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Reduction of plasma concentrations of large neutral amino acids in patients with maple syrup urine disease during crises
  1. M WAJNER,
  1. Medical Genetics Unit, Hospital de Clinicas de Porto Alegre, Porto Alegre, RS, Brazil
  2. email: mwajner{at}

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    Editor,—Neurological dysfunction is a major clinical feature of children with maple syrup urine disease (MSUD). However, the mechanisms underlying the neuropathophysiology of the disorder are poorly known. There is some evidence associating the appearance of the neurological symptoms with increased plasma concentrations of leucine or its ketoacid, α ketoisocaproic acid or both.1 Impairment of brain energy production by inhibition of key mitochondrial enzymes by the acidic metabolites that accumulate in this disease has also been reported.2 Although the reduction of branched chain amino acids and branched chain keto acids has been the main target for treatment of MSUD patients, a notable number of well treated patients have variable degrees of developmental delay accompanied by dysmyelination.3

    We performed a longitudinal study measuring glucose, insulin, and amino acid concentrations in plasma of eight children with MSUD aged 1 month to 7 years admitted to hospital during decompensation episodes, with convulsions, hypotonia, coma, ketonaemia/ketonuria, and metabolic acidosis, as well as after clinical recovery. Plasma from 10 age matched children showing no evidence of metabolic disease were analysed as controls. We found significantly reduced concentrations of various large neutral amino acids (LNAA), namely phenylalanine (5% of controls), tryptophan (13% of controls), methionine (18% of controls), and tyrosine (54% of controls) during decompensation, compared with the controls, apart from the expected increases of the branched chain amino acids leucine (28-fold), isoleucine (ninefold), and valine (threefold). After recovery, the plasma concentrations of all amino acids returned to nearly normal concentrations. Insulin concentrations were significantly lower in the MSUD patients during crises, whereas glucose concentrations were slightly but not significantly decreased.

    These results rule out a possible stimulatory effect of insulin on the amino acid uptake by peripheral tissues. Another explanation for the decrease of plasma LNAA could be sequestration of the amino acids by peripheral tissues through LNAA competition with leucine for the efflux from these tissues, as observed in experimental hyperphenyalaninaemia.4 Considering that for the essential amino acids, brain concentrations are determined in large part by plasma concentrations and transport across the blood–brain barrier, our data might suggest that the decreased concentrations of LNAA in plasma of MSUD patients during decompensation may impair neurotransmitter and protein biosynthesis in the brain, further contributing to the neurological dysfunction characteristic of these patients. In particular, it is possible that patients with MSUD might benefit by supplementing their diets with LNAAs.


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