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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Small Research Grants (R03)
Project #
5R03HD069983-02
Application #
8316153
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Urv, Tiina K
Project Start
2011-08-15
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$77,500
Indirect Cost
$27,500
Name
University of California San Diego
Department
Pediatrics
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093