The Implications of the Sequestosome 1 Mutation P392L in Patients with Paget's Disease in a United States Cohort

Paget's disease of bone (PDB) is associated with a germline mutation in Sequestosome1/p62 (SQSTM1) found in <= 16 % of sporadic cases worldwide, and in 19-46 % of those studied with familial PDB. The P392L is the most prevalent mutation identified to date. This mutation by itself does not confer PDB or define the phenotype of PDB in a given person. Environmental determinants remain elusive, although increasing age of the individual, other gene polymorphisms in the context of SQSTM1 mutations, and measles virus have been implicated. Measles exposure has been unexamined in this context. The goal of this study is to compare the background history and phenotype of patients with PDB carrying the SQSTM1 P392L mutation to those patients without. Focusing on age, ancestry, P329L mutation, family history, measles exposure, distribution of PDB, and age of onset, we examined outcomes at 10 years. We postulated that aging may play a role in defining phenotype, and that this may become more visible in a well-characterized cohort. This is an observational study focused on a cohort of patients with PDB drawn from the New England Registry in whom environmental and family history has been catalogued, linked to radiographic data. Of the 217 persons who were enrolled in the Registry, 42 (19 %) responded to a letter inviting them to participate in testing for the presence of the measles antibody, and in genetic testing for the P392L mutation. The mean age of the cohort in 2001 was 70 years (range 55-79); 27 were men (64 %). The measles antibody was found in all cases tested. Nine patients had the P392L mutation (21 %), 2 with familial PDB. In these persons, early diagnosis of disease and spinal stenosis marked the male phenotype only. European ancestry was noted in the minority of those with P392L mutation. Most deaths recorded occurred in the ninth decade of life or later. Spinal stenosis emerges as a prominent phenotype in SQSTM1 P392L-positive men with aging. In these 42 patients with PDB from the New England Registry, most do not carry the SQSTM1 P392L mutation, and many do not have European ancestry. Exposure to measles was confirmed in the majority.