Deficiency of the enzyme 3-methylcrotonyl-CoA carboxylase sometimes presents with serious metabolic problems, but in some individuals there may be no apparent symptoms. This is a conundrum, because there may be no symptoms even when the enzyme deficiency is profound, and significant metabolic problems uniformly result in deficiencies of enzymes which are immediately above or below 3- methylcrotonyl-CoA carboxylase in the pathway of leucine breakdown. This is a problem, since the enzyme deficiency is frequently found through newborn screening, but it is not clear whether unnecessary anxiety is generated in some cases or if insufficient therapy and monitoring is applied in others. This project looks at genome-wide associations, to see if there are markers which predict which individuals with 3-methylcrotonyl-CoA carboxylase deficiency are prone to develop symptoms. We will be applying advanced DNA sequencing techniques, using DNA from patients who have had metabolic symptoms and from individuals who have not had symptoms, to analyze coding regions and look for changes in any genes, especially those related genes involved with leucine and biotin metabolism, which could explain why symptoms develop in some individuals with this enzyme deficiency.
Deficiency of the enzyme 3-methylcrotonyl-CoA carboxylase sometimes presents with serious metabolic problems, but in some individuals there may be no apparent symptoms. We will be applying exome sequencing of DNA from patients who have had metabolic symptoms and from individuals who have not had symptoms, to look for markers which could explain why symptoms develop in some individuals with this enzyme deficiency. This would permit more informed counseling, and allow more efficient focusing of monitoring and therapy.
| Gertsman, Ilya; Barshop, Bruce A (2018) Promises and pitfalls of untargeted metabolomics. J Inherit Metab Dis 41:355-366 |
| Shepard, Peter J; Barshop, Bruce A; Baumgartner, Matthias R et al. (2015) Consanguinity and rare mutations outside of MCCC genes underlie nonspecific phenotypes of MCCD. Genet Med 17:660-7 |
| Gertsman, Ilya; Gangoiti, Jon A; Barshop, Bruce A (2014) Validation of a dual LC-HRMS platform for clinical metabolic diagnosis in serum, bridging quantitative analysis and untargeted metabolomics. Metabolomics 10:312-323 |
