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.
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.
|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-PÃ©rez, 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|
|ServiÃ¡n-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