The heritability and genetics of frontotemporal lobar degeneration.
BACKGROUND
Frontotemporal lobar degeneration (FTLD) is a genetically and pathologically heterogeneous neurodegenerative disorder.


METHODS
We collected blood samples from a cohort of 225 patients with a diagnosis within the FTLD spectrum and examined the heritability of FTLD by giving each patient a family history score, from 1 (a clear autosomal dominant history of FTLD) through to 4 (no family history of dementia). We also looked for mutations in each of the 5 disease-causing genes (MAPT, GRN, VCP, CHMP2B, and TARDP) and the FUS gene, known to cause motor neuron disease.


RESULTS
A total of 41.8% of patients had some family history (score of 1, 2, 3, or 3.5), although only 10.2% had a clear autosomal dominant history (score of 1). Heritability varied across the different clinical subtypes of FTLD with the behavioral variant being the most heritable and frontotemporal dementia-motor neuron disease and the language syndromes (particularly semantic dementia) the least heritable. Mutations were found in MAPT (8.9% of the cohort) and GRN (8.4%) but not in any of the other genes. Of the remaining patients without mutations but with a strong family history, 7 had pathologic confirmation, falling into 2 groups: type 3 FTLD-TDP without GRN mutations (6) and FTLD-UPS (1).


CONCLUSIONS
These findings show that frontotemporal lobar degeneration (FTLD) is a highly heritable disorder but heritability varies between the different syndromes. Furthermore, while MAPT and GRN mutations account for a substantial proportion of familial cases, there are other genes yet to be discovered, particularly in patients with type 3 FTLD-TDP without a GRN mutation.
Rohrer
J D
JD
Dementia Research Centre, Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Guerreiro
R
R
Vandrovcova
J
J
Uphill
J
J
Reiman
D
D
Beck
J
J
Isaacs
A M
AM
Authier
A
A
Ferrari
R
R
Fox
N C
NC
Mackenzie
I R A
IR
Warren
J D
JD
de Silva
R
R
Holton
J
J
Revesz
T
T
Hardy
J
J
Mead
S
S
Rossor
M N
MN
D000251:Adenosine Triphosphatases / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D018797:Cell Cycle Proteins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D003704:Dementia / Q000235:genetics* / Q000473:pathology; D056827:Endosomal Sorting Complexes Required for Transport; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D016472:Motor Neuron Disease / Q000235:genetics; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D009483:Neuropsychological Tests; D000077153:Progranulins; D034702:RNA-Binding Protein FUS / Q000235:genetics; D011795:Surveys and Questionnaires; D000074405:Valosin Containing Protein; D016875:tau Proteins / Q000235:genetics*
C503812:CHMP2B protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; C054369:MAPT protein, human; D009419:Nerve Tissue Proteins; D000077153:Progranulins; D034702:RNA-Binding Protein FUS; D016875:tau Proteins; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein