**Background:** Multiple acyl-CoA dehydrogenase deficiency (MADD) is a severe inborn error of lipid metabolism caused by deficiency of electron transfer flavoprotein or electron transfer flavoprotein dehydrogenase (ETFDH). This disrupts mitochondrial electron transfer, lipid storage, and amino acid and choline metabolism. MADD can present with hypoketotic hypoglycemia, myopathy, nausea/vomiting, and liver dysfunction, occasionally progressing to liver failure or cirrhosis. The incidence at birth is estimated at 1 in 250,000. MADD is classified into 3 subtypes: types I and II are often fatal homozygous null mutations with neonatal onset within 48 hours of life, while type III (late-onset or riboflavin-responsive MADD) is milder with variable age of onset and clinical course.
**Methods:** This is a single case report of a 20-year-old Asian man with no history of alcohol use who presented to a hepatology clinic for elevated liver enzymes. He had been admitted 2 months prior for diffuse muscle aches, 20-lb unintentional weight loss, elevated aspartate aminotransferase at 380 U/L, and alanine aminotransferase at 117 U/L. Abdominal contrast CT revealed marked hepatomegaly compressing the stomach. Extensive workup for viral hepatitis, autoimmune hepatitis, Wilson disease, celiac disease, alpha-1-antitrypsin deficiency, hemochromatosis, thyroid disease, and malignancy was negative. Liver biopsy showed rare glycogenated nuclei but electron microscopy was negative for glycogen storage disease. One month later, he presented with proximal muscle weakness, severe rhabdomyolysis (creatinine kinase 12,449 U/L), and low glucose at 50 mg/dL. Electrophysiology showed diffuse myopathy without neuropathy.
**Key Results:** Free and total carnitine levels were low at 9 and 24 μmol/L, respectively (reference ranges: 22–63 and 31–78 μmol/L). Urine organic acids showed elevated ethylmalonic acid (7; reference 0–4), pyruvic acid (20; reference 0–15), and suberic acid (4; reference 0–3). Acylcarnitine profile showed moderate elevations of short-chain, medium-chain, and long-chain acylcarnitines (C4 to C18:2) with the highest value for C10 (decanoyl) at 1.9 μmol/L (reference ≤0.3). Genetic testing revealed 2 heterozygous mutations in ETFDH genes: c.560 C>T, p.(A187V) (reported pathogenic by a single submitter) and c.1669 G>A, p.(E557K) (pathogenic significance unknown). The patient declined additional genetic testing. Riboflavin was initiated at 50 mg three times daily for 1 week followed by 100 mg three times daily, resulting in complete resolution of symptoms. The patient gained approximately 17 lbs and had no recurrence of rhabdomyolysis or hypoglycemia.
**Clinical Implications:** Late-onset MADD should be considered in patients presenting with steatohepatitis unrelated to obesity, elevated AST and ALT, nonketotic hypoglycemia, acidosis, and muscle involvement. The diagnosis can be challenging as patients may not display typical patterns of elevated urinary organic acids and serum acylcarnitines during periods of well-being. Therapeutic interventions such as triglyceride oil, valproic acid, or certain antibiotics can mimic the biochemical profile. Diagnosis should rely on blood and urine analysis with confirmation by molecular methods. Late-onset MADD is typically very responsive to riboflavin (100–300 mg daily), carnitine, coenzyme Q10 supplements, and dietary changes. Patients with acute decompensation require intravenous fluids containing at least 10% dextrose and bicarbonate therapy. The condition is treatable with timely intervention, which is lifesaving and improves quality of life. The authors note that MADD is predominant in individuals of Asian descent.