Riboflavin responsive ethylmalonic encephalopathy in two Korean sibs

Abstract

Ethylmalonic encephalopathy is a complex organic aciduria characterized by ethylmalonic aciduria, lactic acidemia with developmental delay, acrocyanosis, petechia and chronic mucoid diarrhea. Since 1994, less than 30 patients have been reported and the underlying metabolic defect is unknown.We report 2 affected sibs with typical clinical and biochemical phenotypes, and brain MRI findings. Patient I is a 5 years old girl who presents with developmental delay, spastic quadriplegia, and chronic diarrhea. She was hospitalized several times due to chronic diarrhea and pneumonia in the early infancy. She developed frequent skin petechiae on compression sites and cyanosis on the lower extremities. Brain MRI taken at the age of 25 months was suggestive of hypoxic ischemic encepahlopathy and no further evaluation was undertaken. Patient 2, her younger sister, is a 34 months old girl who presents with a similar clinical course but had no evaluation until recently when she developed respiratory difficulty due to pneumonia which required hospitalization. She was able to control her head at 4 months of age and crawl at 9 months of age but never sit, stand or talk. Her spastic quadriplegia became worse after this episode and she is almost wheel chair bound. Brain MRI showed multifocal nodular T2 high signals in both basal ganglia with enhancement, patchy T2 high signals in both periventricular white matter, centrum semiovale, and cerebellum. Muscle biopsy showed diffuse atrophy but no evidence of mitocnondrial disorder. Organic acid and acylglycine profiles showed markedly elevated excretion of ethylmalonic acid (134 mmol/mol creatinine: controls: <18), isobutyrylglycine, butyrylglycine, methylbutyrylglycine, and isovalerylglycine were also elevated. Serum lactate was 3.2 mmol/L (control: 0.7-2.0). 100 mg/kg/day oral carnitine supplementation for 2 months had no visible effect. However, they became significantly more active and alert on riboflavin treatment (100 mg/day). Patient 1 rolled over and was socially more active with laughing and sounds. In patient 2, motor improvement was not significant but she became more alert and socially active. Notably, the chronic mucoid diarrhea subsided considerably in both children, but petechiae were unaffected.Our observations suggest that some cases with ethylmalonic encephalopathy could be responsive to riboflavin. In vitro evaluation of fatty acid and branched chain amino acid metabolism is in progress.