Pyruvate dehydrogenase complex (PDC) deficiencies are a major class of mitochondrial diseases, limiting oxidation of carbohydrate for energy production, especially important in the brain. No definitive treatment of these disorders has been established. The proposed """"""""Natural History and Advanced Genetic Study of Pyruvate Dehydrogenase Complex Deficiencies"""""""" will establish a longitudinal natural history database for PDC deficiencies, integrating our data with the NAMDC registry, creating an additional NAMDC natural history sub-database specific to PDC deficiencies, and include clinically detailed and relevant data elements that are derived from patient/family observations. We will enroll a substantial number of diverse subjects with confirmed PDC deficiencies and determine the genetic basis and pathophysiology of up to a third of PDC patients who currently have not been found to have an identified mutation in any of the """"""""primary"""""""" PDC-specific genes.
Our specific aims will be: 1) to establish a PDC-specific NAMDC database within the NAMDC Patient Registry, enroll 150-200 subjects through the NAMDC network, collect detailed diagnostic and clinical information with input from the subjects and their families, monitor blood tests for metabolic and treatment markers, and follow them for 3-4 years;2) to use comprehensive advanced genetic analysis technologies (whole exome sequencing and a panel of 23 selected known genes) to find mutations in those subjects in whom none has been found, in collaboration with the NAM DC-sponsored international data exchange network (MSeqDR);and 3) to correlate these clinical and genetic findings to determine if there are different types of PDC deficiencies that may respond to different treatments, and to identify measurable clinically relevant outcomes and promising forms of treatment that could be evaluated in ongoing and future controlled clinical intervention trials.

Public Health Relevance

This project will establish a NAMDC Patient Registry and genetic databases specific to PDC deficiencies with new clinical information, including patient/family reported outcomes and response to treatments. It will increase knowledge of the;genetic and biochemical causes of PDC deficiencies relevant to diagnosis, prognosis, and potential different modes of treatment. This project will interact with ongoing and future clinical trials and will provide useful information for planning such trials.

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
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
Shin, Ha Kyung; Grahame, George; McCandless, Shawn E et al. (2017) Enzymatic testing sensitivity, variability and practical diagnostic algorithm for pyruvate dehydrogenase complex (PDC) deficiency. Mol Genet Metab 122:61-66

Showing the most recent 10 out of 49 publications