Bezafibrate Can Be a New Treatment Option for Mitochondrial Fatty Acid Oxidation Disorders: Evaluation by in Vitro Probe Acylcarnitine Assay

Overview

Journal Mol Genet Metab

Specialty Endocrinology

Date 2012 Jul 31

PMID 22841441

Citations 20

Authors

Seiji Yamaguchi

Hong Li

Jamiyan Purevsuren

Kenji Yamada

Midori Furui

Tomoo Takahashi

Yuichi Mushimoto

Hironori Kobayashi

Yuki Hasegawa

Takeshi Taketani

Toshiyuki Fukao

Seiji Fukuda

Affiliations

Soon will be listed here.

Abstract

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.

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Shiraishi H, Yamada K, Oki E, Ishige M, Fukao T, Hamada Y Mol Genet Metab Rep. 2019; 20:100496.

PMID: 31372341 PMC: 6661278. DOI: 10.1016/j.ymgmr.2019.100496.