My research focuses on mitochondrial energy metabolism, branched chain amino acid metabolism, inborn errors of metabolism, and development of novel therapies for inborn errors of metabolism. I also have a strong interest in the genetics of the Plain Communities (Amish and Mennonites) and identification of novel genetic disorders in the general population. Many of these disorders have significant liver involvement.

Characterization of a Multifunctional Fatty Acid Oxidation Complex. We have examined key points of crosstalk between fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) through direct physical measurements. We show that these two pathways exist as an integrated protein complex within mitochondria. Our identification of a multifunctional energy complex within mitochondria and provide an opportunity to better understand the clinical implications of inborn errors of energy metabolism.

VLCAD. More than 100 cases of VLCAD deficiency have been documented in the literature, with three different disease phenotypes. A severe infant-onset form is characterized by acute metabolic decompensation with hypoketotic hypoglycemia, hepatopathy dicarboxylic aciduria, liver dysfunction, and cardiomyopathy. We have used its prokaryotic expression system to study multiple missense mutations described in VLCAD-deficient patients. Characterization of purified VLCAD proteins confirmed our hyptohesis that the C-terminus plays a key role in mitochondrial membrane association. The prokaryotic system developed will greatly facilitate investigation of VLCAD structure and function. Funding for this project is included in the above-referenced grant.

Human ACD10. In the last half of the 20th century, the incidence of type 2 diabetes mellitus (T2DM), previously unrecognized in the Pima Indians, began to rise. ACAD10 was one of 30 genes further examined after demonstrating a significant signal for diabetes in a genome-wide association study (GWAS). To characterize the physiologic role of ACAD10 in intermediary metabolism and its possible link to T2DM, we have characterized an ACAD10 gene trap mouse model. Aging animals become obese on a normal diet and develop insulin-resistant hyperglycemia in response to an intraperitoneal glucose challenge. Tissue and blood ACN profiles are similar to those previously described for adult humans with T2DM. Our findings identify ACAD10 deficiency as new monogenic cause of T2DM in mice, and provide valuable insight into its potential role in the development of T2DM in Pima Indians.

Characterizing the Burden of Genetic Disease in Old Order Amish. The Old Order Amish communities (Plain People) of North America have altered health risks that stem from unbalanced population sampling of European founders followed by genetic drift in derivative generations. These population effects have resulted in a high prevalence of specific genetic disorders that vary from the general population and from each other. The Western PA Amish are among the least genetically characterized Amish communities in the United States, with no catalogue of either genetic disorders or variants seen in the community. We have developed a new program to characterize the genetic variability between Amish Mercer County population and other Amish counties by doing whole-exome and mitochondrial DNA sequencing.

Clinical Research. Dr. Vockley continues to coordinate a vigorous program in clinical research for the treatment of inborn errors of metabolism. Inborn errors of mitochondrial fatty acid oxidation are among the most frequent now identified through expanded newborn screening by tandem mass spectrometry. Dr. Vockley has recently had two medications for fatty acid oxidation disorders developed in his laboratory reach Phase 2 and 3 U.S. Food and Drug Administration trials, including triheptanoin, the first drug in development to treat long chain fatty acid oxidation disorders. Additional diseases under study include lysosomal storage diseases, disorders of sterol metabolism, disorders of the urea cycle, and abnormalities of bone mineralization.

Cleveland Family Professor of Pediatric Research

Professor of Human Genetics

Chief of Medical Genetics

Director of the Center for Rare Disease Therapy

Department of Medicine