scholarly journals Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease

2009 ◽  
Vol 187 (6) ◽  
pp. 875-888 ◽  
Author(s):  
Jeong-Sun Ju ◽  
Rodrigo A. Fuentealba ◽  
Sara E. Miller ◽  
Erin Jackson ◽  
David Piwnica-Worms ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Inclusion Body ◽  
Adenosine Triphosphatase ◽  
Binding Protein ◽  
Paget’S Disease ◽  
Paget's Disease ◽  
Rimmed Vacuoles ◽  
Inclusion Body Myopathy ◽  
Associated Proteins ◽  
In Cells

Mutations in valosin-containing protein (VCP) cause inclusion body myopathy (IBM), Paget's disease of the bone, and frontotemporal dementia (IBMPFD). Patient muscle has degenerating fibers, rimmed vacuoles (RVs), and sarcoplasmic inclusions containing ubiquitin and TDP-43 (TARDNA-binding protein 43). In this study, we find that IBMPFD muscle also accumulates autophagosome-associated proteins, Map1-LC3 (LC3), and p62/sequestosome, which localize to RVs. To test whether VCP participates in autophagy, we silenced VCP or expressed adenosine triphosphatase–inactive VCP. Under basal conditions, loss of VCP activity results in autophagosome accumulation. After autophagic induction, these autophagosomes fail to mature into autolysosomes and degrade LC3. Similarly, IBMPFD mutant VCP expression in cells and animals leads to the accumulation of nondegradative autophagosomes that coalesce at RVs and fail to degrade aggregated proteins. Interestingly, TDP-43 accumulates in the cytosol upon autophagic inhibition, similar to that seen after IBMPFD mutant expression. These data implicate VCP in autophagy and suggest that impaired autophagy explains the pathology seen in IBMPFD muscle, including TDP-43 accumulation.

53. Peripheral axonal hyperpolarisation in Inclusion Body Myopathy, Paget’s disease of the bone and Frontotemporal Dementia (IBMPFD)

2010 ◽  
Vol 17 (12) ◽  
pp. 1626
Author(s):  
Kishore Kumar ◽  
Christina Liang ◽  
Merrilee Needham ◽  
David Burke ◽  
Carolyn Sue ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Inclusion Body ◽  
Paget’S Disease ◽  
Paget's Disease ◽  
Inclusion Body Myopathy

scholarly journals MON-LB70 The Association of Paget’s Disease With Inclusion Body Myositis and Fronto Temporal Dementia (IBMFTD)

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Clare Miller ◽  
Siobhan E Mcquaid
Keyword(s):  
Frontotemporal Dementia ◽  
Inclusion Body ◽  
Vertebral Body ◽  
Bone Scan ◽  
Bone Pain ◽  
Paget’S Disease ◽  
Paget's Disease ◽  
Foot Drop ◽  
Whole Body ◽  
Low Grade

Abstract Background: Inclusion body myopathy associated with Paget disease of bone (PDB) and/or frontotemporal dementia (IBMPFD) is a rare, autosomal dominant condition, characterized by adult-onset muscle weakness, early-onset PDB, and premature frontotemporal dementia. Paget’s disease is a chronic disorder of bone resulting in increased bone resorption, followed by a disorganized and excessive formation of bone. Clinical Case: A 43 year old gentleman was referred to neurology services with foot drop, limb weakness and cognitive impairment. Following a prolonged period of diagnostic evaluation a mutation in valosin-containing protein (VCP) gene was uncovered IBMPFD has a variable phenotype which may include PDB. This gentleman denied bony pain and had an alkaline phosphatase within reference range. Plain film radiographs at multiple sights demonstrated no signs of PDB. An MRI whole body was performed which reported coarse trabecular markings in L2 vertebral body and multilevel degenerative changes with bridging osteophytes in the lumbar spine consistent with PDB. At initial review in endocrine clinic, he denied fractures or bone pain. He had no signs of increased cardiac output or cranial nerve deficits. A radionuclide bone scan identified intense radiopharmaceutical accumulation in L2 vertebral body consistent with MRI findings and also curvilinear increased activity in the left occipital bone and low-grade activity in the left hip, thus confirming polyostotic Paget’s disease. He received a 5mg IV infusion of zolendronate, side effects of which included myalgia, pyrexia and lethargy. Six months following the zoledronate infusion a repeat bone scan demonstrated that the extent of uptake at affected sites had decreased significantly. He subsequently fractured his left femur following a mechanical fall. PDB can affect up to 50% of patients with IBMFTD. PDB can lead to complications such as bone pain, localized pain and deformity of the long bones, pathologic fractures and deafness. This case highlights the association of Paget’s disease with IBMFTD and as it can be asymptomatic, as in our case, radiological imaging is required for diagnosis. It also reminds us that Paget’s disease can be due to genetic causes. Understanding the role of VCP in the cell cycle may help in further understanding bone physiology.

scholarly journals Phenotypic diversity in an international Cure VCP Disease registry

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Chiseko Ikenaga ◽  
Andrew R. Findlay ◽  
Michelle Seiffert ◽  
Allison Peck ◽  
Nathan Peck ◽  
...  
Keyword(s):  
Inclusion Body ◽  
Daily Life ◽  
Phenotypic Diversity ◽  
Paget’S Disease ◽  
Disease Patient ◽  
Paget's Disease ◽  
Paget’S Disease Of Bone ◽  
Patient Registry ◽  
Paget's Disease Of Bone ◽  
Inclusion Body Myopathy

Abstract Background Dominant mutations in valosin-containing protein (VCP) gene cause an adult onset inclusion body myopathy, Paget’s disease of bone, and frontotemporal dementia also termed multisystem proteinopathy (MSP). The genotype-phenotype relationships in VCP-related MSP are still being defined; in order to understand this better, we investigated the phenotypic diversity and patterns of weakness in the Cure VCP Disease Patient Registry. Methods Cure VCP Disease, Inc. was founded in 2018 for the purpose of connecting patients with VCP gene mutations and researchers to help advance treatments and cures. Cure VCP Disease Patient Registry is maintained by Coordination of Rare Diseases at Sanford. The results of two questionnaires with a 5-point Likert scale questions regarding to patients’ disease onset, symptoms, and daily life were obtained from 59 participants (28 males and 31 females) between June 2018 and May 2020. Independent of the registry, 22 patients were examined at the Cure VCP Disease annual patient conference in 2019. Results In the questionnaires of the registry, fifty-three patients (90%) reported that they were with inclusion body myopathy, 17 patients (29%) with Paget’s disease of bone, eight patients (14%) with dementia, two patients (3%) with amyotrophic lateral sclerosis, and a patient with parkinsonism. Thirteen patients (22%) reported dysphagia and 25 patients (42%) reported dyspnea on exertion. A self-reported functional rating scale for motor function identified challenges with sit to stand (72%), walking (67%), and climbing stairs (85%). Thirty-five (59%) patients in the registry answered that their quality of life is more than good. As for the weakness pattern of the 22 patients who were evaluated at the Cure VCP Disease annual conference, 50% of patients had facial weakness, 55% had scapular winging, 68% had upper proximal weakness, 41% had upper distal weakness, 77% had lower proximal, and 64% had lower distal weakness. Conclusions The Cure VCP Disease Patient Registry is useful for deepening the understanding of patient daily life, which would be a basis to develop appropriate clinical outcome measures. The registry data is consistent with previous studies evaluating VCP patients in the clinical setting. Patient advocacy groups are essential in developing and maintaining disease registries.

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