Clinical, biochemical, and histopathological data of 49 individuals from nine families with a recently described disorder autosomal dominant proximal myopathy associated with PDB and FTD was analyzed for their usefulness in establishing diagnostic criteria. The CPK levels in affected individuals were only mildly elevated, EMG and muscle biopsies revealed non-specific myopathic changes, and only 39% of muscle biopsies showed rimmed vacuoles and cytoplasmic inclusions characteristic of HIBM, the vast majority of individuals revealing non-specific changes.
In contrast to classic PDB seen in 1–2% of the >50 years population [Klein and Norman, 1995
], the PDB seen in 57% of patients with IBMPFD presented earlier (mean age of 40 years) with typical distribution in the spine, pelvis, and skull and later progression to involve other bones. Elevation of serum ALP was found to be a good indicator of PDB. Fractures were not typically seen except among affected individuals in family 6 with the severe VCP
A232E mutation. The association of familial PDB and neuromuscular disorders is a rare combination, having been reported in a few unrelated families with distinct muscular phenotypes. We have identified the descendants of one family with the familial disorder of combined lower motor neuron degeneration and skeletal disorganization reported by Tucker et al. 
. This family has the VCP
R155Q mutation. At least two of Tucker’s patients with lower motor neuron degeneration and PDB developed dementia as a terminal event. Evaluation of an affected descendant of this family indicates resemblance to members of the other families.
The VCP protein is widely expressed and is a member of the AAA-ATPase super-family [Beyer, 1997
]. It has been implicated in many cellular functions [Wang et al., 2003
; Woodman, 2003
], and is required for the proteasomal degradation of phosphorylated IκB-α [Dai et al., 1998
; Asai et al., 2002
], an essential step in NF-κB activation. Interestingly, the causative mutations in VCP all affect the highly conserved CDC 48 domain, which is involved in ubiquitin-binding [Dai and Li, 2001
; Rape et al., 2001
]. The PDB-causing mutations in the SQSTM1
gene also affect the ubiquitin-binding domain of the gene product, p62 [Layfield and Hocking, 2004
], suggesting that the disease processes in PDB associated with SQSTM1 and IBMPFD may be related [Daroszewska and Ralston, 2006
]. We believe that IBMPFD is currently underdiagnosed among the patients with myopathy and/or dementia. Using an elevated ALP as a screen, with confirmation by radiography or bone scan, should identify more cases of syndromic PDB.
Dementia, mainly of the frontotemporal type, was diagnosed in 27% individuals (mean age of onset 57 years (range 48.9–60.2 years)). The novel pattern of brain histopathology from three individuals from family 16 who were diagnosed with dementia is different from that previously reported for sporadic and familial FTD with ubiquitin inclusions also known as FTLD with motor neuron type inclusions or motor neuron disease inclusion dementia [McKhann et al., 2001
], autosomal-dominant FTD linked to the tau gene on chromosome 17 [Spillantini et al., 1998
], to an unknown gene on chromosome 3 [Brown, 1998
] and the familial corticobasal syndrome associated with mutations in the progranulin gene [Masellis et al., 2006
]. Forman et al. 
analyzed neuropathologic changes in eight patients with VCP
mutations (six with dementia including these three cases from family 16). Characteristic findings include ubiquitin-positive neuronal intranuclear inclusions and dystrophic neurites. There was no biochemical alteration in the VCP protein and only rare intracytoplasmic inclusions were detected with antibodies to VCP in contrast to the reported findings in a 55-year German patient with VCP gene mutations [Schröder et al., 2005
]. The overlap between the histology and composition of the brain protein accumulations in FTD, for example, ubiquitin epitopes, and those found in the muscle fibers of individuals with IBM [Askanas and Engel, 2001
] suggests that cellular deterioration may result from a common cascade of events. Mehta et al. 
studied Apolipoprotein-E (APOE
) as a risk factor for the dementia seen in approximately one-third of patients with IBMPFD based on its known modifier effect in Alzheimer’s disease. They identified a possible association with the presence of one or more alleles of the APOE 4
genotype and FTD (P
= 0.002), but not with IBM (P
= 0.9), or PDB (P
= 0.9). They did not observe an association with FTD and the H2 MAPT haplotype.
The variable presentation of IBMPFD has been noted by other authors. Haubenberger et al. 
discovered a novel missense mutation in VCP
(R159H, 688G>A) in four Austrian siblings, ages ranging from 60 to 70 years, who presented with both progressive proximal myopathy and PDB in whom dementia was excluded in all members by neuropsychological assessment. In contrast, the majority of patients in two French kindreds [Guyant-Marechal et al., 2006
] have been diagnosed with dementia in 100 and 90% of the individuals with a novel R93C missense mutation and a common R155C mutation, respectively. Neuropsychological examination of six affected individuals from the first family identified with dementia was characterized by aggressive behavior, impaired judgment, and paranoia. Fifty percent presented with selectively severe atrophy and symmetric weakness of the proximal and distal muscles of the upper limbs and distal legs (mean age of onset 57 years) and 50% of the patients suffered from PDB at a mean age of onset of 55 years associated with foraminal lumbar stenosis or hearing loss in individuals. In a second family of 30 individuals, previously mistakenly diagnosed with myotonic dystrophy and reported to be linked to chromosome 15q21-24 by Le Ber et al. 
, 10 presented with proximal and axial muscle weakness with clinical and electrical myotonia and associated FTD. Histological analyses confirmed PDB in six individuals. Hepatitis and variable diagnoses of non-specific hepatic fibrosis, cytolysis, and cholestasis was reported.
We hope to increase awareness of this under-diagnosed disorder which shares features with LGMD, FSH, SPMD, late adult onset distal myopathy, spinal muscular atrophy, ALS, and non-specific dementias, among others, suggesting possible underlying common pathogenic mechanisms. An elevated blood ALP may be a useful screen for PDB, which is seen in over half the patients. Testing for VCP
mutations should be considered in any individual with two or more associated features of IBMPFD, or, with one or more features and a suspicious family history. Understanding the basic molecular pathways of VCP disease will hopefully lead to specific therapies as in the case of Paget disease of bone [Deftos, 2005
]. Studying this relatively rare disease has important implications for common disorders such as the muscular dystrophies, myopathies, PDB and related bone disorders and the dementias.