Amino-acid depletion induced by abnormal amino-acid conjugation and protein restriction in isovaleric acidemia.

Background: Previously, we detected 19 'new' amino-acid conjugates in the urine of patients with isovaleric acidemia. There is currently a poor understanding of the relationship between the clinical symptoms and the excreted metabolites occurring in these patients, owing to insufficient metabolite characterization and quantification. Consequently, controversial treatment protocols exist, particularly pertaining to dietary protein restriction.

Objective: To determine the effect of the previously identified amino-acid conjugates and conventional dietary protein restriction therapy, on the free amino-acid concentrations in isovaleric acidemia patients, to better explain the clinical symptoms and develop more effective therapy.

Design: Free amino-acid quantification via liquid chromatography mass spectrometry (LC-MS-MS) was performed on pre- and post-treatment urine or serum samples collected from six isovaleric acidemia patients, previously investigated for the presence of new induced N-isovaleryl and N-acetyl-amino-acid conjugates.

Results: Depleted amino-acid concentrations were detected in varying degrees in all six patients and did not recover after conventional treatment.

Conclusions: The 19 potentially toxic metabolites previously identified and the consequent amino-acid depletions detected in this study, may explain many of the clinical symptoms associated with isovaleric acidemia. Furthermore, the occurrence of amino-acid depletions in these patients, steers away from the controversial dietary protein restriction treatment protocols, and towards dietary leucine restriction alone with essential amino-acid supplementation, in combination with glycine and L-carnitine supplementation.