Clinical studies in familial VCP myopathy associated with Paget disease of bone and frontotemporal dementia.
Inclusion body myopathy with Paget disease of the bone (PDB) and/or frontotemporal dementia (IBMPFD, OMIM 167320), is a progressive autosomal dominant disorder caused by mutations in the Valousin-containing protein (VCP, p97 or CDC48) gene. IBMPFD can be difficult to diagnose. We assembled data on a large set of families to illustrate the number and type of misdiagnoses that occurred. Clinical analysis of 49 affected individuals in nine families indicated that 42 (87%) of individuals had muscle disease. The majority were erroneously diagnosed with limb girdle muscular dystrophy (LGMD), facioscapular muscular dystrophy, peroneal muscular dystrophy, late adult onset distal myopathy, spinal muscular atrophy, scapuloperoneal muscular dystrophy, or amyotrophic lateral sclerosis (ALS) among others. Muscle biopsies showed rimmed vacuoles characteristic of an inclusion body myopathy in 7 of 18 patients (39%), however, inclusion body myopathy was correctly diagnosed among individuals in only families 5 and 15. Frontotemporal dementia (FTD) was diagnosed in 13 individuals (27%) at a mean age of 57 years (range 48.9-60.2 years); however, several individuals had been diagnosed with Alzheimer disease. Histopathological examination of brains of three affected individuals revealed a pattern of ubiquitin positive neuronal intranuclear inclusions and dystrophic neurites. These families expand the clinical phenotype in IBMPFD, a complex disorder caused by mutations in VCP. The presence of PDB in 28 (57%) individuals suggests that measuring serum alkaline phosphatase (ALP) activity may be a useful screen for IBMPFD in patients with myopathy.
Kimonis
Virginia E
VE
Division of Genetics and Metabolism, Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA. vkimonis@uci.edu
Mehta
Sarju G
SG
Fulchiero
Erin C
EC
Thomasova
Dana
D
Pasquali
Marzia
M
Boycott
Kym
K
Neilan
Edward G
EG
Kartashov
Alex
A
Forman
Mark S
MS
Tucker
Stuart
S
Kimonis
Katerina
K
Mumm
Steven
S
Whyte
Michael P
MP
Smith
Charles D
CD
Watts
Giles D J
GD
D000251:Adenosine Triphosphatases / Q000235:genetics*; D000328:Adult; D018797:Cell Cycle Proteins / Q000235:genetics*; D003430:Cross-Sectional Studies; D003704:Dementia / Q000150:complications* / Q000235:genetics*; D005190:Family; D005260:Female; D006801:Humans; D002479:Inclusion Bodies / Q000648:ultrastructure; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000473:pathology / Q000648:ultrastructure; D009135:Muscular Diseases / Q000150:complications* / Q000235:genetics*; D010001:Osteitis Deformans / Q000150:complications* / Q000235:genetics*; D010375:Pedigree; D012189:Retrospective Studies; D000074405:Valosin Containing Protein
D018797:Cell Cycle Proteins; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein