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Riboflavin-responsive glutaryl CoA dehydrogenase deficiency
Ronald A Chalmers1, Murray D Bain, Johannes Zschocke
1CIMOA, London NW1 0NH, UK. rachalmers@cimoa.org.uk
Molecular Genetics and Metabolism
|December 27, 2005
Summary
Riboflavin treatment improved glutaryl CoA dehydrogenase (GCDH) enzyme activity in a patient with GCDH deficiency. While not fully normalizing organic acid excretion, this cofactor precursor therapy shows promise for managing this rare genetic disorder.
Area of Science:
- Biochemistry
- Genetics
- Metabolic Disorders
Background:
- Glutaryl CoA dehydrogenase (GCDH) deficiency is a rare genetic disorder affecting amino acid metabolism.
- Mutations in the GCDH gene lead to reduced enzyme activity, causing accumulation of toxic metabolites.
- Understanding genotype-phenotype correlations and therapeutic responses is crucial for managing GCDH deficiency.
Observation:
- A patient with compound heterozygous GCDH mutations (S139L/P248L) exhibited 20% residual enzyme activity.
- The S139L mutation is located near the FAD cofactor binding site, suggesting potential cofactor-related dysfunction.
- This patient demonstrated responsiveness to riboflavin, a precursor of the FAD cofactor.
Findings:
- Pharmacological doses of riboflavin increased mutant GCDH enzyme activity in vitro.
- The mitochondrial GCDH homotetramer appears to remain intact despite the S139L mutation.
- High cofactor concentrations may overcome steric alterations caused by the S139L substitution.
Implications:
- Riboflavin supplementation may be a viable therapeutic strategy for certain GCDH deficiency mutations.
- Combined dietary therapy (low lysine diet) and riboflavin significantly reduced toxic metabolite excretion.
- This case highlights the potential for cofactor precursor therapy to improve outcomes in GCDH deficiency, contributing to normal clinical and neurological development.