Clinical heterogeneity in 3 unrelated families linked to VCP p.Arg159His.
BACKGROUND
Families associated with missense mutations in the valosin-containing protein (VCP) present with a rare autosomal dominant multisystem disorder of frontotemporal lobar degeneration (FTLD), inclusion body myopathy (IBM), and Paget disease of bone (PDB), referred to as IBMPFD.


METHODS
We used exon-based genomic DNA sequencing to test for VCP mutations in 123 unrelated Belgian patients with FTLD and their relatives, and the absence of such mutations in 157 control individuals. We analyzed haplotype sharing among mutation carriers by genotyping 8 microsatellite markers in the VCP locus. We obtained family history and clinical and pathologic data using established diagnostic instruments.


RESULTS
Mutation analysis of VCP identified 2 Belgian patients with FTLD carrying the p.Arg159His mutation, which segregated in their families. In one family, patients presented with FTLD only, whereas in the other family, patients developed FTLD, PDB, or both without signs of IBM for any of the mutation carriers. We had previously identified p.Arg159His in an Austrian family with patients exhibiting both IBM and PDB. Haplotype sharing analysis indicated that the 3 p.Arg159His families are unrelated. Clinical follow-up of the Austrian family identified dementia symptoms in 1 patient. Autopsy data of 3 patients of the 2 Belgian families revealed FTLD pathology with numerous ubiquitin-immunoreactive, intranuclear inclusions and dystrophic neurites staining positive for TDP-43 protein.


CONCLUSIONS
In 3 unrelated families with IBMPFD segregating VCP p.Arg159His, we observed a high degree of clinical heterogeneity and variable penetrance of the 3 cardinal clinical phenotypes: inclusion body myopathy, Paget disease of bone, and frontotemporal lobar degeneration. In contrast, the neuropathologic phenotype was consistent with FTLD-TDP type 4.
van der Zee
J
J
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, University of Antwerp-CDE, Universiteitsplein 1, B-2610 Antwerpen, Belgium.
Pirici
D
D
Van Langenhove
T
T
Engelborghs
S
S
Vandenberghe
R
R
Hoffmann
M
M
Pusswald
G
G
Van den Broeck
M
M
Peeters
K
K
Mattheijssens
M
M
Martin
J-J
JJ
De Deyn
P P
PP
Cruts
M
M
Haubenberger
D
D
Kumar-Singh
S
S
Zimprich
A
A
Van Broeckhoven
C
C
D000251:Adenosine Triphosphatases / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D001120:Arginine / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D003704:Dementia / Q000175:diagnosis / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D018740:Genetic Heterogeneity; D008040:Genetic Linkage; D006639:Histidine / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics; D018979:Myositis, Inclusion Body / Q000175:diagnosis / Q000235:genetics; D010001:Osteitis Deformans / Q000175:diagnosis / Q000235:genetics; D010375:Pedigree; D019683:Penetrance; D011446:Prospective Studies; D000074405:Valosin Containing Protein
D018797:Cell Cycle Proteins; D006639:Histidine; D001120:Arginine; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein