title: Significant clinical heterogeneity with similar ETFDH genotype in three Chinese patients with late-onset multiple acyl-CoA dehydrogenase deficiency.
abstract: Late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) with electron transfer flavoprotein dehydrogenase (ETFDH) gene mutations is the most common lipid storage myopathy (LSM) in China. Its clinical features vary widely and pose a challenge for diagnosis. We presented the significant clinical heterogeneity among three Chinese late-onset MADD patients with similar ETFDH genotype by collecting clinical information, muscle histology, and genetic analysis. Three novel compound heterozygous variants of ETFDH gene were identified: c.892C > T (p.Pro298Ser), c.453delA (p.Glu152ArgfsTer15), and c.449_453delTAACA (p.Leu150Ter). Moreover, all patients carried a hotspot mutation c.250G > A (p.Ala84Thr). Western blot analysis of the patients' muscular tissue showed a significantly reduced ETFDH expression, and normal electron transfer flavoprotein A (ETFA) and electron transfer flavoprotein B (ETFB) expression. Two patients with similar genotypes (c.453delA and c.449_453delTAACA) presented a significant clinical heterogeneity. Among them, one exhibited muscle weakness and exercise intolerance as initial and major symptoms, and the other showed episodic recurrent gastrointestinal symptoms before a serious muscle weakness appeared in later life. The novel variants in ETFDH and the corresponding clinical features enrich the variant spectrum of late-onset MADD and provide a new insight into the genotype-phenotype relationship. Late-onset MADD should be included in differential diagnosis for adult myopathy along with chronic digestive disease.
authors.affiliation: Department of Neurology and Institute of Neurology, First Affiliated Hospital, Fujian Medical University, 20 Chazhong Road, Fuzhou, 350005, China.
authors.forename: Hong-Xia
authors.initials: HX
authors.lastname: Fu
authors.affiliation: Department of Neurology and Institute of Neurology, First Affiliated Hospital, Fujian Medical University, 20 Chazhong Road, Fuzhou, 350005, China.
authors.forename: Xin-Yi
authors.initials: XY
authors.lastname: Liu
authors.affiliation: Department of Neurology and Institute of Neurology, First Affiliated Hospital, Fujian Medical University, 20 Chazhong Road, Fuzhou, 350005, China.|Fujian Key Laboratory of Molecular Neurology, Fuzhou, China.
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Wang
authors.affiliation: Department of Neurology and Institute of Neurology, First Affiliated Hospital, Fujian Medical University, 20 Chazhong Road, Fuzhou, 350005, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Jin
authors.affiliation: Department of Neurology and Institute of Neurology, First Affiliated Hospital, Fujian Medical University, 20 Chazhong Road, Fuzhou, 350005, China.
authors.forename: Dan-Ni
authors.initials: DN
authors.lastname: Wang
authors.affiliation: Department of Neurology and Institute of Neurology, First Affiliated Hospital, Fujian Medical University, 20 Chazhong Road, Fuzhou, 350005, China.
authors.forename: Jun-Jie
authors.initials: JJ
authors.lastname: He
authors.affiliation: Department of Neurology and Institute of Neurology, First Affiliated Hospital, Fujian Medical University, 20 Chazhong Road, Fuzhou, 350005, China.
authors.forename: Min-Ting
authors.initials: MT
authors.lastname: Lin
authors.affiliation: Department of Neurology and Institute of Neurology, First Affiliated Hospital, Fujian Medical University, 20 Chazhong Road, Fuzhou, 350005, China. ningwang@mail.fjmu.edu.cn.|Fujian Key Laboratory of Molecular Neurology, Fuzhou, China. ningwang@mail.fjmu.edu.cn.
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002331:Carnitine / Q000031:analogs & derivatives / Q000097:blood; D019295:Computational Biology; D004252:DNA Mutational Analysis; D044927:Electron-Transferring Flavoproteins / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D006801:Humans; D007506:Iron-Sulfur Proteins / Q000235:genetics* / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D054069:Multiple Acyl Coenzyme A Dehydrogenase Deficiency / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D018908:Muscle Weakness / Q000150:complications / Q000235:genetics; D009135:Muscular Diseases / Q000150:complications / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics* / Q000378:metabolism
chemical_list: D044927:Electron-Transferring Flavoproteins; D007506:Iron-Sulfur Proteins; C116917:acylcarnitine; D000587:Oxidoreductases Acting on CH-NH Group Donors; C023120:electron-transferring-flavoprotein dehydrogenase; D002331:Carnitine
keywords: Clinical heterogeneity; ETFDH; Late-onset multiple acyl-CoA dehydrogenase deficiency; Lipid storage myopathy; Variants