Background/Purpose: Paget’s disease of bone (PDB) is a metabolic bone disorder whose prevalence increases with age and affects ~3% of Caucasian individuals older than 55 years (1,2). Recent evidence suggests that may be caused by an accumulation of mutations/variants in different genes. In 15 to 30 % of PDB patients, it appears to have an autosomal dominant mode of inheritance but with incomplete penetrance, which makes it often difficult to determine the familiar history due to the high percentage of asymptomatic individuals carrying the mutations. The first gene mutations associated to PDB were identified in the sequestosome1 (SQSTM1) gene at the PDB3 locus (chromosome 5) (3,4). Later, we and others (5,6) have found that PDB6 locus (chromosome 10) was also linked to PDB, including the Optineurin (OPTN) gene, which variant rs1561570 was found to be the most significantly associated with PDB. The aim of this study is to characterize clinically and to investigate the presence of those mutations in PDB patients from the south of Portugal (Algarve and Alentejo).

Methods: This study was approved by the Ethics Committee of University Hospital Center of Algarve, where patients were recruited. In a pilot experiment, the clinical history of 12 patients previously diagnosed with PDB (aged 58 to 81 years old) and 16 healthy controls (aged 47 to 84 years old) was collected and they were also analysed. After DNA extraction from freshly collected biological samples (blood or epithelial swabs), the fragments of interest were amplified by PCR using specific primers for the corresponding loci and the amplified fragments sequenced and compared with the wild type genes.

Results:

PDB patient´s mean age was 70.8±8.2 years. There was a male predominance (10; 83%). There were more patients with the poliostotic form (10; 83%). Three patients (25%) complained about bone pain and that led to the diagnosis of PDB. The others were identified in routine blood tests where alkaline phosphatase (AF) was included.Treatment consisted mainly of zoledronic acid with excellent results in terms of controlling bone pain and AF levels but it wash´t able to avoid some bony deformities, which ocurred in three patients (25%).

The P392L causal mutation of SQSTM1 was detected in one of the patients (8%) without a familial history of PDB and in none of the healthy controls. Our results also showed that the SNP rs1561570 in the OPTN gene had a higher prevalence of allele T in the PDB patients (55%) than in healthy controls (44%) while none of the patients presented the C allele in homozygosity. We have previously shown (7,8) that the presence of the rs1561570 may contribute to PDB since its T allele results in the loss of a methylation site in patients’ DNA, higher levels of OPTN expression in patients’ osteoclasts, higher levels of NF-κB translocation into the nucleus and increasing expression of its target genes, thus contributing to the increased activity of osteoclasts observed in PDB.

Conclusion: The clinical results obtained are in agreement with literature and the genetic study confirm the heterogeneity of PDB and despite the small number of patients so far analyzed the results are in agreement with previous data in terms of type and incidence of mutations in the patients’ population.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/characterization-of-pagets-disease-of-bone-patients-from-the-south-of-portugal-algarve-and-alentejo-clinical-and-genetic-aspects/