Persistently Increased Alloisoleucine in a Patient with Seizures.

Abstract

A 3-year-old female presented to the emergency department with worsening myoclonic and atonic seizures. Several months before presentation, she was diagnosed with epilepsy and was treated with an antiepileptic medication (zonisamide, 10 g/L oral suspension, twice daily). While admitted, clinical laboratory testing for complete cell counts, comprehensive metabolic panel, and plasma lactate and ammonia were all within reference intervals (data not shown). However, nutritional assessment by plasma amino acid (PAA)6 analysis revealed that branched-chain amino acids (BCAAs) were increased for alloisoleucine (allo-ile), normal for leucine (leu), and mildly increased for valine (val) and isoleucine (ile; Fig. 1). Similar results were obtained following repeat PAA analysis despite a history of unremarkable newborn screening (NBS). Due to persistently increased allo-ile concentrations, the biochemical geneticist recommended urine organic acid (UOA) analysis and sequencing for a maple syrup urine disease (MSUD) panel [4 genes: branched chain keto acid dehydrogenase E1, alpha polypeptide ( BCKDHA ),7 branched chain keto acid dehydrogenase E1 subunit beta ( BCKDHB ), dihydrolipoamide branched chain transacylase E2 ( DBT ), and dihydrolipoamide dehydrogenase ( DLD )]. The UOA analysis did not detect any compounds typically associated with MSUD and no previously-reported MSUD variants were identified through genetic testing. Perplexed by the inconsistent results, the geneticist reached out to the clinical laboratory. Fig. 1. BCAA Analysis. The patient's PAAs were measured by the Waters MassTrak UPLC system. With respect to retention times (RT; x -axis) and absorption units ( y -axis), the abbreviated chromatogram displays the BCAAs val (RT, 21.72 min), ile (RT, 27.24 min), leu (RT, 28.04 min), and allo-ile (alle; RT, 27.47 min). Norvaline (Nva; RT, 22.45 min) was used as the internal standard in the analysis. Concentrations of BCAAs at admission are depicted below the abbreviated chromatogram with defined reference intervals in μmol/L. ### QUESTIONS TO CONSIDER 1. What is the clinical significance of increased allo-ile concentrations in plasma? 2. What methodologies are available …