Clinical phenotype of adult offspring carriers of the p.Pro392Leu mutation within the SQSTM1 gene in Paget's disease of bone

Dessay, Mariam; Gervais, François Jobin; Simonyan, David; Samson, Andréanne; Gleeton, Guylaine; Gagnon, Édith; Albert, Caroline; Brown, Jacques P.; Michou, Laëtitia

doi:10.1016/j.bonr.2020.100717

Cited by 6 publications

(5 citation statements)

References 30 publications

(36 reference statements)

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“…The mechanism of PDB pathogenesis however is similar since previous studies have shown that pathogenic variants in VCP can upregulate the NF-kB signaling pathway leading to upregulated osteoclastogenesis and bone resorption [7] and can therefore contribute to PDB [23,24,27]. Similarly, report of VCP's role in osteoblast activity involves complex regulation of bone morphogenetic protein (BMP) receptors via the VCP mediated ubiquitin/protein degradation system which may play a part in PDB pathogenesis [31,32]. Future studies should be considered to explore any pathological differences between the two entities.…”

Section: Discussionmentioning

confidence: 84%

“…Nevertheless, VCP MSP1 is a rare disease, and this series represents a signi cant addition to the literature. Recent studies have reported intergenerational change of PDB phenotype in general population and those with SQSTM1 mutations [32,36]. In our study, we did not characterize these changes as our cohort is small although we anticipate a subsequent study characterizing the severity of PDB phenotype in MSP1 patients.…”

Section: Discussionmentioning

confidence: 90%

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Bone scan findings of Paget's disease of bone in patients with VCP Multisystem Proteinopathy 1 (MSP1)

Columbres,

Din,

Gibbs

et al. 2023

Preprint

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MSP1 disease is a rare genetic disorder caused by mutations in the Valosin-Containing Protein (VCP) gene with clinical features of inclusion body myopathy (IBM), frontotemporal dementia (FTD), and Paget's disease of bone (PDB). We performed bone scan imaging in twelve patients (6 females, 6 males) with confirmed VCP gene mutation six (50%) of which has myopathy alone, four (33%) with both PDB and myopathy, and two (15%) were presymptomatic carriers. We aim to characterize the PDB in diagnosed individuals, and potentially identify PDB in the myopathy and presymptomatic groups. Interestingly, two patients with previously undiagnosed PDB had positive diagnostic findings from bone scan and subsequent radiograph imaging. Among the individuals with PDB, increased radiotracer uptake of the affected bones were of typical distribution as seen in conventional PDB and those reported in other MSP1 cohorts which are the thoracic spine and ribs (75%), pelvis (75%), shoulder (75%) and calvarium (15%). Overall, we show that technetium-99m bone scans done at regular intervals are a sensitive screening tool in patients with MSP1 associated VCP variants at risk for PDB, and diagnostic confirmation should be correlated with clinical history, biochemical analysis, and skeletal radiographs, to enable early treatment and prevention of complications.

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 90%

Bone scan findings of Paget's disease of bone in patients with VCP Multisystem Proteinopathy 1 (MSP1)

Columbres,

Din,

Gibbs

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Nevertheless, VCP MSP1 is a rare disease, and this series represents a significant addition to the literature. Recent studies have reported intergenerational change of PDB phenotype in general population and those with SQSTM1 mutations 20 , 36 . In our study, we did not characterize these changes as our cohort is small although we anticipate a subsequent study characterizing the severity of PDB phenotype in MSP1 patients.…”

Section: Discussionmentioning

confidence: 99%

“…The mechanism of PDB pathogenesis however is similar since previous studies have shown that pathogenic variants in VCP can upregulate the NF-kB signaling pathway leading to upregulated osteoclastogenesis and bone resorption 7 and can therefore contribute to PDB 16 – 18 . Similarly, report of VCP ’s role in osteoblast activity involves complex regulation of bone morphogenetic protein (BMP) receptors via the VCP mediated ubiquitin/protein degradation system which may play a part in PDB pathogenesis 19 , 20 . Despite the lack of treatment options for the neuromuscular and neurological manifestations of MSP1, treatment of PDB with bisphosphonates is very effective in alleviating bone pain, and preventing deformity and other comorbidities.…”

Section: Introductionmentioning

confidence: 99%

Bone scan findings of Paget’s disease of bone in patients with VCP Multisystem Proteinopathy 1

