DESCRIPTION (provided by applicant): A member of the Rare Diseases Clinical Research Network (RDCRN), the North American Mitochondrial Disease Consortium (NAMDC) has established a network of nine clinical centers to improve the diagnosis, natural history, and treatment of mitochondrial diseases due to defects of the respiratory chain (RC). Mitochondrial diseases are clinically and genetically heterogeneous due to primary mutations in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). Only through a consortium, acting in close collaboration with a patient advocacy group, the United Mitochondrial Disease Foundation (UMDF) can we address these complex diseases. With support of an NIH American Recovery and Recovery Act (ARRA) grant, NAMDC has already produced a powerful patient registry (partly supported by UMDF), a website for education and recruitment of patients, and essential consensus diagnostic guidelines. This proposal adds careful designs for five clinical studies: two therapeutic trials, to natural history studies, and one pilot study. The 1st therapeutic trial (PI, Michio Hirano, MD, New York, NY) will assess the safety and biomarker efficacy of allogeneic hematopoetic stem cell transplant (AHSCT) in an autosomal recessive fatal disorder of young adults (MNGIE, mitochondrial neurogastrointestinal encephalomyopathy). The 2nd therapeutic trial project (PI, Peter W. Stacpoole, PhD, MD, and Gainesville, FL) evaluates efficacy of dichloroacetate therapy for private dehydrogenase complex (PDC) deficiency, a devastating childhood-onset neurological disease. One natural history study (PI Russell Saneto, OD, PhD, and Seattle, WA) focuses on Alpers syndrome a lethal childhoodonset hepatocerebal disease while the other (Pl Michio Hirano, MD) will study MNGIE to identify clinical outcome measures, which are critical for therapeutic trials. The initial pilot study (PI Juan M. Pascual, MD, PhD, and Dallas, TX) will apply ultra high-field (7T) nuclear magnetic resonance (NMR) spectroscopy to assess metabolites in muscle and brain of patients with mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS). A NAMDC fellowship program (PI, Richard Haas, MD, and San Diego, CA) will train the next generation of mitochondrial disease clinical investigators and a NAMDC biorepository (PI, Devin Oglesbee, PhD, Rochester, MN) will provide essential biological samples for researchers. The Statistical Analysis Center (SAC) directed by Dr. JLP (Seamus) Thompson (New Yogic, NY), in close collaboration with the RDCRN Data Management and Coordinating Center (DMCC), will provide synergistic advanced data management systems and statistical design capabilities to NAMDC Investigators.

As research on the mitochondrial role in human diseases progresses rapidly, the time is ripe for NAMDC, which provides infrastructure, diagnostic capabilities, and conducts rigorous natural history studies and therapeutic trials that are sorely needed for these generally devastating disorders. Furthermore, because mitochondrial dysfunction is thought to contribute to pathogenesis of many common disorders, such as Parkinson disease and diabetes, studies of mitochondrial diseases have broad implications.