ArticleHuman molecular genetics2011
Phenylbutyrate therapy for maple syrup urine disease.
Article in Human molecular genetics, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers, 2 of them syntheses that pooled it.
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Who cites it
50 citing papers in PubMed, 2 syntheses or guidelines pooled it, 94 citations in OpenAlex.
- Comprehensive Iranian guidelines for the diagnosis and management of maple syrup urine disease: an evidence- and consensus- based approach.Orphanet journal of rare diseases · 2025Guideline
- Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis.PLoS medicine · 2016Pooled it
- Branched-chain amino acids and gut microbiota: coregulation and impact on neurological function via the gut-brain axis.Gut microbes · 2026Review
- Treatment strategies, radiological recovery, and neurodevelopmental outcomes in paediatric Maple Syrup Urine Disease: a 20-year single-centre experience from Türkiye.Metabolic brain disease · 2026Article
- Management of acute metabolic decompensation in maple syrup urine disease: guidance based on international clinical practice.Orphanet journal of rare diseases · 2026Review
- Pyruvate Dehydrogenase Complex Deficiency: A Review of Treatments and Case Series.International journal of molecular sciences · 2026Review
- Review
- Metabolic Adaptations and Therapies in Cardiac Hypoxia: Mechanisms and Clinical Implications/ Potential Strategies.JACC. Basic to translational science · 2025Review
- Emergency Management of Intoxication-Type Inherited Metabolic Disorders.Journal of inherited metabolic disease · 2025Review
- Anaplerotic filling in heart failure: a review of mechanism and potential therapeutics.Cardiovascular research · 2024Review
- Identification of putative allosteric inhibitors of BCKDK via virtual screening and biological evaluation.Journal of enzyme inhibition and medicinal chemistry · 2024Article
- Computational structural genomics and clinical evidence suggest BCKDK gain-of-function may cause a potentially asymptomatic maple syrup urine disease phenotype.JIMD reports · 2024Article
- Branched-chain keto acids promote an immune-suppressive and neurodegenerative microenvironment in leptomeningeal disease.bioRxiv : the preprint server for biology · 2023Article
- Review
- Amino acid metabolism in health and disease.Signal transduction and targeted therapy · 2023Review
- Branched-chain amino acids in cardiovascular disease.Nature reviews. Cardiology · 2023Review
- Role of branched-chain amino acid metabolism in the pathogenesis of obesity and type 2 diabetes-related metabolic disturbances BCAA metabolism in type 2 diabetes.Nutrition & diabetes · 2022Review
- Comparison Between Dichloroacetate and Phenylbutyrate Treatment for Pyruvate Dehydrogenase Deficiency.British journal of biomedical science · 2022Review
- Preliminary results of PBA-loaded nanoparticles development and the effect on oxidative stress and neuroinflammation in rats submitted to a chemically induced chronic model of MSUD.Metabolic brain disease · 2021Article
- Phenylbutyrate, a branched-chain amino acid keto dehydrogenase activator, promotes branched-chain amino acid metabolism and induces muscle catabolism in C2C12 cells.Experimental physiology · 2021Article
Corrections and comments
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Authors and funding
14 authors at 5 institutions in 1 country.
Funding
Abstract
Therapy with sodium phenylacetate/benzoate or sodium phenylbutyrate in urea cycle disorder patients has been associated with a selective reduction in branched-chain amino acids (BCAA) in spite of adequate dietary protein intake. Based on this clinical observation, we investigated the potential of phenylbutyrate treatment to lower BCAA and their corresponding α-keto acids (BCKA) in patients with classic and variant late-onset forms of maple syrup urine disease (MSUD). We also performed in vitro and in vivo experiments to elucidate the mechanism for this effect. We found that BCAA and BCKA are both significantly reduced following phenylbutyrate therapy in control subjects and in patients with late-onset, intermediate MSUD. In vitro treatment with phenylbutyrate of control fibroblasts and lymphoblasts resulted in an increase in the residual enzyme activity, while treatment of MSUD cells resulted in the variable response which did not simply predict the biochemical response in the patients. In vivo phenylbutyrate increases the proportion of active hepatic enzyme and unphosphorylated form over the inactive phosphorylated form of the E1α subunit of the branched-chain α-keto acid dehydrogenase complex (BCKDC). Using recombinant enzymes, we show that phenylbutyrate prevents phosphorylation of E1α by inhibition of the BCKDC kinase to activate BCKDC overall activity, providing a molecular explanation for the effect of phenylbutyrate in a subset of MSUD patients. Phenylbutyrate treatment may be a valuable treatment for reducing the plasma levels of neurotoxic BCAA and their corresponding BCKA in a subset of MSUD patients and studies of its long-term efficacy are indicated.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.