Sodium phenylbutyrate decreases plasma branched-chain amino acids in patients with urea cycle disorders

Lindsay C Burrage, Mahim Jain, Laura Gandolfo, Brendan H Lee, Members of the Urea Cycle Disorders Consortium, Sandesh C S Nagamani, Mark L Batshaw, Mendel Tuchman, Marshall L Summar, Matthias R Baumgartner, Susan A Berry, Stephen Cederbaum, George A Diaz, Annette Feigenbaum, Renata C Gallagher, Cary O Harding, Georg Hoffmann, Douglas S Kerr, Brendan Lee, Uta Lichter-Konecki, Shawn E McCandless, J Lawrence Merritt 2nd, Andreas Schulze, Margretta R Seashore, Tamar Stricker, Susan Waisbren, Derek Wong, Mark Yudkoff, Lindsay C Burrage, Mahim Jain, Laura Gandolfo, Brendan H Lee, Members of the Urea Cycle Disorders Consortium, Sandesh C S Nagamani, Mark L Batshaw, Mendel Tuchman, Marshall L Summar, Matthias R Baumgartner, Susan A Berry, Stephen Cederbaum, George A Diaz, Annette Feigenbaum, Renata C Gallagher, Cary O Harding, Georg Hoffmann, Douglas S Kerr, Brendan Lee, Uta Lichter-Konecki, Shawn E McCandless, J Lawrence Merritt 2nd, Andreas Schulze, Margretta R Seashore, Tamar Stricker, Susan Waisbren, Derek Wong, Mark Yudkoff

Abstract

Sodium phenylbutyrate (NaPBA) is a commonly used medication for the treatment of patients with urea cycle disorders (UCDs). Previous reports involving small numbers of patients with UCDs have shown that NaPBA treatment can result in lower plasma levels of the branched-chain amino acids (BCAA) but this has not been studied systematically. From a large cohort of patients (n=553) with UCDs enrolled in the Longitudinal Study of Urea Cycle Disorders, a collaborative multicenter study of the Urea Cycle Disorders Consortium, we evaluated whether treatment with NaPBA leads to a decrease in plasma BCAA levels. Our analysis shows that NaPBA use independently affects the plasma BCAA levels even after accounting for multiple confounding covariates. Moreover, NaPBA use increases the risk for BCAA deficiency. This effect of NaPBA seems specific to plasma BCAA levels, as levels of other essential amino acids are not altered by its use. Our study, in an unselected population of UCD subjects, is the largest to analyze the effects of NaPBA on BCAA metabolism and potentially has significant clinical implications. Our results indicate that plasma BCAA levels should to be monitored in patients treated with NaPBA since patients taking the medication are at increased risk for BCAA deficiency. On a broader scale, these findings could open avenues to explore NaPBA as a therapy in maple syrup urine disease and other common complex disorders with dysregulation of BCAA metabolism.

Keywords: Branched-chain amino acids; Sodium phenylbutyrate; Urea cycle disorder.

Copyright © 2014 Elsevier Inc. All rights reserved.

Figures

Figure 1. NaPBA specifically decreases plasma BCAA…
Figure 1. NaPBA specifically decreases plasma BCAA but not other essential amino acids
The figure depicts the logarithmic p-values from the GLM analysis for association between NaPBA use and plasma amino acid levels. The corrected p-value is plotted for each essential amino acid. The dashed line represents the level at which P would correspond to a value of 0.05 when corrected for multiple comparisons. Whereas the p-values for BCAA levels are very significant, those of other essential amino acids do not reach statistical significance.

