Browsing by Author "Kimonis, Virginia (7003844615)"

Background Valosin-containing protein (VCP) disease, caused by mutations in the VCP gene, results in myopathy, Paget's disease of bone (PBD) and frontotemporal dementia (FTD). Natural history and genotype-phenotype correlation data are limited. This study characterises patients with mutations in VCP gene and investigates genotype-phenotype correlations. Methods Descriptive retrospective international study collecting clinical and genetic data of patients with mutations in the VCP gene. Results Two hundred and fifty-five patients (70.0% males) were included in the study. Mean age was 56.8±9.6 years and mean age of onset 45.6±9.3 years. Mean diagnostic delay was 7.7±6 years. Symmetric lower limb weakness was reported in 50% at onset progressing to generalised muscle weakness. Other common symptoms were ventilatory insufficiency 40.3%, PDB 28.2%, dysautonomia 21.4% and FTD 14.3%. Fifty-seven genetic variants were identified, 18 of these no previously reported. c.464G>A (p.Arg155His) was the most frequent variant, identified in the 28%. Full time wheelchair users accounted for 19.1% with a median time from disease onset to been wheelchair user of 8.5 years. Variant c.463C>T (p.Arg155Cys) showed an earlier onset (37.8±7.6 year) and a higher frequency of axial and upper limb weakness, scapular winging and cognitive impairment. Forced vital capacity (FVC) below 50% was as risk factor for being full-time wheelchair user, while FVC <70% and being a full-time wheelchair user were associated with death. Conclusion This study expands the knowledge on the phenotypic presentation, natural history, genotype-phenotype correlations and risk factors for disease progression of VCP disease and is useful to improve the care provided to patient with this complex disease. © Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.

Heat shock protein family B (small) member 8 (HSPB8) promotes chaperone-assisted selective autophagy (CASA), which assures proteostasis in muscles and neurons. HSPB8 frameshift mutations found in neuromyopathies are translated on the same frame, generating the same C-terminal extension, which causes HSPB8 aggregation and proteostasis defects. Here, we describe three novel HSPB8 frameshift variants, translated to protein using the third alternative frame to stop codons downstream to the canonical one and to the one used by other known HSPB8 frameshift mutants. Therefore, these variants are predicted to encode a C-terminal extension that is different in length and amino acids. HSPB8 c.562delC and c.520_523delTACT were identified in two unrelated sporadic patients, while c.515delC, in a familial case of early-onset myopathy. Patients may differentially exhibit additional pathological features, such as neuropathy, respiratory insufficiency, and, remarkably, severe cardiomyopathy. Skeletal muscle biopsies revealed variations in fiber size, atrophy, multiple vacuoles, fat infiltration, and eosinophilic inclusions. In a reconstituted cell model of disease the expression of one representative novel HSPB8 mutant results in i) aggregation of the HSPB8 mutant, ii) sequestration of both the HSPB8 wild-type and CASA complex members, as well as iii) the autophagy receptor sequestosome-1 (SQSTM1/p62), iv) accumulation of ubiquitinated substrates, and v) defects in CASA-mediated degradation. Our results prove that the last exon of the HSPB8 gene is highly susceptible to pathogenic mutations, resulting in a wider phenotypic spectrum associated with HSPB8 frameshift variants. Our studies suggest the importance of HSPB8 genetic testing not only for neuropathy and myopathy but also for cardiomyopathy. © The Author(s) 2025.