title: Brain-blood amino acid correlates following protein restriction in murine maple syrup urine disease.
abstract: BACKGROUND
  Conventional therapy for patients with maple syrup urine disease (MSUD) entails restriction of protein intake to maintain acceptable levels of the branched chain amino acid, leucine (LEU), monitored in blood. However, no data exists on the correlation between brain and blood LEU with protein restriction, and whether correction in blood is reflected in brain.
  
  
  METHODS
  To address this question, we fed intermediate MSUD mice diets of 19% (standard) and 6% protein, with collection of sera (SE), striata (STR), cerebellum (CE) and cortex (CTX) for quantitative amino acid analyses.
  
  
  RESULTS
  LEU and valine (VAL) levels in all brain regions improved on average 28% when shifting from 19% to 6% protein, whereas the same improvements in SE were on average 60%. Isoleucine (ILE) in brain regions did not improve, while the SE level improved 24% with low-protein consumption. Blood-branched chain amino acids (LEU, ILE, and VAL in sera (SE)) were 362-434 μM, consistent with human values considered within control. Nonetheless, numerous amino acids in brain regions remained abnormal despite protein restriction, including glutamine (GLN), aspartate (ASP), glutamate (GLU), gamma-aminobutyric acid (GABA), asparagine (ASN), citrulline (CIT) and serine (SER). To assess the specificity of these anomalies, we piloted preliminary studies in hyperphenylalaninemic mice, modeling another large neutral aminoacidopathy. Employing an identical dietary regimen, we found remarkably consistent abnormalities in GLN, ASP, and GLU.
  
  
  CONCLUSIONS
  Our results suggest that blood amino acid analysis may be a poor surrogate for assessing the outcomes of protein restriction in the large neutral amino acidopathies, and further indicate that chronic neurotransmitter disruptions (GLU, GABA, ASP) may contribute to long-term neurocognitive dysfunction in these disorders.
authors.forename: Kara R
authors.initials: KR
authors.lastname: Vogel
authors.forename: Erland
authors.initials: E
authors.lastname: Arning
authors.forename: Brandi L
authors.initials: BL
authors.lastname: Wasek
authors.forename: Sterling
authors.initials: S
authors.lastname: McPherson
authors.forename: Teodoro
authors.initials: T
authors.lastname: Bottiglieri
authors.affiliation: Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, 412 E, Spokane Falls Blvd,, Pharmaceutical and Biomedical Sciences Building, Room 347, P,O, Box 1495, 99210-1495 Spokane, WA, USA. mike.gibson@wsu.edu.
authors.forename: K Michael
authors.initials: KM
authors.lastname: Gibson
mesh_terms: D000596:Amino Acids / Q000097:blood / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D004044:Dietary Proteins / Q000008:administration & dosage*; D004195:Disease Models, Animal; D008375:Maple Syrup Urine Disease / Q000178:diet therapy* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D016133:Polymerase Chain Reaction
chemical_list: D000596:Amino Acids; D004044:Dietary Proteins