BACKGROUND: The number of patients with mitochondrial fatty acid oxidation (FAO) disorders is recently becoming larger with the spread of newborn mass screening. Despite the advances in metabolic and molecular characterization of FAO disorders, the therapeutic studies are still limited. It was reported recently that bezafibrate (BEZ), an agonist of peroxisome proliferating activator receptor (PPAR), can restore FAO activity in cells from carnitine palmitoyltransferase-2 (CPT2) and very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiencies as well as clinical symptoms in the adult patients. METHODS: In this study, the therapeutic effect of BEZ was determined by in vitro probe acylcarnitine (IVP) assay using cultured fibroblasts and tandem mass spectrometry on various FAO disorders. The clinical trial of BEZ treatment for a boy with the intermediate form of glutaric acidemia type 2 (GA2) was also performed. RESULTS: The effect of BEZ was proven in cells from various FAO disorders including GA2, deficiencies of VLCAD, medium-chain acyl-CoA dehydrogenase, CPT2, carnitine acylcarnitine translocase and trifunctional protein, by the IVP assay. The aberrantly elevated long- or medium-chain acylcarnitines that are characteristic for each FAO disorder were clearly corrected by the presence of BEZ (0.4 mmol/L) in culture medium. Moreover, daily administration of BEZ in a 2-year-old boy with GA2 dramatically improved his motor and cognitive skills, accompanied by sustained reduction of C4, C8, C10 and C12 acylcarnitines in blood, and normalized the urinary organic acid profile. No major adverse effects have been observed. CONCLUSION: These results indicate that BEZ could be a new treatment option for FAO disorders.
BACKGROUND: The number of patients with mitochondrial fatty acid oxidation (FAO) disorders is recently becoming larger with the spread of newborn mass screening. Despite the advances in metabolic and molecular characterization of FAO disorders, the therapeutic studies are still limited. It was reported recently that bezafibrate (BEZ), an agonist of peroxisome proliferating activator receptor (PPAR), can restore FAO activity in cells from carnitine palmitoyltransferase-2 (CPT2) and very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiencies as well as clinical symptoms in the adult patients. METHODS: In this study, the therapeutic effect of BEZ was determined by in vitro probe acylcarnitine (IVP) assay using cultured fibroblasts and tandem mass spectrometry on various FAO disorders. The clinical trial of BEZ treatment for a boy with the intermediate form of glutaric acidemia type 2 (GA2) was also performed. RESULTS: The effect of BEZ was proven in cells from various FAO disorders including GA2, deficiencies of VLCAD, medium-chain acyl-CoA dehydrogenase, CPT2, carnitine acylcarnitine translocase and trifunctional protein, by the IVP assay. The aberrantly elevated long- or medium-chain acylcarnitines that are characteristic for each FAO disorder were clearly corrected by the presence of BEZ (0.4 mmol/L) in culture medium. Moreover, daily administration of BEZ in a 2-year-old boy with GA2 dramatically improved his motor and cognitive skills, accompanied by sustained reduction of C4, C8, C10 and C12 acylcarnitines in blood, and normalized the urinary organic acid profile. No major adverse effects have been observed. CONCLUSION: These results indicate that BEZ could be a new treatment option for FAO disorders.
Authors: Shrivani Sriskanthadevan; Danny V Jeyaraju; Timothy E Chung; Swayam Prabha; Wei Xu; Marko Skrtic; Bozhena Jhas; Rose Hurren; Marcela Gronda; Xiaoming Wang; Yulia Jitkova; Mahadeo A Sukhai; Feng-Hsu Lin; Neil Maclean; Rob Laister; Carolyn A Goard; Peter J Mullen; Stephanie Xie; Linda Z Penn; Ian M Rogers; John E Dick; Mark D Minden; Aaron D Schimmer Journal: Blood Date: 2015-01-28 Impact factor: 22.113
Authors: Eugene F Diekman; Sacha Ferdinandusse; Ludo van der Pol; Hans R Waterham; Jos P N Ruiter; Lodewijk Ijlst; Ronald J Wanders; Sander M Houten; Frits A Wijburg; A Christiaan Blank; Folkert W Asselbergs; Riekelt H Houtkooper; Gepke Visser Journal: Genet Med Date: 2015-04-02 Impact factor: 8.822