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.
