Background: Late-onset
multiple acyl-CoA dehydrogenase deficiency (LO-MADD) describes a curable autosomal recessive
genetic disease caused by ETFDH mutations that result in defects in ETF-
ubiquinone oxidoreductase. Almost all patients are responsive to
riboflavin. This study describes the clinical presentations and genetic characteristics of five LO-MADD patients. Methods: From 2018 to 2021, we collected clinical and genetic data on five patients diagnosed with LO-MADD at our hospital and retrospectively analyzed their clinical characteristics, laboratory examination, electromyography, muscle biopsy, genetic analysis, and outcome data. Results: This study included three males and two females with mean onset age of 37.8 years. Fluctuating exercise intolerance was the most common presentation. Serum
creatine kinase (CK) levels were significantly elevated in all patients, and plasma
acylcarnitine profiles revealed an increase in long-chain
acylcarnitine species in three cases. The urinary organic
acid study revealed a high level of hydroxyglutaric
acid in all patients. Electrophysiology demonstrated myogenic impairment. Muscle biopsies revealed
lipid storage myopathy. Molecular analysis identified nine mutations (three novels and six reported) in ETFDH. Exercise intolerance and
muscle weakness were dramatically improved in all patients treated with
riboflavin (100 mg) daily following diagnosis. Conclusions: LO-MADD is caused by ETFDH variants and responds well to
riboflavin. Three novel ETFDH pathogenic variants were identified, expanding their spectrum in the Chinese population and facilitating future interpretation and analysis of ETFDH mutations.