Significant clinical heterogeneity with similar ETFDH genotype in three Chinese patients with late-onset multiple acyl-CoA dehydrogenase deficiency

Neurol Sci. 2016 Jul;37(7):1099-105. doi: 10.1007/s10072-016-2549-2. Epub 2016 Mar 21.


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.

Keywords: Clinical heterogeneity; ETFDH; Late-onset multiple acyl-CoA dehydrogenase deficiency; Lipid storage myopathy; Variants.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Carnitine / analogs & derivatives
  • Carnitine / blood
  • Computational Biology
  • DNA Mutational Analysis
  • Electron-Transferring Flavoproteins / genetics*
  • Electron-Transferring Flavoproteins / metabolism
  • Genotype
  • Humans
  • Iron-Sulfur Proteins / genetics*
  • Iron-Sulfur Proteins / metabolism
  • Magnetic Resonance Imaging
  • Male
  • Multiple Acyl Coenzyme A Dehydrogenase Deficiency / diagnostic imaging
  • Multiple Acyl Coenzyme A Dehydrogenase Deficiency / genetics*
  • Multiple Acyl Coenzyme A Dehydrogenase Deficiency / metabolism
  • Multiple Acyl Coenzyme A Dehydrogenase Deficiency / physiopathology
  • Muscle Weakness / complications
  • Muscle Weakness / genetics
  • Muscular Diseases / complications
  • Muscular Diseases / genetics
  • Mutation / genetics*
  • Oxidoreductases Acting on CH-NH Group Donors / genetics*
  • Oxidoreductases Acting on CH-NH Group Donors / metabolism


  • Electron-Transferring Flavoproteins
  • Iron-Sulfur Proteins
  • acylcarnitine
  • Oxidoreductases Acting on CH-NH Group Donors
  • electron-transferring-flavoprotein dehydrogenase
  • Carnitine