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Muscle Nerve. 2017 Sep;56(3):479-485. doi: 10.1002/mus.25501. Epub 2017 Mar 21.

Neurite growth could be impaired by ETFDH mutation but restored by mitochondrial cofactors.

Liang WC1,2, Lin YF2, Liu TY3, Chang SC2, Chen BH1,3,4, Nishino I5,6, Jong YJ1,3,4,7.

Author information

1
Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
2
Department of Pediatrics, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
3
Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
4
Department of Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
5
Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
6
Department of Clinical Development, Translational Medical Center, National Center of Neurology and Psychiatry, Tokyo, Japan.
7
Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.

Abstract

INTRODUCTION:

c.250G>A (p.Ala84Thr) in ETFDH is the most common mutation that causes later-onset multiple acyl-coenzyme A dehydrogenase deficiency (MADD) in the southern Chinese population. No functional study has targeted this mutation.

METHODS:

Using cells expressing ETFDH-wild-type (WT) or ETFDH-mutant (p.Ala84Thr), reactive oxygen species (ROS) production and neurite length were analyzed, followed by pathomechanism exploration and drug screening.

RESULTS:

Increased ROS production and marked neurite shortening were observed in the cells expressing the ETFDH-mutant, compared with WT. Further studies demonstrated that suberic acid, an accumulated intermediate metabolite in MADD, could significantly impair neurite outgrowth of NSC34 cells, but neurite shortening could be restored by supplementation with carnitine, riboflavin, or Coenzyme Q10.

CONCLUSIONS:

Neurite shortening caused by the c.250G>A mutation in ETFDH suggests that neural defects could be underdiagnosed in human patients with MADD. This impairment might be treatable with mitochondrial cofactor supplementation. Muscle Nerve 56: 479-485, 2017.

KEYWORDS:

ETFDH; carnitine; coenzyme Q10; lipid storage myopathy; multiple acyl-coenzyme A dehydrogenase deficiency; neurite shortening; riboflavin

PMID:
27935074
DOI:
10.1002/mus.25501
[Indexed for MEDLINE]

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