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Scientific syllabus 2012 umdf


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Convegno UMDF, Giugno 2012

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Scientific syllabus 2012 umdf

  1. 1.   is  proud  to  present... Mitochondrial Medicine 2012: Capitol HillFrom Genomics and Systems Biology to Translation Bethesda North Marriott Hotel & Conference Center 5701 Marinelli Road, Bethesda, MD 20851 Scientific Meetings: June 13-16, 2012 Capitol Hill Advocacy Day: June 14, 2012 2012 Course Chair: Vamsi Mootha, M.D. 2012 CME Chair: Bruce H. Cohen, M.D. A special thanks to those organizations that made this event possible:the Northeast Ohio Medical University, the Mitochondrial Medicine Society, the Mitochondrion/Mitochondria Research Society, and the Mitochondrial Physiology Society
  2. 2. Mitochondrial Medicine 2012: Capitol Hill Scientific Program June 13-16, 2012
  3. 3. Mitochondrial Medicine 2012: Capitol Hill From Genomics and Systems Biology to Translation2012 Course DescriptionThe United Mitochondrial Disease Foundation, the Northeast Ohio Medical University, the MitochondrialMedicine Society, the Mitochondria Research Society, and the Mitochondrial Physiology Society havejoined efforts to sponsor and organize another multidisciplinary symposium. Mitochondrial diseases aremore common than previously recognized, and mitochondrial pathophysiology is now a recognized partof many disease processes, including heart disease, cancer, AIDS, and diabetes. There have been signifi-cant advances in the molecular genetics, proteomics, epidemiology and clinical aspects of mitochondrialpathophysiology. This conference is directed toward the scientist and clinician interested in all aspects ofmitochondrial science.The content of this educational program was determined by rigorous assessment of educational needsand includes surveys, program feedback, expert faculty assessment, literature review, medical practice,chart review and new medical knowledge. The format will include didactic lectures from invited experts in-termixed with peer-reviewed platform presentations. There will be ample time for professional discussionboth in and out of the meeting room, and peer-reviewed poster presentations will be given throughoutthe meeting. This will be a four-day scientific meeting aimed at those with scientific and clinical interests.Accreditation StatementThis activity has been planned and implemented in accordance with the Essential Areas and Policies of theAccreditation Council for Continuing Medical Education (ACCME) and the Accreditation Council for Phar-macy Education (ACPE); through the co/joint sponsorship of Northeast Ohio Medical University and theUnited Mitochondrial Disease Foundation. Northeast Ohio Medical University is accredited by the ACCMEand ACPE to provide continuing education for physicians and pharmacists.CreditsNortheast Ohio Medical University designates this live activity for a maximum of 23.25 AMA PRA Category1 CreditsTM. Physicians should claim only the credits commensurate with the extent of their participation inthe activity.Target AudienceScientists, physicians (neurologists, geneticists, pediatrics/generalists, nephrologists, cardiologists, endo-crinologists), nurses, physician assistants, advanced practice nurses, genetic counselors and allied healthprofessionals.AwardsCash awards of $125, $250, $500 and $1,000 will be given to the top four posters, courtesy of the Mito-chondria Research Society (MRS) and the Mitochondrial Medicine Society (MMS).Grantor AcknowledgementThe Northeastern Ohio Universities Colleges of Medicine and Pharmacy and the United Mitochondrial DiseaseFoundation acknowledge educational grants for partial support of this activity from: The Burroughs WellcomeFund.
  4. 4. Mitochondrial Medicine 2012: Capitol Hill Special AnnouncementsName BadgesAll attendees must wear a name badge to all course functions. At the end of the course, pleasereturn your name badge at the registration desk for recycling.Scientific SessionsAll scientific sessions will be held in the Grand Ballroom D.Refreshment BreaksExhibits will be open in the Ballroom Foyer during all breaks and lunches. Posters will be in SalonsA & B. Abstract presenters are asked to station themselves at their posters during breaks to fieldquestions. Times are as follows: Wednesday (even numbers) at 4:15 p.m. and Thursday (oddnumbers) at 4:30 p.m.LunchLunch will be held in the White Oak Conference Room (lower level) on Wednesday and Thursdayand in Salons E & F (upper level) on Friday and Saturday.Friday Night Banquet and Awards CeremonyScientific and family program attendees are invited to attend the Friday Night Banquet featuringKeynote Speaker, William A. Gahl, M.D., Ph.D., Clinical Director, National Human Genome ResearchInstitute. The reception begins at 6:00 p.m. in the Grand Ballroom Foyer with dinner at 7:00 p.m. inthe Grand Ballroom.Evaluation FormsPlease complete the Participant Course Evaluation Form and return them to the registration deskat the conclusion of the symposium. We appreciate your comments and find your feedback veryuseful for future planning.CME CertificatesPhysicians: All physicians were given a 3-part CME Certificate at Registration. Fully complete, sign,and turn in the carbon copies of the form at the end of the meeting (or upon your departure if youwill not be staying for the duration of the meeting). Keep the WHITE copy for your records. Thisserves as your Credit/Attendance Record.Non-Physicians: All non-physicians were given a 3-part Attendance Certificate at registration.Fully complete, sign, and turn in the carbon copies of the form at the end of the meeting (or uponyour departure if you will not be staying for the duration of the meeting). Keep the WHITE copy foryour records. This serves as your attendance certificate.
  5. 5. Mitochondrial Medicine 2012: Capitol Hill 2012 Scientific Planning CommitteeVamsi Mootha, M.D., Course Chair, Harvard Medical School, Boston, MABruce H. Cohen, M.D., 2012 CME Chair, Akron Children’s Hospital, Akron, OHWilliam C. Copeland, Ph.D., NIEHS, Research Triangle Park, NCErich Gnaiger, Ph.D., Innsbruck Medical University, Innsbruck, AustriaCarla Koehler, Ph.D., University of California Los Angeles, Los Angeles, CAGiovanni Manfredi, M.D., Ph.D., Weill Medical College of Cornell University, New York, NYCarlos Moraes, Ph.D., University of Miami, Miami, FLRobert K. Naviaux, M.D., Ph.D., University of California San Diego, San Diego, CAThomas O’Brien, Ph.D., University of Florida, Gainesville, FLRussell Saneto, D.O., Ph.D., Seattle Children’s Hospital/University of Washington, Seattle, WAPeter Stacpoole, Ph.D., M.D., University of Florida, Gainesville, FLKeshav K. Singh, Ph.D., University of Alabama, Birmingham, AL 2012 Abstract PresentersMikhail Alexeyev, Ph.D., University of South Alabama, Mobile, ALLeonardo Alves, University of California, Irvine/ Children’s Hospital of Philadelphia, Philadelphia, PARenkui Bai, M.D., Ph.D., GeneDx, Gaithersburg, MDPenelope Bonnen, Ph.D., Baylor College of Medicine, Houston, TXNicola Brunetti-Pierri, M.D., Telethon Institute of Genetics and Medicine, Naples, ITCarolyn Buzin, Ph.D ., MEDomics, Azusa, CAAnne Chiaramello, Ph.D., George Washington University Medical Center, Washington, DCJeana DaRe, Ph.D., Transgenomic, New Haven, CTAntonio Davila, JR, University of California - Irvine, Irvine, CAFrancisca Diaz, Ph.D., University of Miami, Miami, FLLisa Emerick, M.D., Baylor College of Medicine, Houston, TXAmy Goldstein, M.D., University of Pittsburgh School of Medicine, Pittsburgh, PASteve Hershman, M.S., Broad Institute of MIT/Harvard, Cambridge, MAVeronica Hinton, Ph.D., Columbia University, New York City, NYTim Koves, Ph.D., Duke University, Durham, NCRan Lin, Research Institute of Children’s Hospital of Philadelphia, Philadelphia, PAChun Shi Lin, University of California - Irvine, Costa Mesa, CAIgal Madar, Ph.D., Johns Hopkins Medical Institutions, Baltimore, MDKasturi Mitra, Ph.D., National Institute of Child Health and Human Development, NIH, Bethesda, MDPhil Morgan, M.D., University of Washington, Seattle, WANeal Sondheimer, M.D., Ph.D., The University of Pennsylvania, Philadelphia, PAPeter Stacpoole, Ph.D., M.D., University of Florida, Gainesville, FLJames Stewart, Ph.D., Max Planck Institute for the Biology of Ageing, Cologne, GermanyAshley Wolf, Mootha Lab, Massachusetts General Hospital, Boston, MAFang Ye, Ph.D., Case Western Reserve University, Cleveland, OHXiaoshan Zhou, Ph.D,. M.D., Karolinska Institutet, Stockholom, Sweden
  6. 6. Mitochondrial Medicine 2012: Capitol Hill 2012 Scientific Meeting FacultyRobert S. Balaban, Ph.D., National Heart Lung and Blood Institute, NIH, Bethesda, MDSarah Calvo, Ph.D., Broad Institute of MIT/Harvard, Cambridge, MAPatrick Chinnery, Ph.D., FRCP, FMedSci, Newcastle University, Newcastle upon Tyne, UKRalph J. DeBerardinis, M.D., Ph.D., University of Texas-Southwestern Medical Center, Dallas, TXGregory M. Enns, MB, ChB, Stanford University Medical Center, Palo Alto, CAMarni J. Falk, M.D., Children’s Hospital of Philadelphia, Philadelphia, PAWilliam Gahl, M.D., Ph.D., National Human Genome Research Institute, NIH, Bethesda, MDMichael W. Gray, Ph.D., Dalhousie University, Halifax, Nova Scotia, CanadaRichard H. Haas, MB, BChir, MRCP, University of California San Diego, San Diego, CARon Haller, M.D., University of Texas-Southwestern Medical Center, Dallas, TXMichio Hirano, M.D., Columbia University Medical Center, New York, NYCharles Hoppel, M.D., Case Western Reserve University, Cleveland, OHVamsi Mootha, M.D., Massachusetts General Hospital, Harvard Medical School, and The Broad Institute,Boston, MADave Pagliarini, Ph.D., University of Wisconsin-Madison, WIJoshua Rabinowitz, M.D., Ph.D., Princeton University, Princeton, NJCurt Scharfe, M.D., Ph.D., Stanford Genome Technology Center, Palo Alto, CAEric A. Shoubridge, Ph.D., Montreal Neurological Institute, Montreal, Quebec, CanadaJan Smeitink, M.D., Ph.D., Nijmegen Center for Mitochondrial Disorders, Nijmegen, The NetherlandsDavid Thorburn, Ph.D., Murdoch Children’s Research Institute, Victoria, AustraliaAkhil B. Vaidya, Ph.D., Drexel University College of Medicine, Philadelphia, PACharles P. Venditti, M.D., Ph.D., National Human Genome Research Institute, NIH, Bethesda, MDJennifer van Eyk, Ph.D., John Hopkins University, Baltimore, MDAnu Suomalainen Wartiovaara, M.D., Ph.D., University of Helsinki, Helsinki, FinlandLee-Jun C. Wong, Ph.D., Baylor College of Medicine, Houston, TX Save the Date! Mitochondrial Medicine 2013: Newport Beach Wednesday, June 12, 2013 thru Saturday, June 15, 2013 Newport Beach Marriott Hotel & Spa 900 Newport Center Drive Newport Beach, CA 92660
  7. 7. Mitochondrial Medicine 2012: Capitol Hill Disclosure of Relevant Financial RelationshipsEveryone involved in the planning, reviewing and teaching of this activity is required to complete adisclosure form indicating all relevant financial relationships with any ‘commercial interest’. A ‘commer-cial interest’ is any entity producing, marketing, reselling, or distributing health care goods or servicesconsumed by, or used on, patients. This is done so that the audience can determine whether an indi-vidual’s relationships may influence the presentations.Renkui Bai, M.D., Ph.D.Employee – GeneDXCarolyn H. Buzin, PhDEmployee – Medomics, LLCBruce Cohen, M.D.Speaker, Consultant – Transgenomic, IncMedical Author and Reviewer – New MentorJeana Dare, Ph.D.Ownership Interest – Transgenomic, IncRalph Deberardinis, M.D.Speaker – Genentech, Agius, Pfizer, Glaxo-Smith ClineConsultant – Calithera, Johnson and JohnsonGregory M. Enns, MB, ChBInvestigator – Edison PharmaceuticalsErich Gnaiger, Ph.D.Owner/Director – Oroboros Instruments CorporationMichio Hirano, M.D.Speaker – Athena DiagnosticsInvestigator – Santhera Pharmaceutical, Edison PharmaceuticalsRobert K Naviaux, M.D., Ph.D.Scientific Founder – Clinical MetabolomicsJoshua Rabinowitz, M.D., Ph.D.Consultant – Kadmon PharmaceuticalsJan Smeitink, M.D., Ph.D.Founder and CEO – Khondrion BV
  8. 8. Mitochondrial Medicine 2012: Capitol Hill Bethesda North Marriott Hotel & Conference Center
  9. 9. Mitochondrial Medicine 2012: Capitol Hill Scientific Program Schedule Day 1: Wednesday, June 13, 2012 Morning Platform Session (1)S Platform Title: Genomics of Mitochondrial Biology 8:00 a.m. Speaker: Vamsi K. Mootha, M.D., Course Chair Topic: Identification of the Calcium Uniporter via ComparativeC Genomics 8:45 a.m. Speaker: Michael W. Gray, Ph.D. Topic: Genomics vs. Proteomics: Two Views of Mitochondrial EvolutionH 9:15 a.m. Speaker: Akhil B. Vaidya, Ph.D. Topic: Remaining Relevant: The Minimalist Mitochondrion of Malaria ParasiteE 9:45 a.m. Break 10:15 a.m. Abstract Presentations (7) 12:00 p.m. LunchD Afternoon Platform Session (2) Platform Title: Mitochondrial Proteomics 2:00 p.m. Speaker: Anu Suomalainen Wartiovaara, M.D., Ph.D.U Topic: Omics Approaches Reveal Novel Tools for Mitochondrial Disease Diagnosis 2:30 p.m. Speaker: Dave Pagliarini, Ph.D. Topic: Proteomic Insights into Mitochondrial Form and FunctionL 3:00 p.m. Speaker: Jennifer van Eyk, Ph.D. Topic: Protein Modifications in the Mitochondria - Driving Heart Disease 3:30 p.m. Abstract Presentations (3)E 4:15 p.m. 6:30 p.m. Break & Poster Sessions (Non CME) Even Numbers Stay at Posters Adjourn NOTE
  10. 10. -Day 2: Thursday, June 14, 2012Day 2:Platformand Metabolomics 2010Morning Thursday, (3)Chemical Biology Session June 17,8:00 a.m. Speaker: Gregory M. Enns, MB, ChB Topic: Redox Biomarkers in Mitochondrial Disease S8:30 a.m. Speaker: Marni J. Falk, M.D. C Topic: Treating Regulatory Signaling Network Changes that Cause the Metabolic Sequelae of Mitochondrial Disease9:00 a.m. Speaker: Joshua Rabinowitz, M.D., Ph.D. Topic: Probing Cytosol-Mitochondrial Interplay via Metabolomics9:30 a.m. Speaker: Ralph J. DeBerardinis, M.D., Ph.D. Topic: The Versatility of Mitochondrial Metabolism in Tumor Cell Growth H10:00 a.m. Break10:30 a.m. Abstract Presentations (6) E12:00 p.m. LunchAfternoon Platform Session (4)Platform Title: Systems Biology and Dynamics D2:00 p.m.2:30 p.m. Speaker: Robert S. Balaban, Ph.D. Topic: The Systems Biology of the Cardiac Mitochondrion Speaker: Curt Scharfe, M.D., Ph.D. U Topic: Genome Technology for Mitochondrial Disease3:00 p.m.3:30 p.m. Abstract Presentations (5) Special Clinical Directors’ Workshop - This session is a new L6:30 p.m. opportunity for clinicians, in an open discussion format, to4:30 p.m. work on day-to-day challenges faced by clinicians in their practices (patient care and systems-related). (Non CME) Break and Posters (Non CME) - Odd Numbers Stay at Posters E Reception and Cash Bar6:30 p.m. AdjournNOTE
  11. 11. Day 3: Friday, June 15, 2012 Morning Platform Session (5) Next-Generation Sequencing of Mitochondrial DiseaseS 8:00 a.m. Speaker: David Thorburn, Ph.D. Topic: MitoExome Sequencing of Children with Mitochondrial Disease 8:30 a.m. Speaker: Lee-Jun C. Wong, Ph.D.C Topic: Challenges of Bringing Next Generation Sequencing Technologies to CLIA/CAP Certified Clinical Laboratories 9:00 a.m. Speaker: Eric A. Shoubridge, Ph.D. Topic: Exome Sequencing of Mitochondrial DisordersH 9:30 a.m. 10:00 a.m. 10:30 a.m. Abstract Presentations (2) Break Speaker: Sarah Calvo, Ph.D.E Topic: Diagnostic Efficacy of Targeted Sequencing in Infantile Versus Adult Mitochondrial Disease 11:00 a.m. Abstract Presentations (5) 12:15 p.m. LunchD Afternoon Platform Session (6) Translational Mitochondrial Medicine 2:00 p.m. Speaker: Patrick Chinnery, Ph.D., FRCP Topic: Monitoring Disease: the Newcastle ApproachU 2:30 p.m. Speaker: Charles P. Venditti, M.D., Ph.D. Topic: The Mitochondropathy of Methylmalonic Acidemia: Definition and Therapeutic Approaches 3:00 p.m. Speaker: Jan Smeitink, M.D., Ph.D.L Topic: Disease Severity Scores and Outcome Measures in Mitochondrial Disease 3:30 p.m. Break 3:45 p.m. Speaker: Michio Hirano, M.D.E 4:15 p.m. Topic: North American Mitochondrial Disease Consortium (NAMDC) UMDF 2012 Funded Grant Projects (Abstracts) 5:30 p.m. Adjourn 6:00 p.m. Reception 7:00 p.m. Friday Night Banquet and Awards Ceremony Keynote Address: William Gahl, M.D., Ph.D. NOTE
  12. 12. -Day 4: Saturday, June 16, 2012Platform Session (7) SClinical Algorithms, Biochemical Testing, Exercise Dx8:00 a.m. Speaker: Charles Hoppel, M.D. Topic: Respiratory Chain Testing8:30 a.m. Speaker: Richard Haas, MB, BChir Topic: Biochemical Profiling in Mitochondrial Disease C9:00 a.m. Speaker: Ron Haller, M.D. H Topic: Exercise Diagnosis9:30 a.m. Speaker: Jan Smeitink, M.D., Ph.D. Topic: Oxidative Phosphorylation Disorders: from Bench to E Bedside10:00 a.m. Break10:15 a.m. Speaker: David Thorburn, Ph.D. Topic: Criteria for Diagnosis of Mitochondrial Disease in the Era of Next Generation Sequencing D10:45 a.m. Speaker: Patrick Chinnery, Ph.D., FRCP U Topic: New Treatments for Mitochondrial Diseases11:15 a.m. Break - pick up boxed lunches and return to seats for panel discussion11:30 a.m. Moderator: Vamsi Mootha, M.D. Panel: Chuck Hoppel, M.D.; Richard Haas, MB, BChir; Ron Haller, M.D.; Jan Smeitink, M.D., Ph.D.; L E Eric Shoubridge, Ph.D.; David Thorburn, Ph.D.; Patrick Chinnery, Ph.D., FRCP; Anu Wartiovaara, M.D., Ph.D. and Lee-Jun Wong, Ph.D. Panel Discussion: How to Incorporate Next Generation Profiles into Routine Clinical Diagnosis1:30 p.m. AdjournmentNOTE
  13. 13. Mitochondrial Medicine 2012: Capitol Hill Abstract: Presentation Schedule Wednesday, June 13, 2012A Platform Session 1: Abstracts 1 10:15 a.m. Mikhail Alexeyev Mutagenesis of mouse mitochondrial DNAB 12 10:30 a.m. Neal Sondheimer Spontaneous Elimination of Mitochondrial Mutations During The Induction of Pluripotency 48 10:45 a.m. Ashley Wolf A systematic search for mitochondrial RNAS processing components 78 11:00 a.m. James Stewart The maternal mtDNA mutation load heavily influences phenotypes in mtDNA mutator miceT 88 93 11:15 a.m. 11:30 a.m. Antonio Davila Steve Hershman Epigenetic Memory in the Mitochondria of Human Embryonic Stem Cells Mutations in MTFMT Underlie a Human Disorder of Formylation Causing ImpairedR Mitochondrial Translation 95 11:45 a.m. Leonardo Alves Leber Hereditary Optic Neuropathy (LHON) associated mutation 3394 is also a high- altitude adaptive polymorphismA Platform Session 2: AbstractsC 16 3:30 p.m. Anne Chiaramello The Neurogenic Basic Helix-Loop-Helix Transcription Factor NeuroD6 Induces Mitochondrial Biogenesis and Bioenergetics in Neuronal CellsT 11 3:45 p.m. Peter Stacpoole Rapid Breath Test for In Vivo Determination of Human Pyruvate Dehydrogenase Complex Activity 70 4:00 p.m. Fang Ye Diagnostic application of MeasuringS Oxidative Phosphorylation in Permeabilized Skin Fibroblasts *All Abstracts are listed in the back of this syllabus.
