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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54NS078059-03
Application #
8537981
Study Section
Special Emphasis Panel (ZNS1-SRB-S (52))
Program Officer
Gwinn, Katrina
Project Start
2011-09-30
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
3
Fiscal Year
2013
Total Cost
$1,085,410
Indirect Cost
$339,465
Name
Columbia University (N.Y.)
Department
Neurology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Merkel, Peter A; Manion, Michele; Gopal-Srivastava, Rashmi et al. (2016) The partnership of patient advocacy groups and clinical investigators in the rare diseases clinical research network. Orphanet J Rare Dis 11:66
Shen, Lishuang; Diroma, Maria Angela; Gonzalez, Michael et al. (2016) MSeqDR: A Centralized Knowledge Repository and Bioinformatics Web Resource to Facilitate Genomic Investigations in Mitochondrial Disease. Hum Mutat 37:540-8
Engelstad, Kristin; Sklerov, Miriam; Kriger, Joshua et al. (2016) Attitudes toward prevention of mtDNA-related diseases through oocyte mitochondrial replacement therapy. Hum Reprod 31:1058-65
Karaa, Amel; Kriger, Joshua; Grier, Johnston et al. (2016) Mitochondrial disease patients' perception of dietary supplements' use. Mol Genet Metab 119:100-8
Marin, Samantha E; Saneto, Russell P (2016) Neuropsychiatric Features in Primary Mitochondrial Disease. Neurol Clin 34:247-94
Al-Mehmadi, Sameer; Splitt, Miranda; For DDD Study group* et al. (2016) FHF1 (FGF12) epileptic encephalopathy. Neurol Genet 2:e115
Huang, Xiaoping; Bedoyan, Jirair K; Demirbas, Didem et al. (2016) Succinyl-CoA synthetase (SUCLA2) deficiency in two siblings with impaired activity of other mitochondrial oxidative enzymes in skeletal muscle without mitochondrial DNA depletion. Mol Genet Metab :
Saneto, Russell P (2016) Alpers-Huttenlocher syndrome: the role of a multidisciplinary health care team. J Multidiscip Healthc 9:323-33
Torres-Torronteras, Javier; Cabrera-Pérez, Raquel; Barba, Ignasi et al. (2016) Long-Term Restoration of Thymidine Phosphorylase Function and Nucleoside Homeostasis Using Hematopoietic Gene Therapy in a Murine Model of Mitochondrial Neurogastrointestinal Encephalomyopathy. Hum Gene Ther 27:656-67
Servián-Morilla, Emilia; Takeuchi, Hideyuki; Lee, Tom V et al. (2016) A POGLUT1 mutation causes a muscular dystrophy with reduced Notch signaling and satellite cell loss. EMBO Mol Med 8:1289-1309

Showing the most recent 10 out of 38 publications