Two Australian families with inclusion-body myopathy, Paget’s disease of bone and frontotemporal dementia: Novel clinical and genetic findings

Kumar, Kishore R.; Needham, Merrilee; Mina, Kym; Davis, Mark; Brewer, Janice; Staples, Christopher; Ng, Karl; Sue, Carolyn M.; Mastaglia, Frank

doi:10.1016/j.nmd.2010.03.002

Cited by 56 publications

(33 citation statements)

References 18 publications

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“…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.…”

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“…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.…”

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confidence: 99%

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Motor neuron involvement in multisystem proteinopathy

et al. 2013

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Objective: To explore the putative connection between inclusion body myopathy, Paget disease, frontotemporal dementia (IBMPFD) and motor neuron disease (MND).Methods: Clinical, genetic, and EMG characterization of 17 patients from 8 IBMPFD families.Results: Limb weakness was the most common clinical manifestation (present in 15 patients, median onset age 38 years, range 25-52), with unequivocal evidence of upper motor neuron dysfunction in 3. EMG, abnormal in all 17, was purely neurogenic in 4, purely myopathic in 6, and mixed neurogenic/myopathic in 7. Cognitive/behavioral impairment was detected in at least 8. Mutations in VCP (R155H, R159G, R155C) were identified in 6 families, and in hnRNPA2B1 (D290V) in another family. The genetic cause in the eighth family has not yet been identified. Conclusion:Mutations in at least 4 genes may cause IBMPFD, and its phenotypic spectrum extends beyond IBM, Paget disease, and frontotemporal dementia (FTD). Weakness, the most common and disabling manifestation, may be caused by muscle disease or MND. The acronym IBMPFD is, therefore, insufficient to describe disorders due to VCP mutations or other recently identified IBMPFD-associated genes. Instead, we favor the descriptor multisystem proteinopathy (MSP), which encompasses both the extended clinical phenotype and the previously described prominent pathologic feature of protein aggregation in affected tissues. The nomenclature MSP1, MSP2, and MSP3 may be used for VCP-, HNRNPA2B1-, and HNRNPA1-associated disease, respectively. Genetic defects in MSP implicate a range of biological mechanisms including RNA processing and protein homeostasis, both with potential relevance to the pathobiology of more common MNDs such as amyotrophic lateral sclerosis (ALS) and providing an additional link between ALS and FTD. Neurology Inclusion body myopathy (IBM) with Paget disease and frontotemporal dementia (IBMPFD) is a rare multisystem degenerative disorder named after the organ systems originally recognized to be affected-muscle, bone, and brain. Mutations in the valosin-containing protein (VCP) gene were the first identified cause of IBMPFD, 1,2 but reports of families without linkage to chromosome 9 established the genetic heterogeneity of the disorder.3,4 It has recently emerged that mutations in the HNRNPA2B1 (chromosome 7) and HNRNPA1 (chromosome 12) genes account for some families with IBMPFD. 5 We first raised the possibility of a connection between IBMPFD and amyotrophic lateral sclerosis (ALS) after mutations in the VCP gene were identified in patients with familial ALS.6 Interestingly, the original report of IBMPFD 7 almost 30 years ago described it as a "familial disorder of combined lower motor neuron degeneration and skeletal disorganization"; the presence of fasciculations, EMG evidence of chronic reinnervation, and muscle biopsy showing grouped atrophy all pointing toward a primarily neurogenic process. This family was subsequently found to have an R155Q mutation in the VCP gene. 8 Since the original description, var...

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Motor neuron involvement in multisystem proteinopathy

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“…[2][3][4][5][6][7][8][9][10][11][12][13][14][15] Recently, a study using whole exome sequencing identified a VCP mutation (p.R191Q) in a family in which some individuals presented clinically with amyotrophic lateral sclerosis (ALS). The frequency of VCP mutations in familial ALS (FALS) patients is estimated at approximately 2%.…”

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Novel mutation in VCP gene causes atypical amyotrophic lateral sclerosis