  14. 14. Thursday, June 14, 2012Platform Session 3: Abstracts#13 Time 10:30 a.m. Presenter Lisa Emerick Title Glucose kinetics in subjects with A MELAS syndrome: interim results45 10:45 a.m. Phil Morgan Specific Hypersensitivity to Volatile Anesthetics in a Mouse Lacking Ndufs4, a Subunit of Mitochondrial Complex I B63 11:00 a.m. Nicola Brunetti-Pierri Phenylbutyrate therapy for pyruvate S dehydrogenase deficiency103 11:15 a.m. Tim Koves Absence of malonyl-CoA decarboxylase (MCD) impacts endurance exercise$250 Cash Award Winner capacity and reprograms skeletal T muscle mitochondrial metabolism20 11:30 a.m. Peter Stacpoole Long-term Safety of Dichloroacetate in Congenital Lactic Acidosis R51 11:45 a.m. Igal Madar In Vivo Localization and Quantification of Mitochondrial Dysfunction Using PET Imaging of the Novel Voltage Sensor 18F-FBnTPPlatform Session 4: Abstracts#15 Time 3:00 p.m. Presenter Xiaoshan Zhou Title Thymidine phosphorylation by transgene expression of the Drosophila melanogaster A nucleoside kinase rescues the pathology C of mitochondrial TK2 deficiency80 3:15 p.m. Kasturi Mitra Mitochondrial fission-fusion activities regulate cell fate determination between$125 Cash Award Winner proliferation and differentiation: a possible T link to tumorigenesis31 3:30 p.m. Lisa Emerick PDHA1 Mutations and Continued Clinical and Genetic Heterogeneity: Are there gender Differences?41 3:45 p.m. Veronica Hinton No Evidence of Cognitive Decline among S Carrier Relatives of MELAS Patients82 4:00 p.m. Ran Lin Inactivation of the Drosophila TSPO Inhibits the mPTP, Increases Longevity, Alters Heme Metabolism and Modulates Mitochondrial Bioenergetics *All Abstracts are listed in the back of this syllabus.
  15. 15. Friday, June 15, 2012 Platform Session 5: AbstractsA # 24 Time 9:30 a.m. Presenter Chun Shi Lin Title A Mouse Model with a Missense Kelsey Wright Cash Award Winner - $1,000 Mutation in ND6 for Pre-Leber’sB Hereditary Optic Neuropathy 43 9:45 a.m. Amy Goldstein Triheptanoin Therapy for Inherited Disorders of Fatty Acid OxidationS 47 11:00 a.m. Jeana DaRe Clinical re-sequencing of over 410 genes to diagnose mitochondrial disorders: Results from the first 78 patients 101 11:15 a.m. Francisca Diaz Metabolic Adaptations in Neurons withT $500 Cash Award Winner Complex IV Deficiency 102 11:30 a.m. Carolyn Buzin NextGen Sequencing of the Complete mtDNA Genome: 20% EstimatedR Positive Cases among a Recent 117 Patients 105 11:45 a.m. Penelope Bonnen Exome sequencing and functional biology reveal novel Mitochondrial Disease genesA 108 12:00 p.m. Renkui Bai Comprehensive Analysis of Entire Mitochondrial Genome by Long-Range PCR and Next Generation Sequencing for the Diagnosis of MitochondrialC Disorders: Yield of 216 CasesTS *All Abstracts are listed in the back of this syllabus.
  16. 16. Mitochondrial Medicine 2012: Capitol Hill Abstract#: Posters* (non-CME)Abstract#:Abstract Title:Abstract#:Abstract Title:Abstract#:Abstract Title:Abstract#:Abstract Title:Abstract#: 7Abstract Title:Abstract#: 8Abstract Title: 3Abstract#: 10Abstract Title:Abstract#: 14Abstract Title:Abstract#: 17Abstract Title:Abstract#: 18Abstract Title:Abstract#:Abstract Title: *All Abstracts are listed in the back of this syllabus.
  17. 17. Abstract#:Abstract Title:Abstract#:Abstract Title:Abstract#:Abstract Title:Abstract#:Abstract Title:Abstract#:Abstract Title:Abstract#:Abstract Title:Abstract#:Abstract Title:Abstract#: 30Abstract Title:Abstract#:Abstract Title:Abstract#:Abstract Title:Abstract#:Abstract Title:Abstract#: 35Abstract Title: *All Abstracts are listed in the back of this syllabus.
  18. 18. Abstract#: 36Abstract Title:Abstract#: 37Abstract Title:Abstract#: 38Abstract Title:Abstract#: 39Abstract Title:Abstract#:Abstract Title:Abstract#:Abstract Title:Abstract#: 44Abstract Title:Abstract#: 46Abstract Title:Abstract#:Abstract Title:Abstract#: 50Abstract Title:Abstract#:Abstract Title:Abstract#: 53Abstract Title:Abstract#:Abstract Title: *All Abstracts are listed in the back of this syllabus.
  19. 19. Abstract#:Abstract Title:Abstract#: 56Abstract Title:Abstract#: 57Abstract Title:Abstract#:Abstract Title:Abstract#: 60Abstract Title:Abstract#:Abstract Title:Abstract#: 64Abstract Title:Abstract#: 65Abstract Title:Abstract#: 66Abstract Title:Abstract#:Abstract Title:Abstract#:Abstract Title:Abstract#:Abstract Title: *All Abstracts are listed in the back of this syllabus.
  20. 20. Abstract#:Abstract Title:Abstract#:Abstract Title:Abstract#:Abstract Title:Abstract#:Abstract Title:Abstract#:Abstract Title:Abstract#:Abstract Title:Abstract#: 79Abstract Title:Abstract#:Abstract Title:Abstract#:Abstract Title:Abstract#:Abstract Title:Abstract#:Abstract Title:Abstract#: 86Abstract Title: SURF1 *All Abstracts are listed in the back of this syllabus.
  21. 21. Abstract#: 87Abstract Title:Abstract#: 90Abstract Title:Abstract#: 91Abstract Title:Abstract#:Abstract Title:Abstract#: 94Abstract Title:Abstract#:Abstract Title:Abstract#: 97Abstract Title:Abstract#:Abstract Title:Abstract#: 106Abstract Title:Abstract#: 107Abstract Title:Abstract#: 109Abstract Title: *All Abstracts are listed in the back of this syllabus.
  22. 22. Abstract#: 110Abstract Title:Abstract#: 111 WangAbstract Title:Abstract#:Abstract Title:Abstract:Abstract Title:Abstract:# Iain HargreavesAbstract Title: MULTIPLE MITOCHONDRIAL ELECTRON TRANSPORT CHAIN ENZYME DEFICIENCIESASSOCIATED WITH A DECREASE IN SKELETAL MUSCLE COENZYME Q10 STATUS *All Abstracts are listed in the back of this syllabus.
  23. 23. Mitochondrial Medicine 2012: Capitol Hill Wednesday, June 13, 2012
  24. 24. Platform Session 1Identification of the Calcium Uniporter via Comparative Genomics
  25. 25. Notes
  26. 26. Author:Institution:Title:
  27. 27. Notes
  28. 28. Platform Session 1 Genomics vs. Proteomics:Two Views of Mitochondrial Evolution
  29. 29. Notes
  30. 30. Author:Institution:Title:
  31. 31. Notes
  32. 32. Platform Session 1 Remaining Relevant:The Minimalist Mitochondrion of Malaria Parasite Akhil B. Vaidya, Ph.D.
  33. 33. Notes
  34. 34. Platform Session 2Omics Approaches Reveal Novel Tools for Mitochondrial Disease Diagnosis Anu Suomalainen Wartiovaara, M.D., Ph.D.
  35. 35. Notes
  36. 36. Platform Session 2 Proteomic Insights intoMitochondrial Form and Function Dave Pagliarini, Ph.D.
  37. 37. Notes
  38. 38. Authors: 1 1 1 3 1 1Institution: 1 3Title:
  39. 39. Notes
  40. 40. Platform Session 2Protein Modifications in the Mitochondria - Driving Heart Disease Jennifer van Eyk, Ph.D.
  41. 41. Notes
  42. 42. Authors:Institution:Title:
  43. 43. Notes
  44. 44. Mitochondrial Medicine 2012: Capitol Hill Thursday, June 14, 2012
  45. 45. Platform Session 3Redox Biomarkers in Mitochondrial Disease Gregory M. Enns, MB, ChB
  46. 46. Notes
  47. 47. in vivo
  48. 48. Notes
  49. 49. Platform Session 3Treating Regulatory Signaling Network Changes that Cause the Metabolic Sequelae of Mitochondrial Disease Marni J. Falk, M.D.
