Clinical characteristics and gene mutation analysis of an adult patient with ETFDH‑related multiple acyl‑CoA dehydrogenase deficiency

Wang,Chenyi; Lv,Haihong; Xu,Xia; Ma,Yuping; Li,Qian

doi:10.3892/mmr.2020.11524

Clinical characteristics and gene mutation analysis of an adult patient with ETFDH‑related multiple acyl‑CoA dehydrogenase deficiency

Authors:
- Chenyi Wang
- Haihong Lv
- Xia Xu
- Yuping Ma
- Qian Li
View Affiliations

Affiliations: Department of Endocrinology, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
Published online on: September 18, 2020 https://doi.org/10.3892/mmr.2020.11524
Pages: 4396-4402
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Multiple acyl‑CoA dehydrogenase deficiency (MADD) is a rare autosomal recessive disorder of fatty acid metabolism caused by defects in electron transfer flavoprotein (ETF) or electron transfer flavoprotein dehydrogenase (ETFDH). These defects are mainly classified into the neonatal and late‑onset types, based on their clinical manifestations. ETFDH gene mutations are generally considered to be associated with the late‑onset type. The present study reported an adult woman with late‑onset MADD accompanied with biochemical and muscle biopsy findings indicating metabolic disorders. Gene sequencing analysis showed that the c.1514T>C homozygous mutation in the region of the 12th exon of the ETFDH gene, which led to the amino acid substitution p.I505T (isoleucine > threonine), resulting in defective ETFDH protein function. The results of family verification revealed that the homozygous mutation originated from her parents. The female patient was treated with a large dose of vitamin B2, L‑carnitine and coenzyme Q10, and the symptoms were significantly relieved. The c.1514T>C mutation in the ETFDH gene, was considered as a novel pathogenic mutation that had not been previously reported. Therefore, it was hypothesized that this mutation was responsible for the clinical characteristics of the adult female patient. Overall, this novel mutation could expand the spectrum of the ETFDH gene mutation and provide the basis for the etiological and prenatal diagnosis of MADD.

