1. The Nuts and Bolts of The Energy Pathway Darius J. Adams, M.D. Genetics and Metabolism

2. Diagnostics and Therapeutics

8. Mitochondrial Function ~1200 genes involved in mitochondrial function Combination of: –Nuclear DNA –Mitochondrial DNA 37 genes Reference: http://www.kathleensworld.com/mitochon.html

9. Diagnostics Critical to potential future therapies Nuclear Gene discovery –Autosomal recessive mitochondrial genes –Autosomal dominant mitochondrial genes –X-linked

10. Next Generation Genomic Sequencing Can analyze the coding regions 20,000 genes with one blood test The targeted panels are based on clinical findings –Mito panels now with over 1,200 genes

11. Goals of Treatment Slow or arrest progression of symptoms –Increase mitochondrial ATP production –Support electron transfer –Inhibit free radicals –Stabilize OXPHOS complexes –Avoid drugs capable of affecting the respiratory complexes

12. Management of Mito Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society September 2015 Used the Delphi Process to form consensus based opinions

13. Consensus Statement Sumit Parikh, MD1, Amy Goldstein, MD2, Mary Kay Koenig, MD3, Fernando Scaglia, MD4, Gregory M. Enns, MD5, Russell Saneto, MD, PhD6,7, Irina Anselm, MD8, Bruce H. Cohen, MD9, Marni J. Falk, MD10, Carol Greene, MD11, Andrea L. Gropman, MD12, Richard Haas, MB BChir, MRCP13, Michio Hirano, MD14, Phil Morgan, MD15, Katherine Sims, MD16, Mark Tarnopolsky, MD, PhD17, Johan L.K. Van Hove, MD18, Lynne Wolfe, MS, CRNP19 and Salvatore DiMauro, MD20

14. Enzyme Cofactors

16. Current Cofactor Treatment of Mitochondrial Disorders CoQ10 should be offered to most patients with a diagnosis of mitochondrial disease and not exclusively used for primary CoQ10 deficiency –Reduced CoQ10 (ubiquinol) is the most bioavailable form and, when used, dosing should be appropriately modified –Plasma and/or leukocyte CoQ10 levels are helpful in monitoring absorption and adherence to treatment. Plasma levels are more variable and less reflective of tissue levels.

17. Current Cofactor Treatment of Mitochondrial Disorders ALA and riboflavin should be offered to mitochondrial disease patients Folinic acid should be considered in mitochondrial disease patients with central nervous system manifestations and routinely administered to those with documented CSF deficiency or with disease states known to be associated with deficiency

18. Current Cofactor Treatment of Mitochondrial Disorders L-Carnitine should be administered to mitochondrial disease patients when there is a documented deficiency and levels should be monitored during therapy When beginning supplement therapy, one should begin one at a time when possible, taking into account a patient’s clinical status Exercise

19. Current Cofactor Treatment of Mitochondrial Disorders There is no evidence to suggest that one can adjust a person’s diet on the basis of ETC results Goal levels for most vitamin therapy used are not yet known; it is prudent to replace deficiency states Arginine therapy in MELAS is helpful

20. Medications That Impact Mitochondria AZT (Inhibitor to gamma polymerase) Fialuridine antiviral agent for Treatment of Hepatitis B Valproate, aspirin due to (effect on FAO or CoA sequestration) Nucleoside analogues: didanosine, zalcitabine Lamivudine and famciclovir are permitted Gentamicin and Tetracyclines

21. Conclusion Advancing our diagnostic abilities will allow for the implementation of targeted therapies Nutritional and cofactor interventions continue to be refined and are changing