Autosomal Dominant Osteopetrosis: A Natural History Study

Design/Aims:The proposed natural history study will establish a cohort of serially phenotyped subjects to capture clinically important and patient centered outcomes to characterize variations in disease severity, progression of disease, and novel biomarkers for current or future disease severity, and will provide a source for recruitment into future therapeutic clinical trials of disease modifying agents.Aim 1: Determine key markers of disease severity and endpoints for a clinical trial. Refine and validate a composite clinical severity grading scale to facilitate future clinical trials. 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 prior studies with new prospective serial measurements in participating subjects) Test the hypothesis that Autosomal dominant osteopetrosis type 2 (ADO2) disease severity gets worse with age. Compare measures obtained in the studies outlined above in patients with the most common mutations in our kindreds to identify genotype-phenotype correlations, and whether the individual mutations predict risk of severe disease. Aim 2: Expand our web-based Osteopetrosis Patient Registry to collect population-based, longitudinal quality-of-life, pain, disability, and other patient reported outcome data, along with disease severity data extracted from medical records. Population Information:Patients who do not have a gene mutation for osteopetrosis may be encouraged to continue to participate in the sample collection portion of the study as controls. Those with a confirmed diagnosis either by gene testing or radiologic evidence will be scheduled for a visit to the clinical site for completion of the physical testing, radiographs, and densitometry if they have consented to participate in that portion of the study. They will also be given the information and option to participate in the registry portion of the study. Nonpenetrant carriers will be included in the study. Study Design:Observational. There is no “final” or “end of study” visit to complete. Patients enrolling in the study may have the opportunity for ongoing participation in extension versions of the natural history study, to improve characterization of disease changes over a longer period of monitoring. Screening will focus on patients and family members from known ADO kindreds. Individuals should have either been diagnosed with osteopetrosis and have a clinical phenotype and/or family history that is consistent with osteopetrosis, have been told that they have an abnormally high bone density (e.g., >2 SD above the mean for age and sex), or a clinical presentation consistent with osteopetrosis. Family members who have not been diagnosed but are at risk for having the gene mutation will be encouraged to participate as well. About a third of patients with Chloride channel 7 mutations that cause osteopetrosis actually are asymptomatic carriers (even though the mutation is dominantly inherited). These persons will also be invited to participate. Inclusion of unaffected carriers is important, as this is necessary to detect what factors differ between carriers and affected patients, which is a critically important research question, and could lead to identification of potential novel therapeutic targets. These kindred groups will initially be identified from the investigators clinical practice as well as former research subjects who have expressed interest in being contacted for additional studies.Data that will be available through dbGaPPhenotypic data]]>
Inclusion CriteriaParticipation in field studies, screening visits, and/or on-site visits involving primarily sample collection and analysis, and collection of patient reported history and questionnaires.• Age ≥1 year of age.• Have a known diagnosis of osteopetrosis (either by gene testing or radiographic confirmation) or be a family member of someone affected by osteopetrosis.• Subjects found during this assessment to not to be a carrier or who do not have osteopetrosis will be eligible to serve as controls.Exclusion Criteria• Conditions that in the opinion of the investigator would interfere with the collection or accuracy of data or put the patient at excessive risk of injury or harm from participation.]]>