Columbres,

Din,

Gibbs

et al. 2024

Sci Rep

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Multisystem Proteinopathy 1 (MSP1) disease is a rare genetic disorder caused by mutations in the Valosin-Containing Protein (VCP) gene with clinical features of inclusion body myopathy (IBM), frontotemporal dementia (FTD), and Paget’s disease of bone (PDB). We performed bone scan imaging in twelve patients (6 females, 6 males) with confirmed VCP gene mutation six (50%) of which has myopathy alone, four (33%) with both PDB and myopathy, and two (15%) were presymptomatic carriers. We aim to characterize the PDB in diagnosed individuals, and potentially identify PDB in the myopathy and presymptomatic groups. Interestingly, two patients with previously undiagnosed PDB had positive diagnostic findings on the bone scan and subsequent radiograph imaging. Among the individuals with PDB, increased radiotracer uptake of the affected bones were of typical distribution as seen in conventional PDB and those reported in other MSP1 cohorts which are the thoracic spine and ribs (75%), pelvis (75%), shoulder (75%) and calvarium (15%). Overall, we show that technetium-99m bone scans done at regular intervals are a sensitive screening tool in patients with MSP1 associated VCP variants at risk for PDB. However, diagnostic confirmation should be coupled with clinical history, biochemical analysis, and skeletal radiographs to facilitate early treatment and prevention complications, acknowledging its limited specificity.

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“…However, there is considerable heterogeneity in the clinical manifestations of the disease even in patients with the same mutation, and even within the same family (Laurin et al, 2002;Gennari et al, 2010). Moreover, in keeping with the secular trends, the clinical expressiveness seems to have decreased over time in SQSTM1 mutation carriers, so that the phenotype of PDB is attenuated and less extensive in the more recent generations, and it is delayed by at least 10 years (Bolland et al, 2007;Cundy et al, 2015;Dessay et al, 2020). The reasons for the delayed penetrance of PDB in these offspring remain unknown, but could be likely justified by a reduction in exposure to the putative environmental trigger(s).…”

Section: Sequestosome 1 Genementioning

confidence: 99%

Update on the pathogenesis and genetics of Paget’s disease of bone

Gennari

Rendina

Merlotti

et al. 2022

Front. Cell Dev. Biol.

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Studies over the past two decades have led to major advances in the pathogenesis of Paget’s disease of bone (PDB) and particularly on the role of genetic factors. Germline mutations of different genes have been identified, as a possible cause of this disorder, and most of the underlying pathways are implicated in the regulation of osteoclast differentiation and function, whereas other are involved in cell autophagy mechanisms. In particular, about 30 different germline mutations of the Sequestosome 1 gene (SQSTM1) have been described in a significant proportion of familial and sporadic PDB cases. The majority of SQSTM1 mutations affect the ubiquitin-binding domain of the protein and are associated to a more severe clinical expression of the disease. Also, germline mutations in the ZNF687 and PFN1 genes have been associated to severe, early onset, polyostotic PDB with increased susceptibly to neoplastic degeneration, particularly giant cell tumor. Mutations in the VCP (Valosin Containing Protein) gene cause the autosomal dominant syndrome “Inclusion Body Myopathy, PDB, Fronto-temporal Dementia,” characterized by pagetic manifestations, associated with myopathy, amyotrophic lateral sclerosis and fronto-temporal dementia. Moreover, germline mutations in the TNFRSF11A gene, which encodes for RANK, were associated with rare syndromes showing some histopathological, radiological, and clinical overlap with PDB and in two cases of early onset PDB-like disease. Likewise, genome wide association studies performed in unrelated PDB cases identified other potential predisposition genes and/or susceptibility loci. Thus, it is likely that polygenic factors are involved in the PDB pathogenesis in many individuals and that modifying genes may contribute in refining the clinical phenotype. Moreover, the contribution of somatic mutations of SQSTM1 gene and/or epigenetic mechanisms in the pathogenesis of skeletal pagetic abnormalities and eventually neoplastic degeneration, cannot be excluded. Indeed, clinical and experimental observations indicate that genetic susceptibility might not be a sufficient condition for the clinical development of PDB without the concomitant intervention of viral infection, in primis paramixoviruses, and/or other environmental factors (e.g., pesticides, heavy metals or tobacco exposure), at least in a subset of cases. This review summarizes the most important advances that have been made in the field of cellular and molecular biology PDB over the past decades.

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Clinical phenotype of adult offspring carriers of the p.Pro392Leu mutation within the SQSTM1 gene in Paget's disease of bone

Cited by 6 publications

References 30 publications

Bone scan findings of Paget's disease of bone in patients with VCP Multisystem Proteinopathy 1 (MSP1)

Bone scan findings of Paget's disease of bone in patients with VCP Multisystem Proteinopathy 1 (MSP1)

Bone scan findings of Paget’s disease of bone in patients with VCP Multisystem Proteinopathy 1

Update on the pathogenesis and genetics of Paget’s disease of bone

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