Clinical studies in familial VCP myopathy associated with Paget disease of bone and frontotemporal dementia

Abstract

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.

Fig. 1

Pedigrees of IBMPFD families. The filled in top right corner of a symbol represents myopathy, the bottom right corner of a symbol represents Paget disease of the bone (PDB) and the bottom left corner of a symbol represents frontotemporal dementia (FTD).

Fig. 2

Electron microscopy of typical inclusions in IBMPFD muscle, compared with inclusions in Pagetic nuclei. A: Low magnification of inclusions in a nucleus of a Pagetic osteoclast (×20,000). B: High magnification of PHF in a nucleus of a Pagetic osteoclast (×40,000). C: Nuclei almost completely filled with collections of PHF (paired helical filaments), which appear as inclusions by light microscopy (×16,000).

Fig. 3

A: Muscle biopsy from individual III:7, age 47 years from family 15 showed moderately severe chronic-active myopathic changes with numerous fibers showing one or multiple rimmed vacuoles (white arrows). B: A single fiber showing a hyaline sarcoplasmic inclusion (yellow arrow) (H and E staining). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

Fig. 4

Neuropathology of IBMPFD. Frontal neocortex from patient III:6, family 16 was immunostained with antibodies to B-amyloid (A, 4G8), phosphorylated tau (B, PHF1), alpha synuclein (C, Syn303), and ubiquitin (D, Chemicon). A moderate density of predominantly diffuse senile plaques was present throughout the neocortex (A) and there was no tau (B) or Lewy body (C) pathology identified. In contrast, there were abundant ubiquitin positive inclusions (D) that consisted of nuclear inclusions (inset, panel D) and dystrophic neurites with only a low density of cytoplasmic inclusion. Scale bar = 200 μm.