Frontotemporal dementia and parkinsonism with the P301S tau gene mutation in a Jewish family.
BACKGROUND
Frontotemporal dementia with parkinsonism linked to chromosome 17q21-22 (FTDP-17) is an autosomal dominant tauopathy manifested by a variable combination of personality changes, cognitive decline and hypokinetic-rigid movement disorder. Significant clinical and pathological heterogeneity of FTDP-17 is related in part to more than 20 different pathogenic mutations identified in the tau gene. Among others, the P301S mutation has been previously reported in three families of European and one of Japanese origin presenting with different clinical phenotypes.


OBJECTIVE
To report a three-generation family of Jewish-Algerian origin with FTDP-17 due to the P301S tau mutation.


METHODS
Clinical, neuropsychological and neuroimaging evaluation of 3 patients, tau genotyping, and pathological study of the proband.


RESULTS
The 3 affected family members had a fairly stereotyped clinical course with early personality changes from their late 30s followed within a period of 1-2 years by a progressive cognitive and motor deterioration eventually leading to a state of akinetic mutism or death 3-5 years after the initial symptoms. The main clinical manifestations included severe dementia and hypokinetic-rigid movement disorder associated with supranuclear gaze impairment, pyramidal signs and frontal release signs. Brain imaging disclosed a variable degree of frontotemporal atrophy, ventriculomegaly and regional cerebral hypoperfusion or glucose hypometabolism. Frontal lobe biopsy in the proband revealed weak tau immunoreactivity in a few cortical neurons, in rare neurites and in some glial cells with no neurofibrillary tangles. Molecular DNA analysis identified a P301S mutation in exon 10 of the tau gene.


CONCLUSIONS
The observed clinical features further expand the reported P301S phenotype and confirm a more aggressive course of the disease than in the other known tau mutations.
Lossos
Alexander
A
The Agnes Ginges Center for Human Neurogenetics, Dept. of Neurology, Hadassah University Hospital, POB 12000, Jerusalem 91120, Israel. ALOS@HADASSAH.ORG.IL
Reches
Avinoam
A
Gal
Aya
A
Newman
Joel P
JP
Soffer
Dov
D
Gomori
John Moshe
JM
Boher
Moshe
M
Ekstein
Dana
D
Biran
Iftah
I
Meiner
Zeev
Z
Abramsky
Oded
O
Rosenmann
Hanna
H
D000328:Adult; D000462:Algeria; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000473:pathology; D004252:DNA Mutational Analysis / Q000379:methods; D003704:Dementia / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005192:Family Health; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000378:metabolism; D007585:Jews / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009460:Neurologic Examination; D009483:Neuropsychological Tests; D020734:Parkinsonian Disorders / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010375:Pedigree; D011392:Proline / Q000235:genetics; D012694:Serine / Q000235:genetics; D015899:Tomography, Emission-Computed, Single-Photon; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
D016875:tau Proteins; D012694:Serine; D011392:Proline