Autosomal Dominant Osteopetrosis: A Natural History Study - Abstract NIAMS Natural Hx Proposal Abstract Autosomal dominant osteopetrosis type 2 (ADO2) is a rare osteosclerotic disorder resulting from impaired osteoclastic bone resorption most commonly due to mutations in the Chloride Channel 7 gene, which cause disease by a dominant negative mechanism. Penetrance is approximately 66% and disease severity varies widely. Affected individuals typically have at least one significant clinical manifestation including fractures, osteonecrosis, osteomyelitis, blindness, or bone marrow failure. Ten of our patients have died (out of >80 with clinical manifestations) either of disease manifestations or from attempts at therapy for severe disease. The natural progression of disease manifestations in ADO2 is unknown, although limited data suggests that the disease gets worse with age. Although no effective therapy is currently available, studies in animal models have generated promising data and human trials on are on the horizon. Therefore, it is imperative to understand the natural history of ADO2, including reliable biological markers and relevant patient centered outcomes, to measure therapeutic effect, and to guide the design of clinical trials. The proposed natural history study will establish a cohort of serially phenotyped subjects to capture clinically important outcomes and characterize variations in disease severity, progression of disease, and novel biomarkers for current or future disease severity. The goals of this study are to 1) identify clinically relevant biological and patient-reported outcomes; and 2) use previously obtained data along with data obtained during this 3-year study to determine the natural history of ADO2, including the rate of disease progression. We will focus on the following specific aims: Specific Aim 1: Determine key markers of disease severity and endpoints for a clinical trial. A. Refine and validate a composite clinical severity grading scale. B. Determine which clinical, biological, radiological, and densitometric endpoints best define current disease severity and predict future disease severity and outcomes (combining samples and data obtained in our prior studies with new prospective serial measurements in participating subjects). C. Test the hypothesis that ADO2 disease severity gets worse with age. Specific Aim 2: Expand an electronic patient registry, to collect population-based, longitudinal quality-of-life, pain, disability and other survey-based data from any individual with osteopetrosis, using a secure REDCap platform. This registry will provide 1) long-term follow-up data continuing beyond the completion of this grant, 2) validation of the ADO2 clinical severity grading scale developed in Aim 1, and 3) be an additional ongoing source of potential recruits to future studies using novel therapies.