González-Pérez

Cirulli²,

Drory³

et al. 2012

Neurology

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Objective: To identify the genetic variant that causes autosomal dominantly inherited motor neuron disease in a 4-generation Israeli-Arab family using genetic linkage and whole exome sequencing.Methods: Genetic linkage analysis was performed in this family using Illumina single nucleotide polymorphism chips. Whole exome sequencing was then undertaken on DNA samples from 2 affected family members using an Illumina 2000 HiSeq platform in pursuit of potentially pathogenic genetic variants that comigrate with the disease in this pedigree. Variants meeting these criteria were then screened in all affected individuals.Results: A novel mutation (p.R191G) in the valosin-containing protein (VCP) gene was identified in the index family. Direct sequencing of the VCP gene in a panel of DNA from 274 unrelated individuals with familial amyotrophic lateral sclerosis (FALS) revealed 5 additional mutations. Among them, 2 were previously identified in pedigrees with a constellation of inclusion body myopathy with Paget disease of the bone and frontotemporal dementia (IBMPFD) and in FALS, and 2 other mutations (p.R159C and p.R155C) in IBMPFD alone. We did not detect VCP gene mutations in DNA from 178 cases of sporadic amyotrophic lateral sclerosis. Conclusions:We report a novel VCP mutation identified in an amyotrophic lateral sclerosis family (p.R191G) with atypical clinical features. In our experience, VCP mutations arise in approximately 1.5% of FALS cases. Our study supports the view that motor neuron disease is part of the clinical spectrum of VCP-associated disease.

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“…1,[4][5][6] The variable phenotype is often diagnosed as limb girdle muscular dystrophy, amyotrophic lateral sclerosis (ALS), facioscapular muscular dystrophy, or scapuloperoneal muscular dystrophy. 5,7,8 To date, 31 VCP mutations have been reported in families from several parts of the world, including Germany, 9,10 France, 11 Austria, 12 Italy, 13,14 the United Kingdom, 15 Australia, 16 Brazil, 17 Korea, 18 Japan 19 and the United States. 20,21 VCP mutations have been noted in 2-3% of isolated familial ALS cases, 22 and 10-15% of individuals with hereditary inclusion body myopathy have an ALS-like phenotype characterized as a progressive neurodegenerative disease, involving both upper motor neurons and lower motor neurons.…”

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confidence: 99%

“…VCP, valosin-containing protein; WT, wild-type. Color images available online at www.liebertpub.com/hgtb16 NALBANDIAN ET AL.…”

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Targeted Excision of VCP R155H Mutation by Cre-LoxPTechnology as a Promising Therapeutic Strategy for Valosin-Containing Protein Disease

Nalbandian

Llewellyn

Nguyen

et al. 2015

Human Gene Therapy Methods

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Inclusion body myopathy associated with Paget's disease of the bone and frontotemporal dementia is attributed to mutations in the valosin-containing protein (VCP) gene, mapped to chromosomal region 9p13.3-12. Affected individuals exhibit scapular winging and die from progressive muscle weakness and cardiac and respiratory failure in their 40s to 50s. Mutations in the VCP gene have also been associated with amyotrophic lateral sclerosis in 10-15% of individuals with hereditary inclusion body myopathy and 2-3% of isolated familial amyotrophic lateral sclerosis. Currently, there are no effective treatments for VCP-related myopathy or dementia. To determine the effects of targeted excision of the most common R155H mutation in VCP disease, we generated the Cre-ER™-VCPR155H/+ tamoxifen-inducible model. We administered tamoxifen (0.12 mg/g body weight) or corn oil (vehicle) to the pregnant dams by oral gavage and monitored survival and muscle strength measurements of the pups until 18 months of age. We confirmed efficient removal of exons 4 and 5 and recombination of the mutant/floxed VCP copies by Q-PCR analyses. The activity and specificity of Cre recombinase was confirmed by immunostaining. Herein, we report that Cre-ER™-VCPR155H/+ mice demonstrated improved muscle strength and quadriceps fibers architecture, autophagy signaling pathway, reduced brain neuropathology, decreased apoptosis, and less severe Paget-like bone changes. The Cre-ER™-VCPR155H/+ mouse model provides proof of principle by demonstrating that removal of the mutated exons could be beneficial to patients with VCP-related neurodegenerative diseases, and serves as an excellent platform in understanding the underlying pathophysiological mechanism(s) in the hopes of a promising therapeutic approach.

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Two Australian families with inclusion-body myopathy, Paget’s disease of bone and frontotemporal dementia: Novel clinical and genetic findings

Cited by 56 publications

References 18 publications

Motor neuron involvement in multisystem proteinopathy

Motor neuron involvement in multisystem proteinopathy

Novel mutation in VCP gene causes atypical amyotrophic lateral sclerosis

Targeted Excision of VCP R155H Mutation by Cre-LoxPTechnology as a Promising Therapeutic Strategy for Valosin-Containing Protein Disease

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