patients, and unknown
      (UFH) in 3 patients. In 12 patients, we found five novel mutations (in PS1,
      F105L; in PS2, T122P and M239I; and in PrP, Q160X and T188K) and five previously 
      reported mutations (in APP, in three patients who were most likely unrelated,
      V717I; in PS1, A79V and M139V; and in PrP, P102L and T183A) that are all
      considered to be disease causing. Of these 12 patients, 9 had PFH. This indicates
      a detection rate of 56% (9/16) in patients with PFH. We found two mutations (APP 
      V717I) in two of the three UFH patients, and only one mutation (PrP T188K) in 1
      of the 17 patients with NFH. We conclude that because of the lack of specific
      antemortem diagnostic markers for FAD and hereditary prion disease, all four
      genes should be included in a molecular diagnostic program in patients with EOD
      who had PFH.
FAU - Finckh, U
AU  - Finckh U
AD  - Department of Human Genetics, University Hospital Eppendorf, University of
      Hamburg, Germany. finckh@uke.uni-hamburg.de .
FAU - Muller-Thomsen, T
AU  - Muller-Thomsen T
FAU - Mann, U
AU  - Mann U
FAU - Eggers, C
AU  - Eggers C
FAU - Marksteiner, J
AU  - Marksteiner J
FAU - Meins, W
AU  - Meins W
FAU - Binetti, G
AU  - Binetti G
FAU - Alberici, A
AU  - Alberici A
FAU - Hock, C
AU  - Hock C
FAU - Nitsch, R M
AU  - Nitsch RM
FAU - Gal, A
AU  - Gal A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Am J Hum Genet
JT  - American journal of human genetics
JID - 0370475
RN  - 0 (Amyloid)
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (Membrane Proteins)
RN  - 0 (PRNP protein, human)
RN  - 0 (PSEN1 protein, human)
RN  - 0 (PSEN2 protein, human)
RN  - 0 (Presenilin-1)
RN  - 0 (Presenilin-2)
RN  - 0 (Prion Proteins)
RN  - 0 (Prions)
RN  - 0 (Protein Precursors)
SB  - IM
CIN - Am J Hum Genet. 2000 Oct;67(4):1033-5. PMID: 10986048
MH  - Adult
MH  - Age of Onset
MH  - Aged
MH  - Aged, 80 and over
MH  - Alzheimer Disease/*genetics
MH  - Amyloid/genetics
MH  - Amyloid beta-Protein Precursor/genetics
MH  - DNA Mutational Analysis
MH  - Female
MH  - Humans
MH  - Male
MH  - Membrane Proteins/genetics
MH  - Middle Aged
MH  - Pedigree
MH  - Presenilin-1
MH  - Presenilin-2
MH  - Prion Diseases/*genetics
MH  - Prion Proteins
MH  - Prions
MH  - Protein Precursors/genetics
MH  - Racial Groups
PMC - PMC1288316
EDAT- 2000/01/13 09:00
MHDA- 2000/03/21 09:00
CRDT- 2000/01/13 09:00
PHST- 2000/01/13 09:00 [pubmed]
PHST- 2000/03/21 09:00 [medline]
PHST- 2000/01/13 09:00 [entrez]
AID - S0002-9297(07)62237-X [pii]
AID - 10.1086/302702 [doi]
PST - ppublish
SO  - Am J Hum Genet. 2000 Jan;66(1):110-7. doi: 10.1086/302702.