The NAMDC Pilot Project program was initiated in 2011 as an important component of our RDCRN U54 Cooperative Agreement. Three pilot awards have been given. The first, led by Dr. Juan Pascual (University of Texas Southwestern Medical School) will use 7T nuclear magnetic resonance (NMR) spectroscopy (MRS) to characterize metabolites in brain and skeletal muscle of patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). This project will non-invasively reveal MELAS metabolic biomarkers that may be relevant to other mitochondrial disorders and could potentially be used to monitor disease progression and outcomes in clinical trials. The second pilot grant, directed by Dr. Marni Falk, (Children's Hospital of Philadelphia), will support development of critical software pipeline for the Mitochondrial Disease Sequence Data Resource (MSeqDR) Consortium, an international collaborative effort to identify and prioritize the specific whole-exome sequence (WES) data analysis needs of the mitochondrial disease community. After being developed, the MSeqDR will be linked to the NAMDC Clinical Registry where it will provide a powerful data-mining tool to study genotype-phenotype relationships. The third pilot award is a natural history study led by Dr. Sumit Parikh (Cleveland Clinic). This study will characterize the phenotypes, genotypes, and progression of Pearson syndrome. This study will be continued as part of the NAMDC Clinical Registry (Project 1). Dr. Fernando Scaglia proposes a novel phase I dose-finding and safety study of long-term citrulline supplementation in patients with MELAS due to the m.3243A>G mitochondrial DNA mutation. Dr. Scaglia's strong preliminary studies indicate that patients with MELAS have a deficiency of nitric oxide (NO), which can be ameliorated by citrulline over short periods (up to 48 hours). In this 2-year pilot study. Dr. Scaglia proposes to administer citrulline to subjects with MELAS to identify the maximum tolerated dose over four months of follow-up. Once established, this dose will be used in a future clinical trial. Data on NO synthesis production, biomarkers of mitochondrial dysfunction, and cerebral blood flow in the study subjects will also be collected as pilot data.

Public Health Relevance

The 3 current and 1 proposed NAMDC pilot projects focus on biomarkers, diagnosis, natural history, and treatment of mitochondrial diseases. Development of biomarkers, improving diagnostic tools, and characterizing natural history, and testing therapies for mitochondrial diseases are critical to advance this field and to help afflicted individuals.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZTR1)
Program Officer
Gwinn, Katrina
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Columbia University (N.Y.)
New York
United States
Zip Code
Al-Gadi, Iman S; Haas, Richard H; Falk, Marni J et al. (2018) Endocrine Disorders in Primary Mitochondrial Disease. J Endocr Soc 2:361-373
Hirano, Michio; Emmanuele, Valentina; Quinzii, Catarina M (2018) Emerging therapies for mitochondrial diseases. Essays Biochem 62:467-481
Raghavan, Neha S; Brickman, Adam M; Andrews, Howard et al. (2018) Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer's disease. Ann Clin Transl Neurol 5:832-842
Barca, Emanuele; Ganetzky, Rebecca D; Potluri, Prasanth et al. (2018) USMG5 Ashkenazi Jewish founder mutation impairs mitochondrial complex V dimerization and ATP synthesis. Hum Mol Genet 27:3305-3312
Shen, Lishuang; Attimonelli, Marcella; Bai, Renkui et al. (2018) MSeqDR mvTool: A mitochondrial DNA Web and API resource for comprehensive variant annotation, universal nomenclature collation, and reference genome conversion. Hum Mutat 39:806-810
Garone, Caterina; Taylor, Robert W; Nascimento, Andrés et al. (2018) Retrospective natural history of thymidine kinase 2 deficiency. J Med Genet 55:515-521
Winawer, Melodie R; Griffin, Nicole G; Samanamud, Jorge et al. (2018) Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy. Ann Neurol 83:1133-1146
Zolkipli-Cunningham, Zarazuela; Xiao, Rui; Stoddart, Amy et al. (2018) Mitochondrial disease patient motivations and barriers to participate in clinical trials. PLoS One 13:e0197513
Mancuso, Michelangelo; McFarland, Robert; Klopstock, Thomas et al. (2017) International Workshop:: Outcome measures and clinical trial readiness in primary mitochondrial myopathies in children and adults. Consensus recommendations. 16-18 November 2016, Rome, Italy. Neuromuscul Disord 27:1126-1137
Bedoyan, Jirair K; Yang, Samuel P; Ferdinandusse, Sacha et al. (2017) Lethal neonatal case and review of primary short-chain enoyl-CoA hydratase (SCEH) deficiency associated with secondary lymphocyte pyruvate dehydrogenase complex (PDC) deficiency. Mol Genet Metab 120:342-349

Showing the most recent 10 out of 49 publications