Riboflavin Nonresponsive Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) with Early Severe Cardiomyopathy: Favorable Long-Term Outcome of a Severe Neonatal Presentation on D,L-3-hydroxybutyrate Supplementation

Objectives: MADD is an extremely rare autosomal recessive disorder resulting in deficient electron transfer from FAD-dependent dehydrogenases to the mitochondrial respiratory chain. The riboflavin nonresponsive phenotype presents as a potentially life-threatening disorder in the neonatal period complicated by severe acidosis, hyperammonemia, hypoglycemia, and seizures. Early severe cardiomyopathy is common and often lethal. The mainstay of MADD treatment is a low fat, low protein diet. Orally supplemented D,L-3-hydroxybutyrate (OHB) is an additional treatment option to be considered in severe cases. The exogenous OHB is theorized to replace ketone bodies whose endogenous production through &β-Oxidation of fatty acids is blocked by the deficient electron transfer flavoproteins.

Methods: We report on two cousins (now 18 and 19 years old) with enzymatically and genetically confirmed riboflavin nonresponsive MADD. There is a strong family history of severe MADD: three siblings of the elder cousin died in neonatal period. Both cousins developed a neonatal life-threatening cardiomyopathy unresponsive to conventional treatment. We report the outcome of life-long supplementation with doses of OHB between 250 and 770 mg/kg/day.

Result: After commencing OHB, the cardiac contractility showed progressive and sustained improvement. Metabolic parameters including acylcarnitines, amino acids, lactate, glucose, and &β-hydroxybutyrate levels in blood and organic acids in urine were monitored. Cardiac surveillance involved NT-pro-brain natriuretic peptide (pro-BNP) measurement, regular electrocardiograms, and echocardiography were performed. Both children developed infrequent episodes of metabolic decompensations, some associated with cardiac worsening. The elder cousin presented with a prolonged out-of-hospital cardiac arrest presumed secondary to ventricular arrhythmias in association with cardiomyopathy at the age of 12 years. He was successfully resuscitated. As a preventive measure, both children underwent an implantable cardioverter-defibrillator (ICD) insertion. The younger cousin needed mitral clip placement at the age of 18 years because of severe mitral valve regurgitation on a background of a longstanding history of left atrial enlargement.

Conclusion: Early and long-term treatment with OHB is a promising life-saving therapeutic add-on option for patients with severe MADD. It has ameliorated the potential neonatal lethal outcome in our patients. However, the risk of long-term complications, particularly cardiac life-threatening adverse events, necessitate careful monitoring and management.