Inclusion body myopathy with paget disease of bone and frontotemporal dementia associated with a novel G156s mutation in the <i>VCP</i> gene

Komatsu, Junji; Iwasa, Kazuo; Yanase, Daisuke; Yamada, Masahito

doi:10.1002/mus.23960

Cited by 17 publications

(6 citation statements)

References 7 publications

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“…70 Consequently, a number of European and Asian cases detailing progressive myopathy with signs and symptoms consistent with FTD have been associated with VCP mutations. 71–77 Of particular note is one study 78 that investigated how the location of VCP gene mutations in 27 families related to the progression and severity of symptoms. Critically, the investigators found that the onset of neurocognitive deterioration foreshadowed a rapid progression of the disease leading to an average life span of 6 years.…”

Section: Familial Frontotemporal Dementia Caused By Frontotemporal Dementioning

confidence: 99%

Frontotemporal dementia: latest evidence and clinical implications

Young

Lavakumar

Tampi

et al. 2017

Therapeutic Advances in Psychopharmacology

126

100

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Background: Frontotemporal dementia (FTD) describes a cluster of neurocognitive syndromes that present with impairment of executive functioning, changes in behavior, and a decrease in language proficiency. FTD is the second most common form of dementia in those younger than 65 years and is expected to increase in prevalence as the population ages. This goal in our review is to describe advances in the understanding of neurobiological pathology, classification, assessment, and treatment of FTD syndromes. Methods: PubMed was searched to obtain reviews and studies that pertain to advancements in genetics, neurobiology, neuroimaging, classification, and treatment of FTD syndromes. Articles were chosen with a predilection to more recent preclinical/clinical trials and systematic reviews. Results: Recent reviews and trials indicate a significant advancement in the understanding of molecular and neurobiological clinical correlates to variants of FTD. Genetic and histopathologic markers have only recently been discovered in the past decade. Current therapeutic modalities are limited, with most studies reporting improvement in symptoms with nonpharmacological interventions. However, a small number of studies have reported improvement of behavioral symptoms with selective serotonin reuptake inhibitor (SSRI) treatment. Stimulants may help with disinhibition, apathy, and risk-taking behavior. Memantine and cholinesterase inhibitors have not demonstrated efficacy in ameliorating FTD symptoms. Antipsychotics have been used to treat agitation and psychosis, but safety concerns and side effect profiles limit utilization in the general FTD population. Nevertheless, recent breakthroughs in the understanding of FTD pathology have led to developments in pharmacological interventions that focus on producing treatments with autoimmune, genetic, and molecular targets. Conclusion: FTD is an underdiagnosed group of neurological syndromes comprising multiple variants with distinct neurobiological profiles and presentations. Recent advances suggest there is an array of potential novel therapeutic targets, although data concerning their effectiveness are still preliminary or preclinical. Further studies are required to develop pharmacological interventions, as there are currently no US Food and Drug administration approved treatments to manage FTD syndromes.

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Section: Familial Frontotemporal Dementia Caused By Frontotemporal Dementioning

confidence: 99%

Frontotemporal dementia: latest evidence and clinical implications

Young

Lavakumar

Tampi

et al. 2017

Therapeutic Advances in Psychopharmacology

126

100

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“…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 UK [ 15 ], Australia [ 16 ], Brazil [ 17 ], Korea [ 18 ], Japan [ 19 ] and the United States [ 20 , 21 ]. Fifteen percent of individuals with hereditary inclusion body myopathy have an ALS-like phenotype and VCP mutations have been noted in 2–3% of isolated familial amyotrophic lateral sclerosis (fALS) cases [ 5 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

Rapamycin and Chloroquine: The In Vitro and In Vivo Effects of Autophagy-Modifying Drugs Show Promising Results in Valosin Containing Protein Multisystem Proteinopathy

et al. 2015

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Mutations in the valosin containing protein (VCP) gene cause hereditary Inclusion body myopathy (hIBM) associated with Paget disease of bone (PDB), frontotemporal dementia (FTD), more recently termed multisystem proteinopathy (MSP). Affected individuals exhibit scapular winging and die from progressive muscle weakness, and cardiac and respiratory failure, typically in their 40s to 50s. Histologically, patients show the presence of rimmed vacuoles and TAR DNA-binding protein 43 (TDP-43)-positive large ubiquitinated inclusion bodies in the muscles. We have generated a VCPR155H/+ mouse model which recapitulates the disease phenotype and impaired autophagy typically observed in patients with VCP disease. Autophagy-modifying agents, such as rapamycin and chloroquine, at pharmacological doses have previously shown to alter the autophagic flux. Herein, we report results of administration of rapamycin, a specific inhibitor of the mechanistic target of rapamycin (mTOR) signaling pathway, and chloroquine, a lysosomal inhibitor which reverses autophagy by accumulating in lysosomes, responsible for blocking autophagy in 20-month old VCPR155H/+ mice. Rapamycin-treated mice demonstrated significant improvement in muscle performance, quadriceps histological analysis, and rescue of ubiquitin, and TDP-43 pathology and defective autophagy as indicated by decreased protein expression levels of LC3-I/II, p62/SQSTM1, optineurin and inhibiting the mTORC1 substrates. Conversely, chloroquine-treated VCPR155H/+ mice revealed progressive muscle weakness, cytoplasmic accumulation of TDP-43, ubiquitin-positive inclusion bodies and increased LC3-I/II, p62/SQSTM1, and optineurin expression levels. Our in vitro patient myoblasts studies treated with rapamycin demonstrated an overall improvement in the autophagy markers. Targeting the mTOR pathway ameliorates an increasing list of disorders, and these findings suggest that VCP disease and related neurodegenerative multisystem proteinopathies can now be included as disorders that can potentially be ameliorated by rapalogs.

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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.…”

Section: Introductionmentioning

confidence: 99%

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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Inclusion body myopathy with paget disease of bone and frontotemporal dementia associated with a novel G156s mutation in the VCP gene

Cited by 17 publications

References 7 publications

Frontotemporal dementia: latest evidence and clinical implications

Frontotemporal dementia: latest evidence and clinical implications

Rapamycin and Chloroquine: The In Vitro and In Vivo Effects of Autophagy-Modifying Drugs Show Promising Results in Valosin Containing Protein Multisystem Proteinopathy

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

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