View Figures

View References

1	Frerman FE and Goodman SI: Deficiency of electron transfer flavoprotein or electron transfer flavoprotein: Ubiquinone oxidoreductase in glutaric acidemia type II fibroblasts. Proc Natl Acad Sci USA. 82:4517–4520. 1985. View Article : Google Scholar : PubMed/NCBI
2	Vergani L, Barile M, Angelini C, Burlina AB, Nijtmans L, Freda MP, Brizio C, Zerbetto E and Dabbeni-Sala F: Riboflavin therapy. Biochemical heterogeneity in two adult lipid storage myopathies. Brain. 122:2401–2411. 1999. View Article : Google Scholar : PubMed/NCBI
3	Wen B, Dai T, Li W, Zhao Y, Liu S, Zhang C, Li H, Wu J, Li D and Yan C: Riboflavin-responsive lipid-storage myopathy caused by ETFDH gene mutations. J Neurol Neurosurg Psychiatry. 81:231–236. 2010. View Article : Google Scholar : PubMed/NCBI
4	Nilipour Y, Fatehi F, Sanatinia S, Bradshaw A, Duff J, Lochmüller H, Horvath R and Nafissi S: Multiple acyl-coenzyme A dehydrogenase deficiency shows a possible founder effect and is the most frequent cause of lipid storage myopathy in Iran. J Neurol Sci. 411:1167072020. View Article : Google Scholar : PubMed/NCBI
5	Fu HX, Liu XY, Wang ZQ, Jin M, Wang DN, He JJ, Lin MT and Wang N: Significant clinical heterogeneity with similar ETFDH genotype in three Chinese patients with late-onset multiple acyl-CoA dehydrogenase deficiency. Neurol Sci. 37:1099–1105. 2016. View Article : Google Scholar : PubMed/NCBI
6	Przyrembel H, Wendel U, Becker K, Bremer HJ, Bruinvis L, Ketting D and Wadman SK: Glutaric aciduria type II: Report on a previously undescribed metabolic disorder. Clin Chim Acta. 66:227–239. 1976. View Article : Google Scholar : PubMed/NCBI
7	Chautard R, Laroche-Raynaud C, Lia AS, Chazelas P, Derouault P, Sturtz F, Baaj Y, Veauville-Merllié A, Acquaviva C, Favreau F and Faye PA: A case report of a mild form of multiple acyl-CoA dehydrogenase deficiency due to compound heterozygous mutations in the ETFA gene. BMC Med Genom. 13:122020. View Article : Google Scholar
8	Lucas TG, Henriques BJ and Gomes CM: Conformational analysis of the riboflavin-responsive ETF:QO-p.Pro456Leu variant associated with mild multiple acyl-CoA dehydrogenase deficiency. Biochim Biophys Acta Proteins Proteom. 1868:1403932020. View Article : Google Scholar : PubMed/NCBI
9	Chen S, Zhou Y, Chen Y and Gu J: fastp: An ultra-fast all-in-one FASTQ preprocessor. Bioinformatics. 34:i884–i890. 2018. View Article : Google Scholar : PubMed/NCBI
10	McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, Garimella K, Altshuler D, Gabriel S, Daly M and DePristo MA: The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20:1297–1303. 2010. View Article : Google Scholar : PubMed/NCBI
11	Jian X, Boerwinkle E and Liu X: In silico prediction of splice-altering single nucleotide variants in the human genome. Nucleic Acids Res. 42:13534–13544. 2014. View Article : Google Scholar : PubMed/NCBI
12	Paternostro-Sluga T, Grim-Stieger M, Posch M, Schuhfried O, Vacariu G, Mittermaier C, Bittner C and Fialka-Moser V: Reliability and validity of the Medical Research Council (MRC) scale and a modified scale for testing muscle strength in patients with radial palsy. J Rehabil Med. 40:665–671. 2008. View Article : Google Scholar : PubMed/NCBI
13	Koenig M, Beggs AH, Moyer M, Scherpf S, Heindrich K, Bettecken T, Meng G, Müller CR, Lindlöf M, Kaariainen H, et al: The molecular basis for Duchenne versus Becker Muscular Dystrophy: Correlation of severity with type of deletion. Am J Hum Genet. 45:498–506. 1989.PubMed/NCBI
14	Moser H: Duchenne muscular dystrophy: Pathogenetic aspects and genetic prevention. Human Genetics. 66:17–40. 1984. View Article : Google Scholar : PubMed/NCBI
15	Goodman SI and Frerman FE: Glutaric acidaemia type II (multiple Acyl-Coa dehydrogenation deficiency). J Inherit Metab Dis. 7:33–37. 1984. View Article : Google Scholar : PubMed/NCBI
16	Gordon N: Glutaric aciduria types I and II. Brain Dev. 28:136–140. 2005. View Article : Google Scholar : PubMed/NCBI
17	al-Essa MA, Rashed MS, Bakheet SM, Patay ZJ and Ozand PT: Glutaric aciduria type II: Observations in seven patients with neonatal- and late-onset disease. J Perinatol. 20:120–128. 2000. View Article : Google Scholar : PubMed/NCBI
18	Schiff M, Froissart R, Olsen RK, Acquaviva C and Vianey-Saban C: Electron transfer flavoprotein deficiency: Functional and molecular aspects. Mol Genet Metab. 88:153–158. 2006. View Article : Google Scholar : PubMed/NCBI
19	Zhang J, Frerman FE and Kim JJ: Structure of electron transfer flavoprotein-ubiquinone oxidoreductase and electron transfer to the mitochondrial ubiquinone pool. Proc Natl Acad Sci USA. 103:16212–16217. 2006. View Article : Google Scholar : PubMed/NCBI
20	Angelini C, Tavian D and Missaglia S: Heterogeneous phenotypes in lipid storage myopathy Due to ETFDH gene mutations. JIMD Rep. 38:33–40. 2018. View Article : Google Scholar : PubMed/NCBI
21	Champion M: An approach to the diagnosis of inherited metabolic disease. Arch Dis Child Educ Pract Ed. 95:40–46. 2010. View Article : Google Scholar : PubMed/NCBI
22	Li Q, Wei S, Wu D, Wen C and Zhou J: Urinary metabolomics study of patients with gout using gas chromatography-mass spectrometry. Biomed Res Int. 2018:34615722018. View Article : Google Scholar : PubMed/NCBI
23	Wang ZQ, Chen XJ, Murong SX, Wang N and Wu ZY: Molecular analysis of 51 unrelated pedigrees with late-onset multiple acyl-CoA dehydrogenation deficiency (MADD) in southern China confirmed the most common ETFDH mutation and high carrier frequency of c.250G>A. J Mol Med (Berl). 89:569–576. 2011. View Article : Google Scholar : PubMed/NCBI
24	Usselman RJ, Fielding AJ, Frerman FE, Watmough NJ, Eaton GR and Eaton SS: Impact of mutations on the midpoint potential of the [4Fe-4S]+1,+2 cluster and on catalytic activity in electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO). Biochemistry. 47:92–100. 2008. View Article : Google Scholar : PubMed/NCBI
25	Olsen RKJ, Olpin SE, Andresen BS, Miedzybrodzka ZH, Pourfarzam M, Merinero B, Frerman FE, Beresford MW, Dean JC, Cornelius N, et al: ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency. Brain. 130:2045–2054. 2007. View Article : Google Scholar : PubMed/NCBI