104 Hypoketotic hypoglycemia and hyperammonemia as presenting features of early onset multiple acyl-CoA dehydrogenase deficiency

Abstract

<h3>Introduction</h3> Multiple acyl-coenzyme A dehydrogenase deficiency (MADD) or glutaric aciduria type II is a rare, autosomal recessive disorder of fatty acid and amino acid oxidation. Disease is caused by pathogenic mutations in ETFA or ETFB genes, which encode two subunits of electron transfer flavoprotein (ETF), or ETFDH gene, encoding for ETF-dehydrogenase. Phenotype is heterogenous, from severe neonatal acute metabolic decompensation, with or without congenital anomalies, to milder, late onset forms. Diagnosis is made by acylcarnitine and urinary organic acid analysis, and gene testing. Treatment is based on restricted fat and protein intake, high carbohydrate diet, with carnitine, riboflavin and CoQ10 supplementation. <h3>Case Report</h3> Patient is a second child of unrelated parents. Family history unremarkable. Pregnancy was complicated by oligohydramnios. Delivery was on term, uneventful, BW 3740 g, BL 53 cm, AS 10,10. Tremor occurred as manifestation of hypoglycemia (BG 1.8 mmol/l), corrected with 10% oral glucose, on the first day of life. The newborn was euglycemic until 20 hours of life when irritability and somnolence were noticed in hypoglycemia (capillary glucose 2.3 mmol/L, venous glucose was immeasurably low). Glucose infusion was started but patient deteriorated to bradypnea and bradycardia. Cardiopulmonary reanimation lasted 40 minutes. Upon admission in NICU, patient was cardio-respiratory stable, but unconscious, hypertonic and soon developed seizures. Laboratory findings revealed metabolic acidosis (pH 7.3, BE -15.6), hyperlactatemia (14 mmol/L), hyperammonemia (230 µmol/L), increased aminotransferases and CK, normal blood glucose and positive urinary ketones. Brain MRI revealed cortical cytotoxic edema, restricted diffusion in corticospinal tracts and pons, and temporal atrophy. Ammonia normalized following high caloric intake, nitrogen scavengers, L-arginine, L-carnitine and vitamin B12. Urgent metabolic work-up revealed typical plasma acylcarnitine and urine organic acid profile for MADD. We started low protein and fat, high carbohydrate diet, continued with L-carnitine and added CoQ and riboflavin in therapy. Ultrasound showed mild hypertrophic cardiomyopathy and no malformations of other organs. Gene analysis revealed homozygous mutation c.1250C&gt;A (p.Thr266Met) of the ETFA gene. In further course patient was stable, but with severe developmental delay, epilepsy and impaired vision. <h3>Conclusion</h3> Beta oxidation defects, even with positive ketones, should be in differential diagnosis of neonatal hyperammonemia, as treatment is different than for other diseases. Lipid infusions, used to provide adequate caloric supply in other disorders, are contraindicated. Urgent metabolic work-up is mandatory for early diagnosis and optimal patient management. Clinical course with early acute cardio-respiratory failure, hypoglycemia and moderate hyperammonemia may be indicative for beta-oxidation defects.