ArticleProceedings of the National Academy of Sciences of the United States of America2004
A gene encoding a putative FAD-dependent L-2-hydroxyglutarate dehydrogenase is mutated in L-2-hydroxyglutaric aciduria.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 114 papers, 1 of them a synthesis that pooled it.
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Who cites it
114 citing papers in PubMed, 1 synthesis or guideline pooled it, 193 citations in OpenAlex.
- Cerebral neoplasms in L-2 hydroxyglutaric aciduria: 3 new cases and meta-analysis of literature data.AJNR. American journal of neuroradiology · 2012Pooled it
- 2-Hydroxyglutarate Redirects Fatty Acid Partitioning to Mitigate Lipotoxic Stress and Preserve Metabolic Fuel.bioRxiv : the preprint server for biology · 2026Article
- Non-convulsive Status Epilepticus in L-2-Hydroxyglutaric Aciduria With a Novel L2HGDH Variant: A Case Report.Cureus · 2026Article
- Article
- ExplainBind: Explainable Physicochemical Determinants of Protein-Ligand Binding via Non-Covalent Interactions.bioRxiv : the preprint server for biology · 2026Article
- Riboflavin treatment in L-2-hydroxyglutaric aciduria: report on a pediatric patient and literature review.Journal of applied genetics · 2026Review
- l-2-Hydroxyglutarate impairs neuronal differentiation through epigenetic activation of MYC expression.The Journal of clinical investigation · 2026Article
- The return of metabolism: biochemistry and physiology of glycolysis.Biological reviews of the Cambridge Philosophical Society · 2026Review
- Glutamatergic Neurotransmission Disruption as a Pathomechanism of Brain Damage in Disorders of Amino Acid and Organic Acid Metabolism: Insights from Animal and Cellular Studies.Neurochemical research · 2026Review
- MECP2 Duplication Uncouples Mitochondrial and Purine Metabolism During neuronal maturation.bioRxiv : the preprint server for biology · 2025Article
- Genetic, neuroimaging, and clinical characteristics of a cohort of individuals with L-2-hydroxyglutaric aciduria from Türkiye.Journal of pediatric endocrinology & metabolism : JPEM · 2025Article
- Cardiometabolic disease and cardio-oncology: Insights from iPSC models and tissue engineering.Cell reports. Medicine · 2025Review
- Novel neuropathological findings in a long-term survivor of D-2-hydroxyglutaric aciduria type 1.Virchows Archiv : an international journal of pathology · 2024Article
- An Ultrasensitive Biosensor for Probing Subcellular Distribution and Mitochondrial Transport of l-2-Hydroxyglutarate.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Both Enantiomers of 2-Hydroxyglutarate Modulate the Metabolism of Cultured Human Neuroblastoma Cells.Neurochemical research · 2024Article
- Tricarboxylic Acid Cycle Relationships with Non-Metabolic Processes: A Short Story with DNA Repair and Its Consequences on Cancer Therapy Resistance.International journal of molecular sciences · 2024Review
- Late-onset cerebellar ataxia and a new frameshift L2HGDH mutation in a Chinese adult with L-2-hydroxyglutaric aciduria: a case report.Acta neurologica Belgica · 2024Article
- Focused Screening Identifies Different Sensitivities of Human TET Oxygenases to the Oncometabolite 2-Hydroxyglutarate.Journal of medicinal chemistry · 2024Article
- A universal metabolite repair enzyme removes a strong inhibitor of the TCA cycle.Nature communications · 2024Article
- Malignant glioma in L-2-Hydroxyglutaric Aciduria: thorough molecular characterization of a case and literature review.Free neuropathology · 2024Article
54 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The purpose of this study was to identify the biochemical and genetic defect in L-2-hydroxyglutaric aciduria, a neurometabolic disorder characterized by the presence of elevated concentrations of L-2-hydroxyglutaric acid in urine, plasma, and cerebrospinal fluid. Evidence is provided for the existence in rat tissues of a FAD-dependent enzyme catalyzing specifically the oxidation of L-2-hydroxyglutarate to alpha-ketoglutarate. This enzyme is mainly expressed in liver and kidney but also at lower levels in heart, brain, and other tissues. Subcellular fractionation indicates that the liver enzyme is present in mitochondria, where it is bound to membranes. Based on this information, a database search led to the identification of a gene encoding a human hypothetical protein homologous to bacterial FAD-dependent malate dehydrogenases and targeted to mitochondria. The gene encoding this protein, present on chromosome 14q22.1, was found to be in a region homozygous in patients with L-2-hydroxyglutaric aciduria from two consanguineous families. Three mutations that replaced a highly conserved residue (Lys-71-Glu and Glu-176-Asp) or removed exon 9 were identified in homozygous state in patients from three distinct families and were found to cosegregate with the disease. It is concluded that L-2-hydroxyglutarate is normally metabolized to alpha-ketoglutarate in mammalian tissues and that L-2-hydroxyglutaric aciduria is caused by mutations in the gene that most likely encodes L-2-hydroxyglutarate dehydrogenase. The pathological findings observed in this metabolic disorder must therefore be due to a toxic effect of L-2-hydroxyglutarate on the central nervous system.
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