Résumé :
|
Very-Long-Chain-AcylCoA (VLCAD) deficiency is one of the more common mitochondrial ß-oxidation defect, without treatment to date, with three distinct phenotypes including neonatal-onset severe cardiomyopathy, liver failure in infancy, or adolescent-onset myopathy with exercise intolerance, myalgia and rhabdomyolysis. Because of the severity of symptoms, newborn screening of VLCAD deficiency is performed in several countries. Molecular studies have revealed >80 VLCAD gene missense mutations, with generally unpredictable effects on enzyme activity, and for which genotype/phenotype correlations are globally unclear. We sought to determine if, via activation of the PPAR (Peroxisome Proliferator Activated Receptors) signaling pathway, bezafibrate could be effective to stimulate residual metabolic capacities in this disorder. Palmitate oxidation tests were performed in a panel of patient fibroblasts from the three phenotypes, representing 36 genotypes and 45 missense mutations. About two thirds of the cell lines exhibited a marked increase in Fatty Acid Oxidation (FAO) in response to bezafibrate, whereas treatment was ineffective in the remaining cell lines. Similar increases in VLCAD mRNA were found in all cell lines, and the differences in FAO could then be ascribed to variable increases in VLCAD residual enzyme activity in response to the drug. Unresponsive genotypes were all found to correspond to severe clinical presentations whereas cells that responded to bezafibrate were from patients with the myopathic form of the disorder. Cross-analysis of genotypes allowed to characterize groups of individual severe or mild missense mutations accounting for the response to the drug. This pharmacogenetics study provides a new way for functional analysis of VLCAD-deficient genotypes, demonstrates the potential of bezafibrate in the correction of the more common myopathic form of the disorder, and provides a rationale for the selection of patients who might respond to bezafibrate in a future clinical trial, based on the association of in vitro tests and molecular data.
|