References

    1. Burlina AB, Ogier H, Korall H, Trefz FK. Long-term treatment with sodium phenylbutyrate in ornithine transcarbamylase-deficient patients. Mol Genet Metab. 2001;72:351–355.
    1. Brusilow SW. Phenylacetylglutamine may replace urea as a vehicle for waste nitrogen excretion. Pediatr Res. 1991;29:147–150.
    1. Brusilow S, Tinker J, Batshaw ML. Amino acid acylation: a mechanism of nitrogen excretion in inborn errors of urea synthesis. Science. 1980;207:659–661.
    1. Batshaw ML, MacArthur RB, Tuchman M. Alternative pathway therapy for urea cycle disorders: twenty years later. J Pediatr. 2001;138:S46–S54. discussion S54–45.
    1. Iannitti T, Palmieri B. Clinical and experimental applications of sodium phenylbutyrate. Drugs R D. 2011;11:227–249.
    1. Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, Gorgun CZ, Hotamisligil GS. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science. 2006;313:1137–1140.
    1. Basseri S, Lhotak S, Sharma AM, Austin RC. The chemical chaperone 4-phenylbutyrate inhibits adipogenesis by modulating the unfolded protein response. J Lipid Res. 2009;50:2486–2501.
    1. Brunetti-Pierri N, Lanpher B, Erez A, Ananieva EA, Islam M, Marini JC, Sun Q, Yu C, Hegde M, Li J, Wynn RM, Chuang DT, Hutson S, Lee B. Phenylbutyrate therapy for maple syrup urine disease. Hum Mol Genet. 2011;20:631–640.
    1. Maestri NE, Clissold DB, Brusilow SW. Long-term survival of patients with argininosuccinate synthetase deficiency. J Pediatr. 1995;127:929–935.
    1. Darmaun D, Welch S, Rini A, Sager BK, Altomare A, Haymond MW. Phenylbutyrate-induced glutamine depletion in humans: effect on leucine metabolism. Am J Physiol. 1998;274:E801–E807.
    1. Scaglia F, Carter S, O'Brien WE, Lee B. Effect of alternative pathway therapy on branched chain amino acid metabolism in urea cycle disorder patients. Mol Genet Metab. 2004;81(Suppl 1):S79–S85.
    1. Seminara J, Tuchman M, Krivitzky L, Krischer J, Lee HS, Lemons C, Baumgartner M, Cederbaum S, Diaz GA, Feigenbaum A, Gallagher RC, Harding CO, Kerr DS, Lanpher B, Lee B, Lichter-Konecki U, McCandless SE, Merritt JL, Oster-Granite ML, Seashore MR, Stricker T, Summar M, Waisbren S, Yudkoff M, Batshaw ML. Establishing a consortium for the study of rare diseases: The Urea Cycle Disorders Consortium. Mol Genet Metab. 2010;100(Suppl 1):S97–S105.
    1. Tuchman M, Lee B, Lichter-Konecki U, Summar ML, Yudkoff M, Cederbaum SD, Kerr DS, Diaz GA, Seashore MR, Lee HS, McCarter RJ, Krischer JP, Batshaw ML. Cross-sectional multicenter study of patients with urea cycle disorders in the United States. Mol Genet Metab. 2008;94:397–402.
    1. Team RC. R Foundation for Statistical Computing. Vienna, Austria: 2012. R: A language and environment for statistical computing.
    1. Rodney S, Boneh A. Amino Acid Profiles in Patients with Urea Cycle Disorders at Admission to Hospital due to Metabolic Decompensation. JIMD Rep. 2013;9:97–104.
    1. Garcia-Cazorla A, Oyarzabal A, Fort J, Robles C, Castejon E, Ruiz-Sala P, Bodoy S, Merinero B, Lopez-Sala A, Dopazo J, Nunes V, Ugarte M, Artuch R, Palacin M, Rodriguez-Pombo P, Alcaide P, Navarrete R, Sanz P, Font-Llitjos M, Vilaseca MA, Ormaizabal A, Pristoupilova A, Agullo SB. Two novel mutations in the BCKDK (branched-chain keto-acid dehydrogenase kinase) gene are responsible for a neurobehavioral deficit in two pediatric unrelated patients. Hum Mutat. 2014;35:470–477.
    1. Novarino G, El-Fishawy P, Kayserili H, Meguid NA, Scott EM, Schroth J, Silhavy JL, Kara M, Khalil RO, Ben-Omran T, Ercan-Sencicek AG, Hashish AF, Sanders SJ, Gupta AR, Hashem HS, Matern D, Gabriel S, Sweetman L, Rahimi Y, Harris RA, State MW, Gleeson JG. Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy. Science. 2012;338:394–397.
    1. Tso SC, Qi X, Gui WJ, Chuang JL, Morlock LK, Wallace AL, Ahmed K, Laxman S, Campeau PM, Lee BH, Hutson SM, Tu BP, Williams NS, Tambar UK, Wynn RM, Chuang DT. Structure-based design and mechanisms of allosteric inhibitors for mitochondrial branched-chain alpha-ketoacid dehydrogenase kinase. Proc Natl Acad Sci U S A. 2013;110:9728–9733.

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