Multiple acyl-CoA dehydrogenase (MADD) deficiency, which is a rare metabolic disorder involving electron transport flavoproteins, has a wide array of clinical phenotypes. In this article, we describe 25 patients with MADD deficiency and present the clinical and laboratory characteristics and diagnostic challenges associated with riboflavin-responsive MADD deficiency.Hospital records of patients with biallelic mutations in ETFA, ETFB, or ETFDH genes diagnosed in a single center were analyzed retrospectively. Demographic, clinical, and laboratory characteristics of patients with riboflavin-responsive and riboflavin-unresponsive MADD deficiency were compared using Mann-Whitney U and Fisher's exact tests.Respiratory distress and depressed consciousness were significantly more common in patients with riboflavin-unresponsive MADD deficiency (P = 0.015 and P < 0.001), who presented at a younger age (P < 0.001). Patients with riboflavin-responsive MADD deficiency had favorable outcomes but also had life-threatening complications, longer diagnostic delay (median of two years versus 30 days; P < 0.001), and multiple differential diagnoses, resulting in unnecessary investigations and maltreatment. Biopsies showed lipid storage, and complete autopsy was performed in one newborn with riboflavin-unresponsive MADD deficiency, revealing multiple abnormalities. Metabolic profiles were not distinguishable between riboflavin-responsive and riboflavin-unresponsive MADD deficiency (P > 0.05). Four novel variants were detected in ETFDH, one of which (c.1790C>T) may confer riboflavin responsiveness. Siblings with the common myopathic ETFDH c.1130T>C mutation presented with a new phenotype dominated by chronic fatigue without apparent myopathy.Symptoms and outcomes significantly differed between riboflavin-responsive and unresponsive MADD deficiency, but metabolic profiles did not. Functional studies are needed to better characterize the novel ETFDH variants. As treatment is available for riboflavin-responsive MADD deficiency, physicians should maintain a high index of suspicion for MADD deficiency in all age groups.
