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.

Motor neuron involvement in multisystem proteinopathy

“…5 Although there has been no report of TDP-43 pathology in Pagetoid bone from patients with IBMPFD (perhaps no one has yet looked), ultrastructural analysis of bone from patients with IBMPFD demonstrates tubulofilamentous inclusions similar to the inclusions identifiable in muscle tissue. 1,8,13,25 The role of TDP-43, hnRNPA2B1, and hnRNPA1 in disease pathogenesis is strongly supported by the fact that missense mutations in any of the 3 genes is sufficient to cause ALS or MSP. 5,[26][27][28] The significance of defining the phenotypic overlap between IBMPFD and ALS is best understood in the context of the recent discovery that mutations in HNRNPA2B1 and HNRNPA1 are novel genetic causes of MSP.…”

“…This family was subsequently found to have an R155Q mutation in the VCP gene. 8 Since the original description, various reports of families with IBMPFD have made some reference to ALS, Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.…”

“…8,9 Invariably, these reports overlooked the possible direct connection between VCP mutations and ALS. We have therefore conducted the present study to more clearly define the relationship between IBMPFD and motor neuron disease.…”

“…8 Since the original description, various reports of families with IBMPFD have made some reference to ALS, either explicitly (e.g., by the mention of "family member with ALS") or implicitly (e.g., through clinical and electrophysiologic findings that indicate motor neuron involvement, such as fasciculations, spasticity, hyperreflexia, extensor plantar responses, chronic reinnervation changes on EMG, and prolonged central motor conduction time). 8,9 Invariably, these reports overlooked the possible direct connection between VCP mutations and ALS. We have therefore conducted the present study to more clearly define the relationship between IBMPFD and motor neuron disease.…”

Altered Intersubunit Communication Is the Molecular Basis for Functional Defects of Pathogenic p97 Mutants

“…Although diverse single-amino acid changes in IBMPFD patients at 14 positions of the primary sequence of p97 have been identified (2)(3)(4), no clear correlation has been found between the site/type of mutations and clinical manifestations of the disease; individuals having the same mutation can exhibit different symptoms. Nevertheless, a common pathology found in patient muscle and brain tissues is the accumulation of cytoplasmic proteinous inclusions (1,5), suggesting cellular deficiency in removing unwanted proteins. Progress has been made in in vitro studies using cultured cells expressing IBMPFD p97 mutants, revealing impairment in various protein degradation pathways, including endoplasmic reticulum-associated degradation (6), autophagy (7)(8)(9), and sorting of ubiquitylated cargo in the endocytic pathway (10).…”