Clinical, pathological and genetic features and follow-up of 110 patients with late-onset MADD: a single-center retrospective study

Hum Mol Genet. 2022 Mar 31;31(7):1115-1129. doi: 10.1093/hmg/ddab308.


To observe a long-term prognosis in late-onset multiple acyl-coenzyme-A dehydrogenation deficiency (MADD) patients and to determine whether riboflavin should be administrated in the long-term and high-dosage manner, we studied the clinical, pathological and genetic features of 110 patients with late-onset MADD in a single neuromuscular center. The plasma riboflavin levels and a long-term follow-up study were performed. We showed that fluctuating proximal muscle weakness, exercise intolerance and dramatic responsiveness to riboflavin treatment were essential clinical features for all 110 MADD patients. Among them, we identified 106 cases with ETFDH variants, 1 case with FLAD1 variants and 3 cases without causal variants. On muscle pathology, fibers with cracks, atypical ragged red fibers (aRRFs) and diffuse decrease of SDH activity were the distinctive features of these MADD patients. The plasma riboflavin levels before treatment were significantly decreased in these patients as compared to healthy controls. Among 48 MADD patients with a follow-up of 6.1 years on average, 31 patients were free of muscle weakness recurrence, while 17 patients had episodes of slight muscle weakness upon riboflavin withdrawal, but recovered after retaking a small-dose of riboflavin for a short-term. Multivariate Cox regression analysis showed vegetarian diet and masseter weakness were independent risk factors for muscle weakness recurrence. In conclusion, fibers with cracks, aRRFs and diffuse decreased SDH activity could distinguish MADD from other genotypes of lipid storage myopathy. For late-onset MADD, increased fatty acid oxidation and reduced riboflavin levels can induce episodes of muscle symptoms, which can be treated by short-term and small-dose of riboflavin therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyl Coenzyme A / genetics
  • Death Domain Receptor Signaling Adaptor Proteins / genetics
  • Electron-Transferring Flavoproteins / genetics
  • Electron-Transferring Flavoproteins / metabolism
  • Follow-Up Studies
  • Guanine Nucleotide Exchange Factors / genetics
  • Humans
  • Iron-Sulfur Proteins* / genetics
  • Multiple Acyl Coenzyme A Dehydrogenase Deficiency* / diagnosis
  • Multiple Acyl Coenzyme A Dehydrogenase Deficiency* / drug therapy
  • Multiple Acyl Coenzyme A Dehydrogenase Deficiency* / genetics
  • Muscle Weakness / pathology
  • Muscle, Skeletal / metabolism
  • Mutation
  • Oxidoreductases Acting on CH-NH Group Donors* / genetics
  • Retrospective Studies
  • Riboflavin / genetics
  • Riboflavin / therapeutic use


  • Acyl Coenzyme A
  • Death Domain Receptor Signaling Adaptor Proteins
  • Electron-Transferring Flavoproteins
  • Guanine Nucleotide Exchange Factors
  • Iron-Sulfur Proteins
  • MADD protein, human
  • Oxidoreductases Acting on CH-NH Group Donors
  • Riboflavin