Unusual isoleucine concentration kinetic in the follow-up of 2 patients affected by maple syrup urine disease

Background and objectives: Maple syrup urine disease (MSUD) is due to branched-chain ketoacid dehydrogenase deficiency that leads to accumulation of branched-chain amino acids. Treatment relies on a protein-restricted diet supplemented with branched- chain amino acid-free medical mixtures. Plasma leucine concentrations are regularly checked and kept between 150 and 250 microM, since leucine is viewed as the most toxic compound. Case report: We report on 2 neonatal MSUD patients diagnosed at 28 and 6 days of life with neonatal coma. Both patients were genetically confirmed (homozygous for BCKDHA p.Gln177Ter and BCKDHB p.Gln267Ter respectively). Surprisingly, during the follow-up, they presented episodes of dramatically increased isoleucine up to 1700 microM, and alloisoleucine up to 1350 microM, unrelated with leucine or valine concentrations. These episodes were not associated with any clinical deterioration, and usually occurred during periods without any isoleucine supplementation and following relative leucine depletion. Discussion: isoleucine likely comes from endogenous source as patients had adapted isoleucine intake, but dissociation with valine and leucine remains unexplained. Molecular mechanisms underlying our findings remain to be elucidated. Moreover, long-term exposure to high isoleucine levels could impact the outcome whereas low-protein diet does not seem to influence isoleucine levels in these particular patients.