Abstract NIAMS Natural Hx Proposal Abstract Autosomal dominant osteopetrosis type 2 (ADO2) is a rare osteosclerotic disorder resulting from impaired osteoclastic bone resorption 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 (clinical, biochemical, densitometric, or radiographic) and patient-reported outcomes and 2) 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. A. Combine samples and measurements from our prior studies with prospectice serial measurements in participating subjects to determine which clinical, biological, radiological, and densitometric endpoints best define current disease severity and predict future disease severity and outcomes. B. Test the hypothesis that ADO2 disease severity gets worse with age. C. Compare measures obtained in the studies outlined above in patients with the 3 most common mutations in our kindreds (G215R, R286W, and R767W) to identify genotype-phenotype correlations, and whether the individual mutations predict disease severity. Specific Aim 2: Establish an electronic ADO2 patient registry, which will collect population-based, longitudinal quality-of-life, pain, disability and other survey-based data from any individual with osteopetrosis. This registry will serve as a data repository for subjects participating in the research aims above, will provide long-term follow-up data continuing beyond the completion of this grant, and be an ongoing source of potential recruitment to future clinical trials of novel therapies.

Narrative: Autosomal dominant osteopetrosis type 2 (ADO2) is a rare sclerotic bone disorder resulting from impaired osteoclastic bone resorption due to mutations in the Chloride Channel 7 gene. Clinical manifestations include fractures, osteonecrosis (particularly of the jaw), osteomyelitis, blindness, and bone marrow failure. The goals of this natural history study are to 1) identify clinically relevant biological (clinical, biochemical, densitometric, or radiographic) and patient- reported outcomes and 2) determine the natural history of ADO2, including the rate of disease progression, to inform the design of future clinical trials.