Case Presentation: High anion gap metabolic acidosis is a frequently encountered problem with a very specific workup based on history and physical. This case brings to light a possible rare cause of anion gap metabolic acidosis. 49-year-old female with Asperger’s disorder and seizures who was brought to the emergency department by her caregiver because of increasing agitation over one week. She was recently taken off clonazepam by her psychiatrist without a taper. Initial workup showed a high anion gap metabolic acidosis with anion gap of 23. Glucose of 71. Urinalysis consistent with UTI and 3+ ketones. Lactic acid was normal. Salicylate, ethanol and acetaminophen levels were unremarkable. Acetone and betahydroxybutyrate elevated at 45 and 105 respectively. Osmolal gap was 16. She was tested for toxic alcohol ingestions. A fomepizole dose was given prior to the workup for toxic ingestion coming back negative. Patient improved clinically with IV dextrose fluids and antibiotics and the metabolic acidosis resolved. It was concluded that patient most likely ingested something causing metabolic acidosis. However, patient was brought back to the ED again for altered mental status five days later. At the group home, she was acting up, refusing food, throwing tantrums and then had a seizure like episode with facial twitching and staring into space. Labs showed metabolic acidosis with anion gap of 26. Glucose of 79 and urine positive for ketones. Both acetone and Beta-hydroxybutyrate levels were elevated. Osmolal gap slightly elevated at 12. Salicylate, acetaminophen, lactic acid, ethanol levels were unremarkable. Retested for toxic ingestion of alcohols including propylene glycol which was negative. Her acute encephalopathy and acidosis resolved with IV fluids again. No clear cause of metabolic acidosis was identified, and her workup was extended to include a plasma acylcarnithine and urine organic acid profiles. The results suggested late onset multiple Acyl-CoA dehydrogenase deficiency (MADD).
Discussion: MADD is an autosomal recessive disorder affecting the electron transfer flavoprotein resulting in impaired metabolism of fatty acids. Late onset MADD in adulthood can affect any organ but most commonly presents as progressive proximal myopathy with intermittent vomiting, hypoglycemia and metabolic acidosis. Our patient had recurrent high anion gap metabolic acidosis and hypoglycemia but no neurological findings besides acute encephalopathy. Three genes ETF-A, ETF-B and ETFDH have been identified in causing MADD. The ETFDH gene causes most cases of riboflavin responsive MADD. Genetic testing for ETFDH gene was negative in our patient but she wasn’t tested for the ETFA and ETFB gene. Though it wasn’t clear if our patient has late onset MADD, we started her on riboflavin supplements and she has been doing well since.
Conclusions: This case highlights a rare genetic disorder as a possible cause for high anion gap metabolic acidosis and an extremely treatable disease.