Abstract
Valine, leucine, and isoleucine are essential branched chain amino acids (BCAAs). When BCAA metabolism is genetically impaired in human, serum levels of BCAA and/or their metabolites rise considerably, causing severe neurological dysfunction. The first step in BCAA catabolism is catalyzed by branched chain aminotransferase (BCAT). Hypervalinemia and hyperleucine-isoleucinemia caused by BCAT gene mutation in human have not been reported previously. A 25-year-old man presented with headache complaints and mild memory impairment for about six years. Brain MRI showed symmetric white matter abnormal signals. Metabolic studies revealed remarkably elevated plasma valine and leucine concentrations. Maple syrup urine disease (MSUD) diagnosis was not supported since all genes for the branched-chain α-keto acid dehydrogenase complex (BCKD) gene were normal. Interestingly, two heterogeneous BCAT2 gene mutations were found in the patient, including c.509G > A (p.Arg170Gln) and c.790G > A (p.Glu264Lys). In addition, c.509G > A (p.Arg170Gln) and c.790G > A (p.Glu264Lys) were found in his father and mother, respectively, suggesting an autosomal recessive disorder. BCAT2 functional studies demonstrated that the two BCAT2 gene mutations resulted in decreased BCAT2 enzyme activity. After treatment with vitamin B6, the levels of BCAA, especially valine were remarkably decreased and brain MRI lesions were improved. These findings suggest a new type of branched chain amino acid metabolism disorder. This rare case provides great insight into the further understanding of BCAA metabolism and its defect in human. BCAT2 gene mutations can cause hypervalinemia and hyperleucine-isoleucinemia, which are associated with brain white matter lesions.
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Acknowledgments
This work was supported by the Specialized Research Fund for the Doctoral Program of Higher Education (20131107120002). We acknowledge Professor Yanling Yang and Peng Yu for providing metabolite analyses.
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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (the Institutional Review Board of Xuan Wu Hospital, Capital Medical University, Beijing, China) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Written informed consent was obtained from the patient.
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Communicated by: Jerry Vockley
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Wang, X.L., Li, C.J., Xing, Y. et al. Hypervalinemia and hyperleucine-isoleucinemia caused by mutations in the branched-chain-amino-acid aminotransferase gene. J Inherit Metab Dis 38, 855–861 (2015). https://doi.org/10.1007/s10545-015-9814-z
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DOI: https://doi.org/10.1007/s10545-015-9814-z