17q-linked frontotemporal dementia-amyotrophic lateral sclerosis without tau mutations with tau and alpha-synuclein inclusions.
BACKGROUND
Frontotemporal dementia (FTD) is a clinically heterogeneous condition that can be associated with clinical manifestations of an extrapyramidal disorder or motor neuron disease. A range of histologic patterns has been described in patients with FTD. The most common familial form of this condition is caused by mutations in the microtubule-associated protein tau gene (MAP tau) and is associated with neuronal or glial tau inclusions.


OBJECTIVE
To determine the clinical, anatomic, and pathological features of San Francisco family A and to map the mutation responsible for disease in this family.


METHODS
A systematic clinical, neuropsychologic, neuroimaging, and chromosome segregation analysis of San Francisco family A was performed. A pathological and biochemical assessment of a family member was made.


METHODS
Family study.


METHODS
San Francisco family A, with FTD, variable extrapyramidal symptoms, and prominent motor neuron disease. Afflicted family members do not have a MAP tau coding or splice regulatory sequence mutation, and the MAP tau is genetically excluded.


METHODS
Comparison of clinical, neuropsychologic, neuroimaging, and linkage findings of San Francisco family A with other familial forms of FTD and amyotrophic lateral sclerosis (ALS).


RESULTS
The most probable location for the mutation responsible for this condition is on chromosome arm 17q, distal to the MAP tau. All previously identified susceptibility loci for FTD and ALS are excluded. Autopsy findings from an afflicted family member show distinctive tau and alpha-synuclein inclusions. Another unique feature is that the insoluble tau protein consists predominantly of the 4R/0N isoform.


CONCLUSIONS
The condition affecting members of San Francisco family A is clinically, pathologically, and genetically distinct from previous familial forms of FTD and ALS.
Wilhelmsen
Kirk C
KC
Ernest Gallo Clinic and Research Center, Emeryville, CA, USA. kirk@med.unc.edu
Forman
Mark S
MS
Rosen
Howard J
HJ
Alving
Loren I
LI
Goldman
Jill
J
Feiger
Jennie
J
Lee
James V
JV
Segall
Samantha K
SK
Kramer
Joel H
JH
Lomen-Hoerth
Catherine
C
Rankin
Katherine P
KP
Johnson
Julene
J
Feiler
Heidi S
HS
Weiner
Michael W
MW
Lee
Virginia M-Y
VM
Trojanowski
John Q
JQ
Miller
Bruce L
BL
D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002886:Chromosomes, Human, Pair 17; D003704:Dementia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism*; D008126:Lod Score; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009460:Neurologic Examination / Q000379:methods; D009483:Neuropsychological Tests; D016133:Polymerase Chain Reaction / Q000379:methods; D020033:Protein Isoforms / Q000378:metabolism; D051843:Synucleins; D051844:alpha-Synuclein; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D016875:tau Proteins