Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive inherited disorder. In most MADD cases are caused by the absence or inactivity of either electron-transfer-flavoprotein (ETF) or electron-transfer-flavoprotein ubiquinone oxidoreductase (ETF:QO, also called ETFDH). More than 93% of MADD patients harbor ETFDH gene mutations. Especially, c.250G>A mutation is the hot spot mution in Taiwanese. The ETFDH-encoded ETF:QO has been reported to serves as electron transfer in mitochondrial electron transport chain and coupled with fatty acids oxidation. Meanwhile, ETF:QO also contribute to Redox homeostasis and QH2/Q isopotential group. In our previous finding, the MADD pedigree harboring homologous c. 92C>T and c.250G>A compound mutations was identified with myopathy that oil droplet accumulation, abnormal plasma fatty acid compositions, and mitochondrial abnormality. The impact of ETF:QO deficiency on the bioenergetics and differentiation of human skeletal muscle remains uncertain. Thus, we suggest that ETFDH mutations impair energetic metabolism and in vitro differentiation in human skeletal muscle. To underlying the pathogenesis of this fatty acid disorder, we plan to establish four types of plasmids with ETFDH wild type gene, c. 92C>T, c.250G>A, or c. 92C>T/c.250G>A compound mutations in human skeletal myoblasts (HSKM). We plan to set up this project for three parts. In the first part, we plan to investigate whether ETF:QO variants would impair mitochondrial bioenergetics result in a defect in a defect in muscle cell survival. The second part, we plan to verify whether ETF:QO variants would impair mitochondrial function result in a defect in a defect in muscular differentiation in vitro. The third part, we will establish disease-related metabolites or drug screening platform for seeking the biosignature for early diagnosis and potential therapeutic drug for late-onset MADD. The CellASIC® ONIX Live Cell Microfluidic Platform combined with Mass Spectrometry will be performed for seeking the disease-related metabolites and therapeutic drugs by monitoring intracellular oil drop formation and mitochondrial dynamics. The important issue should be considered early in differential diagnosis of late-onset MADD and therapeutic drug supplementation to avoid metabolic decompensations in the MADD adults with myopathy.
|Effective start/end date||8/1/16 → 7/31/17|
- Multiple Acyl-CoA Dehydrogenase Deficiency
- ETFDH gene
- electron-transfer-flavoprotein-ubiquinone oxidoreductase
- mitochondrial dysfunction
- lipid droplet accumulation
- Live Cell Microfluidic Platform