Caracterização clínica, bioquímica e molecular de pacientes com doença da urina do xarope de bordo

Abstract

Maple Syrup Urine Disease (MSUD) is an inborn error of metabolism of branched chain amino acids: leucine, isoleucine and valine. The cause is the deficiency of the enzymatic complex branched chain keto acid dehydrogenase. The symptoms are neurological and one of the best described models to explain them is based on the competition of neutral amino acids for the influx through blood-brain barrier, which use large amino acid transporter type 1 (LAT1). Increases of leucine concentrations in the plasma saturate the transporter and, consequently, the influx of other amino acids on the central nervous system decreases, leading to impaired development. In Brazil, patients are diagnosed late and have poor clinical and laboratorial control, resulting in unfavorable outcomes. The aim of this study was, therefore, to evaluate six patients with MSUD in treatment in the Hospital das Clínicas (HC – UFMG), regarding clinical, diagnosis and molecular characteristics, as well as the impact of the treatment through the study of amino acids profile. The methodology was based on the study of medical records and on clinical and nutritional periodical evaluations. The quantification of amino acids in the plasma was conducted by high performance liquid chromatography and the reference values adopted were calculated from a control group of 60 healthy children. The molecular study was based on sequencing of genes involved. All patients presented the classical form of the disease, with early onset of the symptoms, however five had late diagnosis. The age at the moment of the diagnosis correlated with the clinical outcome. The establishment of reference intervals for plasma amino acids and brain influx allowed the identification of increased levels of branched chain amino acids (BCAA), as well as deficiencies of many amino acids. The high plasma concentrations of leucine and isoleucine are associated with alanine deficiency. Deficiencies of serotonin and catecholamines in the central nervous system should be treated by nutritional replacement of deficient amino acids. The application of a more consistent method of dietary survey is required for adequate estimation of amino acids intake. Concerning the molecular characterization it was observed that, besides locus heterogeneity, there was also a great allelic heterogeneity in individuals with MSUD in our population and four new mutations were described. There was no apparent correlation between the genotype and phenotype.