  50. 50. Notes
  51. 51. Authors: 1 1 1 1 1 1 1 1 1 3 3 3 1Institutions: 1 3Title: kd/kd
  52. 52. Notes
  53. 53. Platform Session 3Probing Cytosol-Mitochondrial Interplay via Metabolomics Joshua Rabinowitz, M.D., Ph.D.
  54. 54. Notes
  55. 55. Authors: 1 1Institution: 1Title: 13 14
  56. 56. Notes
  57. 57. Platform Session 3The Versatility of Mitochondrial Metabolism in Tumor Cell Growth Ralph J. DeBerardinis, M.D., Ph.D.
  58. 58. Notes
  59. 59. Authors:Institution:Title:
  60. 60. Notes
  61. 61. Platform Session 4 The Systems Biology ofthe Cardiac Mitochondrion Robert S. Balaban, Ph.D.
  62. 62. Notes
  63. 63. Platform Session 4Genome Technology for Mitochondrial Disease Curt Scharfe, M.D., Ph.D.
  64. 64. Notes
  65. 65. Authors: 1 1 3 1Institutions: 1 3Title:Abstract:
  66. 66. Mitochondrial Medicine 2012: Capitol Hill Friday, June 15, 2012
  67. 67. Platform Session 5MitoExome Sequencing of Children with Mitochondrial Disease David Thorburn, Ph.D.
  68. 68. Notes
  69. 69. Authors: 1 1 4 6 13 7Institutions:13456789 10 1113Title:Abstract:
  70. 70. de novo
  71. 71. Notes
  72. 72. Notes
  73. 73. Platform Session 5Challenges of Bringing Next GenerationSequencing Technologies to CLIA/CAP Certified Clinical Laboratories Lee-Jun C. Wong, Ph.D.
  74. 74. Notes
  75. 75. Authors:Institution:Title:
  76. 76. Notes
  77. 77. Platform Session 5 Exome Sequencing ofMitochondrial Disorders Eric A. Shoubridge, Ph.D.
  78. 78. Notes
  79. 79. Author:Institution:Title:
  80. 80. Notes
  81. 81. Platform Session 5 Diagnostic Efficacy of Targeted Sequencingin Infantile Versus Adult Mitochondrial Disease Sarah Calvo, Ph.D.
  82. 82. Notes
  83. 83. Authors: 4 1 1 1 6 6 1Institutions:13456Title:
  84. 84. Notes
  85. 85. Platform Session 6Monitoring Disease: the Newcastle Approach Patrick Chinnery, Ph.D., FRCP
  86. 86. Notes
  87. 87. Institution:Title:
  88. 88. Notes
  89. 89. Platform Session 6The Mitochondropathy of Methylmalonic Acidemia: Definition and Therapeutic Approaches Charles P. Venditti, M.D., Ph.D.
  90. 90. Notes
  91. 91. Author:Institution:Title:Description:
  92. 92. Notes
  93. 93. Platform Session 6Disease Severity Scores and Outcome Measures in Mitochondrial Disease Jan Smeitink, M.D., Ph.D.
  94. 94. Notes
  95. 95. Authors:Institution:Title:
  96. 96. Notes
  97. 97. North American Mitochondrial Disease Consortium (NAMDC) Michio Hirano, M.D.
  98. 98. Notes
  99. 99. 1Authors: 1 1 3 4 5 6 7 7 8 9 9 10 10 10 11 13 13 14 14 15 16 1Institutions: 1 3 4 5 6 7 8 9 10 11 13 14 15 16Title:
  100. 100. Notes
  101. 101. 2012 UMDF Grant RecipientsM
  102. 102. 2012 UMDF Grant Recipients
  103. 103. 2011 UMDF Grant Recipients Department of Animal Biology,University of Pennsylvania Telethon Institute of Genetics andMedicine, Fondazione Telethon, Rome, Italy Department of PharmacologicalSciences, Stony Book University, New York Department of Neurology,Beth Israel Deaconess Medical Center, Boston mut0
  104. 104. 2010 UMDF Grant Recipients University of British Columbia,Vancouver Johns Hopkins School of Medicine, Baltimore, MD Hospital for Sick Children, Toronto, Canada 2009 UMDF Grant Recipients Institute of Physiology, University of Zurich Medical Research Council Dunn Human NutritionUnit, Cambridge, UK Harvard Medical SchoolRestriction Biochemistry & Biophysics, University ofCalifornia, San Francisco
  105. 105. UMDF Grant Recipients 1998-20082008200720062005
  106. 106. UMDF Grant Recipients 1998-20082004200320022001200019991998
  107. 107. Notes
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  131. 131. Mitochondrial Medicine 2012: Capitol Hill AbstractsAbstract #: 1Presenter: Mikhail AlexeyevAuthors: Mikhail Alexeyev and Rafik FayzulinInstitution: University of South Alabama, 5851 USA Dr North, Mobile, ALTitle: Mutagenesis of mouse mitochondrial DNAMitochondrial diseases can be caused by mutations in both nuclear and mitochondrial DNA (nDNA and mtDNA,respectively) and have estimated prevalence of at least 1:5000. While many anecdotal reports describe positiveprognoses for an occasional patient or patients treated with various vitamins, cofactors or reagents, there is nocure or reliable treatment for these often fatal disorders. Animal (mouse) models of human disease are instru-mental in developing and testing new therapeutic modalities. Although the development of mouse modelsof human mitochondrial diseases caused by mutations in nuclear DNA is relatively straightforward, the routinedevelopment of animal models for the diseases caused by mtDNA mutations is not yet feasible. Recently, severalgroups demonstrated their ability to transfer mutant mtDNA from cultured cells into mice thus creating transmi-tochondrial mice. However, routine modeling of mitochondrial disorders caused by mtDNA mutations remainslimited by the unavailability of a reliable supply of mouse cell lines bearing mutations in mtDNA. To date, somemutations in mouse mtDNA were isolated employing selection for resistance to various inhibitors, or by chemi-cal mutagenesis. These strategies are inherently biased (e.g., by the spectrum of mtDNA mutations that can beinduced by a given mutagen), and do not allow for the isolation of the full spectrum of mtDNA mutations. Wedeveloped a mtDNA mutagenesis strategy that utilizes proofreading-deficient mutant of the mitochondrialDNA-polymerase gamma (mPolGexo-). Mouse cells are engineered for inducible (Tet-On) expression of the floxedmPolGexo-. These cells are induced with doxycycline, and mutagenesis is terminated at about one mutation permtDNA by excising mPolGexo- with Cre recombinase. Following excision, cells are subjected to depletion to alevel of about one mtDNA molecule per cell followed by repletion to normal copy number and cloning. Resultingclones are expanded and their mtDNA is sequenced to determine the nature of the mutation. The distribution ofmutations obtained using this technique is fairly unbiased, which enables systematic mutagenesis and genera-tion of banks of mtDNA mutations, which may be useful for both modeling of the human mitochondrial diseasein mice and for the functional analysis of the Electron Transfer Chain. Using this approach, we isolated more than40 homoplasmic mouse cell lines with single homoplasmic nonsynonymous substitutions in mtDNA. This ex-ceeds the combined number of similar cell lines generated to date using all other approaches.Abstract #: 3Presenter: Saskia KoeneAuthors: Saskia Koene1, Saskia Wortmann1, Eva Morava1, Maaike de Vries1, Jan Smeitink1Institution: 1 Nijmegen Centre for Mitochondrial Disorders, Radboud University Nijmegen Medical Centre, Geert Grooteplein 10, 6500 HB, PO BOX 9101, Nijmegen, The NetherlandsTitle: Optimizing patient care and outcome measures: which complaints are most burdensome to patientsand their parents?Body of Abstract:To optimize patient care and to target supportive care efficiently, it is important to know what disabilities pa-tients experience in daily life. The obtained information will also be useful in identifying outcome measuredomains for future clinical trials. We investigated which complaints and symptoms in paediatric mitochondrialdisease patients and their families are present and which of these complaints are most disabling.A questionnaire, designed to assess which symptoms are most burdensome to patients and their parents, wassent to all known Dutch-speaking patients with a mitochondrial disorder. Inclusion criteria: one or more enzymecomplex deficiencies, a decreased ATP and PCr production in fresh muscle tissue, and/or a confirmed pathogenicmtDNA mutation. The questionnaire contained three main questions and numerous answer possibilities. Themain questions were: i) Which complaints or symptoms are present?; ii) Which symptoms are most burdensomeand wanted to improve mostly, indicated by the child or expected by the parent(s); iii) Which three symptomswould the parents like to change?
  132. 132. Mitochondrial Medicine 2012: Capitol HillThe questionnaire response rate was 56% (83 out of 149). Eighty-nine percent (74 out of 83) of the parentsand their children filled main questions ii) and iii). Thirty-two percent would (think that the child would) like tochange the lack of energy, followed by tiredness (31%), and reduced muscle power (22%). Symptoms the par-ents would like to change include tiredness (25%), lack of energy (23%), and behavioural problems (23%).Of the 54 children with tiredness, 43% of the children and 39% of their parents rate this symptom as one of thethree problems they would like to change most. In the 55 patients with lack of energy, these percentages are42 and 35%, respectively. In the 53 patients with developmental delay, 32% of the parent rate this as one of themost important problems. Of the 39 patients with speech difficulties, 36% of the children and 30% of the par-ents rates this symptom in the top three. For the 27 children with epilepsy, these percentages are 37 and 41%respectively. For the 26 children with behavioural problems, 66% of the parents rate this symptom as a majorpoint they would like to change.In conclusion, behavioural, speech and language problems are more cumbersome to parents and childrenthen we would have expected. We advise to take these aspects into account more frequently in supportive caremanagement.Abstract#: 4Presenter: Yasutoshi KogaAuthors: Yasutoshi Koga1, Toshi Abe2, Takayuki Taniwaki3, Povalko Nataliya1Institution: 1 Department of Pediatrics and Child Health, 2Department of Radiology, 3Department of Neurology, Kurume University School of Medicine, 67 Asahi-Machi, Kurume, Fukuoka 830-0011, JapanTitle: MELAS and L-arginine therapy –therapeutic timing and long term effects -.Body of Abstract: Investigator-initiated clinical trial of L-arginine to cure the symptoms of the acute phase ofstroke-like episodes (SLE) and to prevent the SLE in the interictal phase of MELAS has been finished by June 30,2010. We are now cleaning the date and are processing the date for approval. However we still do not knowwhat is the best therapeutic timing of IV on SLE, and whether it can prevent the disease progression of MELASduring long term administration. We used L-arginine infusion at hyper-acute phase of SLE in 2 MELAS patientsand evaluate the therapeutic effects by clinical and the serial neuroimaging analysis. Patient 1 is a 6-year-oldgirl who was diagnosed with MELAS/Leigh overlap syndrome based on a finding of clinical symptoms and 78%mutation in an A3243G in the mitochondrial tRNALeu(UUR) gene. Patient 2 is a 32-year-old girl who fulfilledthe diagnostic criteria of MELAS and has a 55% mutation of A3243G in muscle. She has a bilateral sensorineu-ral hearing loss and diabetes mellitus at the age of 31 years-old. She has two histories of stroke-like episodesand was then followed as MELAS. Within 2 hours after the onset of SLE, we infused 0.5g/kg/dose of L-argininewithin 1 hour after the onset and took the brain MRI seriously. All of clinical symptoms disappeared within 30min after L-arginine infusion without using anti-convulsants. The series of MRI were performed 1st, 7th days andone month from onset of stroke-like episodes. MRI obtained at 24 hours after the onset showed high intensitysignal in T2WI, and DWI and low in apparent diffusion coefficient (ADC), however those abnormal findingswere completely normalized on MRIs taken at 7 days and one month later. We also administered L-arginineon MELAS for more than 5 years and evaluated the long term effects of it by duration of hospitalization, byJapanese Mitochondrial Disease Rating Scale (JMDRS) compared with MELAS cohort study in Japan withoutusing L-arginine. L-arginine therapy significantly decreases the JMDRS and prevents the disease progression ascompared with cohort study. Our data indicated that L-arginine infusion at hyper-acute phase shows promisein cure the stroke-like episodes seen in MELAS, and long term of L-arginine therapy prevent the disease pro-gression of MELAS.
  133. 133. Mitochondrial Medicine 2012: Capitol HillAbstract #: 5Presenter: Nataliya PovalkoAuthors: Nataliya Povalko, MD, PhD1, Yoshihisa Nagatoshi, MD, PhD2, Hiroko Inada, MD, PhD1, Shuichi Yatsuga, MD, PhD1, Yasutoshi Koga, MD, PhD1Institution: 1 Department of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahi-Machi, Kurume, Fukuoka 830-0011, Japan, 2 Section of Pediatrics, National Kyushu Cancer Center, 3-1-1 Notame, Minamiku, Fukuoka 811-1395, JapanTitle: A novel sequence variant of tRNAThr in mtDNA, transferred by bone marrow transplantation in patientwith ALLBody of Abstract: Bone marrow transplantation (BMT) is one of the possible choices for the therapy of mi-tochondrial disorders such as MINGIE. However current donor matching system is only focused on the HLAtyping based on the major histocompatibility antigens to avoid the graft-versus-host disease (GVHD). Wehad a 5-year old patient with ALL (acute lymphoblastic leukemia) who showed recurrent stroke-like episodesbefore and after the BMT. We found the novel mtDNA sequence variant which has not been found in a patientmtDNA before BMT. Analysis of entire sequence of mtDNA was performed twice (before and after BMT). Firstanalysis was done after the first stroke-like episode. Patient under the chemotherapy suddenly showed severeheadache, and a left tonic seizure with right hemiplegia. MRI of the brain showed high intensity areas on T2and FLAIR in occipital, frontal, parietal lobes. The parameters of endothelial function, including plasma level ofL-arginine, and FMD (flow mediated dilatation), were abnormal. No pathogenic mtDNA mutations were foundat his original mitochondrial DNA. The second entire sequencing of mtDNA was performed when he got thesecond episode of stroke in 5 month after BMT. He showed cortical blindness, vomiting and headache. Sincethe parameters of endothelial function were abnormal, infusion of L-Arginine was immediately started. Noabnormalities were found on MRI taken after the stroke-like episode. We found a novel A15929G in the mito-chondrial tRNAThr gene. The heteroplasmy of this mutation was 90% in white blood cell, 8% in nail, however thismutation was not detected in urine, and recipient’s bone marrow before BMT, WBCs from mother, brother andsister of the proband, which suggesting that this mutation was transfer by BMT. According to the haplogroupanalysis of mtDNA, original mtDNA belonged to haplogroup D4a (superhaplogroup M), on the other hand,donor’s mtDNA belonged to haplogroup F1 (superhaplogroup N). Since mtDNA has a very high mutation rateand has at least 30 polymorphic sites, minor antigen mismatching caused by the amino acid sequence poly-morphism may occur to lead the GVHD. On the other hand, many oligo-symptomatic or asymptomatic carriershaving a pathogenic mtDNA mutation may become a potential donor for BMT and thus transmit the mutationto the recipient. Current donor matching system may have a risk of transmission of pathogenic mtDNA muta-tion and may contribute the GVHD by the proteins which are generated by the transmitted mtDNA.Abstract #: 6Presenter: Meghan BuckleyAuthors: Caitlin A. Baker, Meghan F. Buckley, Taylor L. DeRosa, Jenna A. Hernandez, Erin L. Hillis, Caroline R. Luciani, Rita Matta, Alexandra R. Novak, Christine C. Smith, Qingyu Xu, Sr. Mary Jane Paolella.Institution: Sacred Heart Academy, 265 Benham St. Hamden, CT 06514.Title: The Comparative Study of Actin and Myosin Genes in Molgula manhattensis, Styela clava, and Limu-lus polyphemus: Implication on Mitochondrial DNA Maintenance.Body of Abstract: One of the bewildering observations about mitochondrial diseases to scientists and clini-cians alike is the absence of a direct link between mtDNA mutations and a specific abnormality in a cell ortissue. Different diseases such as CCD (Central Core Disease) and cardiomyopathy are caused by mutations ofthe myosin (lt. chain) gene which directly results in the absence of mitochondria in the muscle fibers and isindicative of mitochondrial disease. In addition, β-actin gene silencing has also shown to cause a decrease in
  134. 134. Mitochondrial Medicine 2012: Capitol HillmtDNA copy number (Reyes, 2011). The study also concluded that collectively, these results strongly implicatethe actomyosin cytoskeleton in mammalian mitochondrial DNA maintenance. Myosin and actin are genes ofinterest in tunicates and shellfish due to their conservative nature and their structural and functional similari-ties. Myosin’s dependence on actin, as cited above, caused the focus of research to be redirected to actin, aprotein that functions in the cell as a contractile system for the muscles. Classified under the phylum Chordata,tunicates are small, sea-dwelling organisms that are often defined by the presence of siphons. Molgula man-hattensis, the sea grape, and Styela clava, the sea squirt, are invasive to Long Island Sound and pose a threatas fouling organisms by depleting the resources of local shellfish such as Limulus polyphemus, the horseshoecrab. The blue blood of the endangered Lp is highly coveted in the field of medicine as a detector for bacterialendotoxins. The tunicates and crabs are the targets of this actin research. DNA was extracted from the tunicatebody wall and gonads using spin columns, and from the shellfish blood clots using FTA cards. Then student-de-signed primers were created using the actin sequence similarities in M.citrina, M.occulata, and S.clava. After am-plification through PCR, the products were purified and quantitated to obtain the DNA concentration in prepa-ration for downstream analysis. Templates from M.manhattensis, S.clava and L.polyphemus were sequenced inthe school-owned ABI Prism 310 Genetic Analyzer, a single capillary automated sequencer. Subsequent resultswere evaluated using NCBI and EMBL to determine the evolutionary relationships between the tunicates andthe horseshoe crab.Abstract #: 7Presenter: Marisa FerraroAuthors: Katie E. Arnone, Elizabeth H. Bailey, Clare J. Donohue, Marisa K. Ferraro, Andrea L. Grammatico, Anna V. Marren, Angela M. Onofrio, Emily R. Roth, Xenia D. Zueva, Sr. Mary Jane PaolellaInstitution: Sacred Heart Academy, 265 Benham St. Hamden, CT 06514Title: Evolution of the Actin gene: Comparing DNA Sequences Of Limulus polyphemus and Argopecten irradiansand the Implication in Mitochondrial Function.Body of Abstract: Actin is a highly conserved protein found in cytoskeletons, thin filaments, and part of thecontractile apparatus of the muscle. This gene interplays with mitochondrial function in the cytoskeletons ofmany types of cells. A recent study found that these interactions are essential for normal mitochondrial mor-phology, motility, and distribution. In neurons, actin is required for mitochondrial transport and the actin in thecytoskeleton is a prerequisite for mitochondrial movement and immobilization. Mutations in actin and the lossof ATP production result in defects of these functions and/or high rates of mitochondrial DNA loss (Bolbogh,Pon 2006). In certain myopathies, cells will contain aggregates of actin filaments with a decrease in mitochon-dria. The study organisms, Argopecten irradians and Limulus polyphemus, (the Bay Scallop the Atlantic Horse-shoe Crab respectively), are highly sought-after organisms indigenous to Long Island Sound. The Scallop servesas an important food source for the fishing industry; the Horseshoe Crab’s blood is of medicinal importancecontaining LAL, Limulus Amoebocyte Lysate, as a detector of bacterial endotoxins. The organisms were provid-ed to Sacred Heart Academy by NOAA and the University of New Haven for experimentation and analysis. DNAwas extracted from the blue blood of L. polyphemus with FTA cards and from the adductor muscle and gonadsof A. irradians using spin columns. These DNA samples were quantitated using a biophotometer to obtain a tar-geted concentration of 50-100ng and an A260:A280 of 1.7-1.9 as an indication of the purity of the sample, priorto PCR. To amplify the gene, students designed two sets of primers unique to the organisms utilizing GenBankand ClustalW as resources. The purified products were re-quantitated and diluted in order to be sequencedusing the school’s ABI Prism 310 Genetic Analyzer. The results, analyzed using the bioinformatics sources, NCBIand EMBL, will be used this spring to study how divergence and duplication play a role in the evolution of theactin gene. Sequences will be submitted to GenBank by June 2012.
  135. 135. Mitochondrial Medicine 2012: Capitol HillAbstract #: 8Presenter: Danielle DiPernaAuthors: Danielle DiPerna and Lori BuhlmanInstitution: Midwestern University- Glendale, AZTitle: Nicotine affects mitochondrial dynamics and function by modulating nicotinic acetylcholine receptor (nAChR) 3 4 and via nAChR independent mechanisms.The neuroprotective role of nicotine in Parkinson’s disease (PD) has been documented in epidemiologicalstudies and subsequent in vivo studies. Though the current cause of PD pathology remains unknown for bothfamilial and idiopathic forms of the disease, there is reason to suspect mitochondrial pathology may contrib-ute to the development and/or progression of this neurodegenerative disorder. Research also has shown thatprotective effects of nicotine can occur via modulation of nicotinic acetylcholine receptors (nAChR), thoughthe exact nAChR subtypes, ligands and potential downstream mechanisms involved remain largely unknown.Thus, identification of specific nAChR subtypes involved and understanding of the mechanisms by which theirmodulation is protective would create an attractive avenue for pharmaceutical developments. This study inves-tigates the affect of acute and chronic nicotine exposure on the human 3 4 nAChR using an in vitro modelsystem with SH-SY5Y cells. Additionally, receptor independent effects will be studied by blocking SH-SY5YnAChR and though the use of SHEP-1 cells which are nAChR null. Research has demonstrated several protectiveeffects of nicotine in regard to re-establishment of the mitochondrial network as well as inhibition of the gen-eration of reactive oxygen species and limiting mitochondrial damage. This investigation focuses on nicotineeffects on mitochondrial dynamics electron transport chain enzyme function. To this end, we have determinedthe effects of nicotine on mitochondrial dynamics when only 3 4 nAChR binding sites are available and whenall nAChR binding sites are blocked, demonstrating receptor independent effects of nicotine exposure. Wehave also analyzed the effects of alpha3beta4 nAChR modulation on Complex V activity by measuring ATP gen-eration using the same nicotine exposure parameters. Subsequently, our study investigates whether nicotinecan preserve mitochondrial dynamics, and preserve ATP production following exposure to carbonyl cyanidem-chlorphenol-hydrozone (CCCP; a uncoupler of mitochondrial membrane potential and ATP production).Abstract #: 10Presenter: Sarika SrivastavaAuthors: Sarika Srivastava1, Karina N. Gonzalez Herrera1, Vincent Proacccio2, Douglas C. Wallace3 and Marcia C. Haigis1*Institutions: 1 Department of Cell Biology, Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, Boston MA 02115 USA; 2Department of Biochemistry and Genetics, Angers University Hospital, School of Medicine, and UMR INSERM, U771-CNRS6214, Angers, France; 3Center for Mitochondrial and Epigenomic Medicine, Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USATitle: Low Level of MtDNA Mutation Promotes Mitochondrial Bioenergetics and Oxidative Metabolism viaRetrograde SignalingBody of Abstract: Point mutations in mitochondrial tRNA genes have been associated with mitochondrial en-cephalomyopathies. The mitochondrial 3243A>G tRNA Leu(UUR) gene mutation exceeding a critical threshold (>85%) leads to a clinical onset of MELAS disease. Below the critical threshold, the mitochondrial DNA (mtDNA)mutation load is clinically asymptomatic with no deleterious impact on cellular bioenergetics. In this study, wereport that the low level of m3243A>G mutation activates mitochondrial bioenergetics, biogenesis and cellularmetabolism in the MELAS 28% heteroplasmic cybrid (M28) cells compared to the 143B wild-type control cells.Strikingly, we found that the rate of mitochondrial respiration, oxidative capacity, enzyme complex activitiesand mtDNA levels were significantly higher in the M28 cybrid cells relative to the 143B control cells. The mi-croarray data analysis revealed increased expression of several genes involved in oxidative phosphorylation,TCA cycle and fatty-acid metabolism pathways in the M28 cybrid cells relative to the 143B control. Mechanisti-cally, we found that multiple transcription factors and coactivators involved in regulating mitochondrial gene
  136. 136. Mitochondrial Medicine 2012: Capitol Hillexpression and lipid metabolism were markedly stimulated in M28 cybrid cells relative to the 143B control cells.Furthermore, the energy and nutrient sensing AMPK signaling pathway was significantly activated in the M28cybrid cells relative to the 143B control cells. Our findings suggest that the low level of mtDNA mutation is apotential signal for mitochondrial dysfunction and that the nuclear genome apparatus senses and respondsvia retrograde signaling which consequently leads to the activation of the transcriptional regulatory networkto further enhance mitochondrial bioenergetics, biogenesis and metabolism. This overall positive impact of thelow level of mtDNA mutation on mitochondrial function implicates that the pharmacological modulation of theunderlying signaling pathways may boost mitochondrial bioenergetics and opens new avenues for mitochon-drial disease therapeutics.Abstract #: 11Presenter: Peter W. Stacpoole, PhD, MDAuthors: Peter W. Stacpoole, PhD, MD1; David A. Wagner, PhD2Institution: 1 University of Florida College of Medicine, Division of Endocrinology, Diabetes and Metabolism, Gainesville, FL; 2Metabolic Solutions, Inc., Nashua, NH, USATitle: Rapid Breath Test for In Vivo Determination of Human Pyruvate Dehydrogenase Complex ActivityAbstract: The pyruvate dehydrogenase complex (PDC) is a key regulatory enzyme in cellular energy metabo-lism. Under aerobic conditions, PDC catalyzes the rate-determining step in glucose oxidation by irreversiblydecarboxylating pyruvate to acetyl CoA and CO2. In this way, the PDC links glycolysis with the citric acid cycleand gluconeogenesis, as well as both lipid and amino acid metabolism. Regulation of the PDC is achieved byreversible phosphorylation by families of pyruvate dehydrogenase kinases (PDKs) and phosphatases (PDPs), inwhich the phosphorylated form of the PDC is inactive. Prior human research on PDC regulation has mainly em-ployed in vitro assays of isolated human cells or invasive skeletal muscle biopsies. However, these approachesfail to provide a safe and facile means of serially assessing whole body PDC activity. We have addressed theseshortcomings by developing the Pyruvate Breath Test (PBT) that uses a small, oral dose of sodium 1-13C-pyruvateto determine PDC activity based on the conversion of 13C-pyruvate to 13CO2.A pilot study in two subjects was conducted to provide proof-of-concept for the use of an oral PBT as a tool forassessing mitochondrial activity of the PDC and in response to therapeutic intervention using dichloroacetate(DCA), a prototypic PDK inhibitor. 13CO2 production in exhaled air was measured from an oral 100 mg dose of1-13C-pyruvate in the basal, overnight fasted state and, after one-week washout, again in the fasted state onehour after oral administration of 25 mg/kg of DCA.Oral 13C-pyruvate administration resulted in a typical concentration vs. time-dependent curve, with 13CO2 detect-able within 5 minutes of dosing, reaching maximum levels in 20-40 minutes and decreasing gradually over 2+hours. In both subjects, DCA exposure rapidly stimulated PDC activity during the initial 30 minutes of breathcollections, as evidenced by the upward and leftward shift in the concentration-time curve. We determined inone subject whether a lower oral 1-13C-pyruvate dose could be utilized. Cumulative % recovery of the dose as13 CO2 over 30 minutes was the same following doses of 25, 50 and 100 mg of 1-13C-pyruvate, indicating that anoral dose of 25 mg could be employed in future studies, using fewer samples and a shorter duration. In sum-mary, these data suggest that the PBT may provide a safe and rapid in vivo measure of a dynamic and criticallyimportant mitochondrial bioenergetic reaction within 30 minutes of oral substrate administration and can beperformed serially under physiological, pharmacological and pathological conditions.Abstract#: 12Presenter: Neal SondheimerAuthors: Neal Sondheimer1, Ornella Zollo1, Jason A. Mills2, Catherine E. Glatz1, Paul Gadue2, Deborah L. French2Institutions: 1 Division of Child Rehabilitation and Biochemical Genetics and 2Center For Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104Title: Spontaneous Elimination of Mitochondrial Mutations During The Induction of Pluripotency
  137. 137. Mitochondrial Medicine 2012: Capitol HillBody of Abstract:Introduction: The correction of genetic lesions in pluripotent stem cells represents an important first step inthe development of cell-based therapies. Disorders due to mitochondrial DNA (mtDNA) mutations present anintriguing target for cell-based therapy because of unique features of mitochondrial genetics. mtDNA mutationsare often heteroplasmic, where both wild-type and mutant sequences are present at the level of the organism,tissue or cell. The effect of these mutations is often determined by the level or load of heteroplasmy, and thereduction of pathological heteroplasmy is an important goal of mitochondrial therapies. The objective of thisstudy was to determine the dynamics of mitochondrial heteroplasmy during the conversion of fibroblasts toinduced pluripotent stem cells (iPSCs).Methods: We generated iPSCs from four patients with heteroplasmic disease-causing mutations, one withmitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes and three with Leigh syndrome andone unaffected infant. Mitochondrial function in iPSCs was assessed by fluorescence-associated cell sortinganalysis of Mito Tracker CMXRos straining and oxygen consumption.Results: The generated cell lines fulfilled criteria for pluripotency, including the expression of pluripotencymarkers and the ability to form teratomas in mice. An evaluation of mitochondrial genotype demonstrated thespontaneous elimination of heteroplasmy. The iPSC lines generated were homoplasmic, with mutations eitherentirely eliminated or with no remaining wild-type DNA. Generation of iPSCs from a cell line with non-patho-genic heteroplasmy gave a similar result, suggesting that this result was not due to any selection for or againstpathogenic mutations. Studies of the cells from which iPSCs were derived suggested that the bottleneck couldbe due to the presence of homoplasmic fibroblast clones within an otherwise mixed population. Functionalstudies of mitochondrial activity demonstrated that mitochondrial membrane potential was impaired in iPSCsbearing pathogenic mutations.Conclusions: Our ability to generate homoplasmic, pluripotent cells from patients with disease may be amechanism for eliminating disease-causing mutations in cells with future therapeutic potentialAbstract #: 13Presenter: Lisa EmrickAuthors: Ayman W. El-Hattab1, Lisa Emrick2, Jean W.C. Hsu3, Farook Jahoor3, Fernando Scaglia2, William Craigen2Institutions: 1 Division of Medical Genetics, Department of Child Health, University of Missouri Health Care, Columbia, MO, 2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 3US Department of Agriculture/Agricultural Research Service–Children’s Nutrition Research Center, Baylor College of Medicine, Houston, TexasTitle: Glucose kinetics in subjects with MELAS syndrome: interim resultsBackground: The mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syn-drome is one of the most frequent maternally inherited mitochondrial disorders in which diabetes mellitus (DM)occurs in one third of affected individuals. The pathogenesis of DM in MELAS syndrome remains unclear. Wehypothesize that DM develops in individuals with MELAS syndrome due to multiple defects in glucose me-tabolism, including decreased glucose utilization, increased glucose production, decreased insulin secretion,and increased insulin resistance. Individuals with MELAS syndromes who do not yet have DM may have alteredglucose metabolism.Methods: In this study we aim to measure the rates of endogenous glucose production, gluconeogenesis, glu-cose oxidation, and glucose clearance via stable isotope infusion technique in subjects with MELAS syndromewho have DM, subjects with MELAS syndrome who do not have DM, and in healthy control subjects. In addition,we measure the concentrations of fasting blood glucose, insulin, and glycosylated hemoglobin (HbA1c); and as-
  138. 138. Mitochondrial Medicine 2012: Capitol Hillsess insulin resistance using Homeostatic Model Assessment (HOMA). The research subjects are admitted to theGeneral Clinical Research Center at Texas Children’s Hospital. After a 12 hour-fast, the isotope infusion is startedwith a priming dose of NaH13CO3 and U-13C6 glucose followed by continuous infusion of U-13C6 glucose for 6hours. Blood and breath samples are collected and analyzed for isotopic enrichments.Results: To date, 6 control subjects, 4 subjects with MELAS and DM, and 4 non-diabetic subjects with MELAShave completed the study. Both groups of subjects with MELAS (with and without diabetes) show increasedglucose production and gluconeogenesis rates when compared to the control subjects. Diabetic subjects withMELAS exhibit higher insulin resistance as calculated by HOMA, whereas non-diabetic subjects with MELASshow a higher rate of glucose clearance.Conclusions: This interim analysis reveals that subjects with MELAS syndrome have abnormalities in glucosemetabolism. Subjects with MELAS who do not have DM have higher rates of glucose production and gluco-neogenesis that can predispose them to develop diabetes. Subjects with MELAS and diabetes showed bothincreased glucose production and higher insulin resistance, suggesting that DM develops due to multipledefects in glucose metabolism in MELAS. The completion of this study will result in a better understanding ofthe pathophysiological mechanisms of DM in subjects with MELAS syndrome, which can influence the manage-ment and prognosis of the disorder and may provide further insights into the pathogenesis of DM in mitochon-drial diseases in general.Abstract #: 14Presenter: Chian Ju JongAuthors: Chian Ju Jong1, Ramila K.C.1, Takashi Ito2, Junichi Azuma2, Stephen Schaffer1Institutions: 1 University of South Alabama, Department of Pharmacology, College of Medicine, Mobile, AL 36688, 2Hyogo University of Health Sciences, School of Pharmacy, Kobe, JapanTitle: The Role of a Taurine-containing Wobble Modification Deficiency in MELASBody of Abstract: MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) is amitochondrial disease that usually coexists with a cardiomyopathy. The most common pathogenic mutation inMELAS is an A to G transition at position 3243 in the aminoacyl stem of mitochondrial tRNALeu(UUR). The A3243Gmutation affects tRNALeu(UUR) structure and stability, aminoacylation and posttranscriptional modification of awobble base, all of which, presumably, lead to a decrease in the synthesis of mitochondrial proteins. However, itis unclear if wobble modification deficiency causes MELAS-like changes in the respiratory chain that lead to car-diac contractile dysfunction. To examine the effect of wobble modification deficiency in mitochondrial function,we developed a mouse model lacking taurine transporter (TauTKO), which diminishes the levels of a substrate(taurine) required for the conversion of uridine to 5-taurinomethyluridine at the wobble position of tRNALeu(UUR).We showed that TauTKO hearts demonstrated decreased levels of several complex I subunits, reduced complexI activity and suppressed oxygen consumption. There was also evidence of oxidative stress, as exemplified bya decrease in both aconitase activity and glutathione redox ratio, and an increase in MitoSox fluorescence. Wealso showed activation of protein kinase C (PKC)-δ and PKC-ε and an increase in the phosphorylation state oftroponin I, which regulates contractile function. Taurine depletion was also associated with development ofcardiac dysfunction, as characterized by a decrease in both fractional shortening and ejection fraction, a declinein Ca2+-dependent myofibrillar ATPase activity and an increase in mRNA levels of heart failure markers such asANP, BNP and β-MHC genes. Our findings suggest that a wobble defect leads to impaired respiratory chain ac-tivity, resulting in oxidative stress. This is consistent with the idea that a wobble defect decreases the efficiencyof UUG decoding for synthesis of mitochondrial proteins. This leads to a defect in respiratory chain flux and adiversion of electrons from the respiratory chain to the acceptor, oxygen, forming in the process superoxide.Oxidative stress is a potential trigger of contractile defects, in part through PKC activation, which results in thephosphorylation of troponin I, reducing the binding affinity of calcium for troponin C. Therefore, we showedthat a wobble defect is responsible for MELAS-like respiratory chain abnormalities. In addition, it triggers oxida-tive stress-mediated contractile dysfunction. These results support an important role of a wobble modificationdeficiency in the pathogenesis of MELAS.
  139. 139. Mitochondrial Medicine 2012: Capitol HillAbstract #: 15Presenter: Xiaoshan Zhou#*Authors: Shuba Krishnan#, Xiaoshan Zhou#*, Joao Paredes and Anna KarlssonInstitution: Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, F68, SE-14186 Huddinge, Sweden# These authors contributed equally to this work* Presenting authorTitle: Thymidine phosphorylation by transgene expression of the Drosophila melanogaster nucleosidekinase rescues the pathology of mitochondrial TK2 deficiencyAbstractA strategy to reverse the symptoms of thymidine kinase 2 (Tk2) deficiency in a mouse model was investi-gated. The nucleoside kinase from Drosophila melanogaster (Dm-dNK) was expressed in Tk2 deficient micethat previously were characterized to present a severe phenotype caused by mitochondrial DNA depletion.The mtDNA depletion in the Tk2 knockout mice was fully rescued by intercrossing with the Dm-dNK+/- trans-genic mice. The Dm-dNK+/- /Tk2-/- mice had a normal content of mtDNA, and survived for 6-month withoutany abnormal behavior observed so far. Mice expressing Dm-dNK showed a substantial increase in thymidinephosphorylating activity in investigated tissues. The Dm-dNK expression also resulted in highly elevated dTTPpools. The dTTP pool alterations did not cause specific mitochondrial DNA mutations or deletions when 6months old mice were analyzed. The mitochondrial DNA was also detected at normal levels in the Dm-dNK+/-mice. In conclusion, the Dm-dNK+/- /TK2-/- mouse model illustrates how dTMP can be synthesized in the cytosoland that transport of thymidine nucleotides to the mitochondrial compartment can compensate for loss ofintra mitochondrial synthesis. The data presented open new possibilities to treat the severe symptoms of TK2deficiency.Abstract #: 16Presenter: Anne ChiaramelloAuthors: Martine Uittenbogaard, Kristin Baxter, Anne ChiaramelloInstitution: George Washington University, School of Medicine and Health Sciences, Department of Anatomy and Regenerative Biology, Washington, DC 20037Title: The Neurogenic Basic Helix-Loop-Helix Transcription Factor NeuroD6 Induces Mitochondrial Biogen-esis and Bioenergetics in Neuronal CellsBody of Abstract: Developing neurons are vitally dependent on mitochondria for energy due to their need ofhigh ATP levels to fuel dynamic changes in cytoskeletal assembly and plasmalemmal biogenesis associatedwith axonal and dendritic development. Although great progress has been made toward elucidating thetranscription regulation of mitochondrial biogenesis and bioenergetics, little is known about the identity ofneuronal-specific transcriptional factors adapting mitochondrial homeostasis with the onset of neuronal dif-ferentiation. Gene set enrichment of our genome-wide microarray analysis has revealed a link between Neu-roD6 expression and a cluster of mitochondrial bioenergetic-related genes, while our confocal fluorescencemicroscopy analysis has shown NeuroD6-mediated increase of the mitochondrial biomass during the earlystages of neuronal differentiation. Moreover, NeuroD6 concomitantly sustains the mitochondrial biomassand keeps low levels of ROS during oxidative stress. Thus, the goal of our present study was to determinewhether NeuroD6 could coordinate mitochondrial biogenesis and bioenergetics during the early stages ofneuronal differentiation using our in vitro cellular paradigm, the PC12-NeuroD6 (PC12-ND6) cell line. PC12-ND6 cells behave as neuronal progenitor cells poised to undergo cell cycle withdrawal and execute terminaldifferentiation upon neurotrophic cues. Our collective studies have shown that NeuroD6 induces cytoskeletalremodeling and neuritogenesis characteristic of the first four stages of neuronal differentiation independentlyof nerve growth factor, events that were accompanied by increased mitochondrial mass, as demonstrated
  140. 140. Mitochondrial Medicine 2012: Capitol Hillby confocal microscopy, flow cytometry and mitochondrial fractionation. In this study, we report that NeuroD6triggers mitochondrial biogenesis in the early stages of neuronal differentiation by inducing mtDNA replicationand expression of the key regulator Tfam. Furthermore, we observed that NeuroD6 increases the expressionlevels of key subunits of the respiratory complexes, COXI, COXIV and COXV, which resulted in increased ATP levelsproduced by oxidative phosphorylation. Finally, we measured the mitochondrial membrane potential (ΔΨm) bylive-cell imaging using two distinct cationic fluorescent lipophilic dyes, TMRM and JC-10, both of which accu-mulate in the mitochondrial matrix in a ΔΨm-dependent manner. We found that NeuroD6 stimulates the mito-chondrial bioenergetic functions by increasing ΔΨm, thereby generating a bioenergetic reserve. In conclusion,our results indicate that NeuroD6 plays an integrative role in regulating and coordinating the onset of neuronaldifferentiation with acquisition of adequate energetic capacity to sustain cytoskeletal remodeling, plasmalem-mal expansion and growth cone development, events that are highly ATP demanding.Abstract #: 17Presenter: Victor Wei ZhangAuthors: Victor Wei Zhang, Hong Cui, Lee-Jun WongInstitution: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030Title: Implementation of Next Generation Sequencing for Clinical Molecular Diagnosis of Mitochondrial Disor-dersBody of Abstract:The next generation sequencing (NGS) technology is being gradually adapted as the primary sequenc-ing platform for the molecular diagnosis in clinical laboratories. The ability to sequence a group of targetgenes by NGS is exceptionally useful for molecular diagnosis of genetically and clinically heterogeneoussyndromes, such as complex mitochondrial disorders. Comprehensive molecular diagnosis of mitochondrialdisorders requires the evaluation of both nuclear and mitochondrial genomes at high accuracy for clinicaldiagnosis. The next generation sequencing based panel testing becomes the major driving force for suchapplication. However, the complexity of NGS based sequencing present unprecedented challenge for qualityassurance and quality control to warrant the correct result for our patients.We develop a one-step comprehensive NGS for molecular diagnosis of mitochondrial disorders in a clinical set-ting with the implementation of proper quantitative and qualitative controls. A target gene selection followedby high throughput “deep” coverage NGS approach was validated with the indexed qualitative and quantita-tive controls analyzed along with each sample for quality assurance. We demonstrated an average coverageof >500X for targeted nuclear genes and >20,000x for each of the 16,569 bases of the mitochondrial genome.Nucleotide changes are correctly called with quantitative information. The limit of detection of a heteroplasmicchange is calculated to be about 1.5%. Small and large insertion/deletions were correctly detected with clearbreakpoints and percentage of heteroplasmy.We have demonstrated the feasibility and effectiveness of the QA/QC system for routine NGS based testing forup to tens to hundreds sample per sequencing run. In combination of newly developed capture based analysisof a group of target nuclear genes and the one-step comprehensive analysis of mitochondrial genome, we areable to deliver molecular testing results to our patients in a timely, accurate, and cost-effective manner usingthe state-of-the-art technology. The inclusion of quality control system assures the highest quality performancerequired in a certified clinical laboratory.Abstract #: 18Presenter: Peter W. StacpooleAuthors: Peter W. Stacpoole, PhD, MD, for the CoQ10 Study Group.Institution: University of Florida, College of Medicine, Gainesville, FL, 32611Title: Phase 3 trial of coenzyme Q10 in children with mitochondrial diseases.
  141. 141. Mitochondrial Medicine 2012: Capitol HillAbstract: Treatment of mitochondrial diseases has been generally disappointing and has usually been ap-proached in an uncontrolled manner. Although there is no proven therapy for any congenital mitochondrialdisease, coenzyme Q10 (CoQ10) is a potential treatment for specific deficiencies of the respiratory chain, becauseof its apparent safety, its integral role in the processes of electron transport and cellular energetics and itsantioxidant properties. We postulate that CoQ10 is a safe and effective treatment for children with inborn er-rors of mitochondrial energetics due to defects in specific respiratory chain (RC) complexes or mitochondrialDNA (mtDNA) mutations, and that this beneficial action will be reflected in improved motor, neurobehavioraland sleep function and in quality of life. This postulate is currently being tested by accomplishing the followingspecific aims:Specific Aim 1. Complete a multicenter, prospective, randomized, double-blind, placebo controlled cross-over trial of oral CoQ10 in children with biochemically proven deficiencies of complex I, II, III or IV of the RC orwith mutations of a gene coding for an RC component (mtDNA and nDNA). This aim tests the hypothesis thatsupplementation with CoQ10 (10 mg/kg/d) is safe and more effective in improving outcome than placebo. Clini-cal Research Centers (CRCs) or similar facilities will be the venues for this phase 3 clinical trial.Specific Aim 2. Determine the effectiveness of CoQ10 in improving the morbidity of affected patients. Thisaim addresses the postulate that high dose CoQ10 improves motor function and quality of life, as determined bya validated questionnaire for this patient population, and by objective, standardized measures of motor func-tion.Specific Aim 3. Determine the safety of CoQ10 in the target population. This aim tests the postulate that theformulation and dose of CoQ10 employed is well tolerated and the administration of this product is not associ-ated with significantly more numerous or more severe adverse events than is administration of placebo.Abstract #: 19Presenter: Peter W. StacpooleAuthors: Peter W. Stacpoole for the DCA/PDC Collaborative GroupInstitution: Departments of Medicine (Division of Endocrinology and Metabolism) and Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, 32611Title: Phase 3 Trial of Dichloroacetate for Pyruvate Dehydrogenase Complex Deficiency.Abstract:We have organized a phase 3 trial of dichloroacetate (DCA) in young children with deficiency of the pyruvatedehydrogenase complex (PDC). PDC deficiency is one of the most common causes of congenital lactic acidosis;it is a frequently fatal disease of childhood that causes progressive neurological and neuromuscular degenera-tion for which no proven treatment exists. We predict that DCA represents targeted potential therapy for PDCdeficiency because of its ability to increase both the catalytic activity and stability of the enzyme complex. Theconclusions of numerous laboratory investigations and open label clinical trials are consistent with this postu-late and have led to the designation of DCA as an Orphan Product for congenital lactic acidosis by the Food andDrug Administration.We plan to conduct a double-blind trial of 67 evaluable children, aged 3 months through 17 years, with provendeficiency of PDC. Subjects will be randomized to receive 9 months of DCA at a dose of either 12.5 mg/kg/12hr (20 patients) or 25 mg/kg/12 hr (20 patients) or placebo (27 patients) by mouth. After 9 months, patients inthe DCA treatment arms will be crossed over to receive the alternate dose and all patients will be studied foran additional 9 months, for a total of 18 months of exposure to DCA or placebo. At randomization, patients willbe stratified according to age <2 years or ≥2 years and according to prior exposure to a ketogenic diet (KD). Ourprimary hypothesis, stated as the null, is that the three groups are equivalent vs. the alternate conclusion thatthere is a difference between the active treatments and placebo. As a secondary comparison we shall comparethe two DCA doses in the crossover study. Our primary hypothesis will be tested by accomplishing the followingspecific aims:
  142. 142. Mitochondrial Medicine 2012: Capitol HillSpecific Aim 1 is to determine the efficacy of DCA based on outcome from two primary efficacy aims: 1) grossmotor function and 1) dietary carbohydrate tolerance. Primary efficacy aim 1 will be quantitated using the GrossMotor Function Measure (GMFM), version 88, which is a validated, age-appropriate tool applicable to childrenwith severe neurological and neuromuscular impairment. Primary efficacy aim 2 will determine carbohydratetolerance by measuring blood lactate response to a standard carbohydrate-rich meal.Specific Aim 2 is to evaluate the safety and tolerability of DCA by comparing 1) motor and sensory nerve con-duction of the lower extremities in patients to age-appropriate normative values; and 2) differences in stan-dard serum biomarkers of hepatic function, namely aspartate aminotransferase and alanine aminotransferase,between treatment and placebo groups.Specific Aim 3 is to address the following secondary questions:For efficacy, does DCA differ from placebo in affecting: 3a. quality of life? 3b. endogenous PDC activity? 3c. the frequency and severity of lactic acidosis or other clinical/metabolic events requiring hospitalization? 3d. survival?For safety, does DCA differ from placebo in: 3e. maintaining standard clinical and biochemical measures of general health? 3f. exhibiting toxicity that correlates with plasma drug concentrations?Abstract #: 20Presenter: Peter W. StacpooleAuthors: Monica Abdelmalak, Alicia Lew, Ryan Ramezani, Albert L. Shroads, Bonnie S. Coats, Meena N. Shankar and Peter W. StacpooleInstitution: University of Florida, College of Medicine, Gainesville, FL, 32611Title: Long-term Safety of Dichloroacetate in Congenital Lactic Acidosis.We have followed 8 patients (4 males) with biochemically and/or molecular genetically proven deficiencies ofthe E1α subunit of the pyruvate dehydrogenase complex (PDC; 3 patients) or complexes I (1 patient), IV (3 pa-tients) or I+IV (1 patient) for 10.9 to 16.5 years. All subjects originally participated in randomized controlled trialsfor dichloroacetate (DCA) and were continued on an open-label chronic safety study. Patients (1 adult) rangedin age from 3.5 to 40.2 years at the start of DCA administration and are currently aged 16.9 to 49.9 years (mean ±SD: 23.5 ± 10.9 years). Subjects were either normal or below normal body weight for age and gender. They havebeen evaluated at least twice annually for routine tests of hematopoietic, renal, hepatic, lipid and lipoproteinmetabolism, peripheral nerve conduction and plasma trough DCA concentrations. The 3 PDC deficient patientsconsumed a modestly increased fat diet (~2 fat:1 carbohydrate+protein). Oral DCA was administered at a doseof 12.5 mg/kg every 12 hours. Potentially relevant concomitant medications included carbamazepine and clon-azepam (1 patient) and progesterone (1 patient).DCA was well-tolerated and maintained normal blood lactate concentrations, even in PDC deficient children onessentially unrestricted diets. Hematological, renal and electrolyte status remained stable. Mean serum ala-nine transaminases (ALT) levels were modestly higher on DCA (1.609-fold above baseline; p=0.008), but serumaspartate transaminases and lipid and lipoprotein levels were not significantly altered while on the drug. Nerveconduction either did not change or decreased modestly and led to reduction or temporary discontinuation of