small molecules

2026-01-14 | Early manifestations of D-2-hydroxyglutaric aciduria type II

D-2-hydroxyglutaric aciduria type II (ICD-10 code E72.8: Other specified disorders of amino-acid metabolism, ОMIM #613657) is a rare neurometabolic disorder associated with a pathogenic mutation in the IDH2 gene, which encodes a mitochondrial enzyme called isocitrate dehydrogenase 2. The pathogenesis of the disease is based on the accumulation of neurotoxic and cytotoxic 2-hydroxyglutarate in the body fluids, leading to the development of characteristic clinical manifestations. These include neurological disorders and eye conditions, hypotonia, neurodevelopmental delay, seizures, and cardiomyopathy. D-2-hydroxyglutaric aciduria type II has not been sufficiently studied. Despite the introduction of many metabolic disorders in expanded newborn screening, including glutamic acidemias, which are similar in name and course, this disease is still diagnosed only with the help of special biochemical and molecular genetic tests. This article presents early manifestations, developmental characteristics, neuropsychological and infectious status in a child with D-2-hydroxyglutaric aciduria. Key words: D-2-hydroxyglutaric aciduria type II, D-2-hydroxyglutarate, IDH2 gene, epilepsy, cardiomyopathy, infectious process, developmental delay, hypoxic-ischemic encephalopathy, floppy infant syndrome

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2025-12-25 | Successful Treatment of 2-Hydroxyglutaric Aciduria Diagnosed in Adulthood, Three Decades after the Onset: A Case Report and Literature Review.

2-Hydroxyglutaric aciduria is a rare genetic metabolic disorder, especially in Japan. Although magnetic resonance images show characteristic abnormalities in the subcortical white matter, some cases have been diagnosed in adulthood, namely many decades after onset. We herein report the case of a bedridden 37-year-old 2-hydroxyglutaric aciduria male patient who was diagnosed three decades after onset. Despite this, combination treatment with riboflavin and levocarnitine improved his condition, thus allowing him to walk by himself. Considering our case and the previous literature, we emphasize the importance of correctly diagnosing and treating patients with 2-hydroxyglutaric aciduria.

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2024-12-29 | Inactivation of the SLC25A1 gene during embryogenesis induces a unique senescence program controlled by p53

Germline inactivating mutations of the SLC25A1 gene contribute to various human disorders, including Velocardiofacial (VCFS), DiGeorge (DGS) syndromes and combined D/L-2-hydroxyglutaric aciduria (D/L-2HGA), a severe systemic disease characterized by the accumulation of 2-hydroxyglutaric acid (2HG). The mechanisms by which SLC25A1 loss leads to these syndromes remain largely unclear. Here, we describe a mouse model of SLC25A1 deficiency that mimics human VCFS/DGS and D/L-2HGA. Surprisingly, inactivation of both Slc25a1 alleles results in alterations in the development of multiple organs, and in a severe proliferation defect by activating two senescence programs, oncogene-induced senescence (OIS) and mitochondrial dysfunction-induced senescence (MiDAS), which converge upon the induction of the p53 tumor suppressor. Mechanistically, cells and tissues with dysfunctional SLC25A1 protein undergo metabolic and transcriptional rewiring leading to the accumulation of 2HG via a non-canonical pathway and to the depletion of nicotinamide adenine dinucleotide, NAD+, which trigger senescence. Replenishing the pool of NAD+ or promoting the clearance of 2HG rescues the proliferation defect of cells with dysfunctional SLC25A1 in a cooperative fashion. Further, removal of p53 activity via RNA interference restores proliferation, indicating that p53 acts as a critical barrier to the expansion of cells lacking functional SLC25A1. These findings reveal unexpected pathogenic roles of senescence and of p53 in D/L-2HGA and identify potential therapeutic strategies to correct salient molecular alterations driving this disease.

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2024-12-09 | Protective effects of the PPAR agonist bezafibrate against disruption of redox and energy homeostasis, neuronal death, astroglial reactivity, and neuroinflammation induced in vivo by D-2-hydroxyglutaric acid in rat brain.

The biochemical hallmark of D-2-hydroxyglutaric aciduria is brain accumulation of D-2-hydroxyglutaric acid (D2HG). Patients present predominantly neurological manifestations, whose pathogenesis is still unknown. Thus, we examined the impact of elevated brain levels of D2HG, induced by intracerebral injection of this metabolite in juvenile rats, on redox and mitochondrial homeostasis and histochemical landmarks in the cerebral cortex. D2HG administration disrupted redox homeostasis by increasing the levels of reactive oxygen species and lipid peroxidation and the activities of superoxide dismutase, glutathione peroxidase, and glutathione reductase and decreasing reduced glutathione levels. Furthermore, the complex IV and mitochondrial creatine kinase activities, as well as the protein contents of voltage-dependent anion channel 1, translocase of outer mitochondrial membrane 20, and peroxisome proliferator-activated receptor-γ coactivator 1-α, were diminished by D2HG, indicating bioenergetics dysfunction and disrupted mitochondrial biogenesis. D2HG also reduced neuronal nuclear protein content and augmented cleaved caspase-3, S100 calcium-binding protein B, glial fibrillary acidic protein, and ionized calcium-binding adaptor molecule 1, indicating neuronal loss, apoptosis, astrogliosis, and microglial activation, respectively. The tumor necrosis factor alpha expression was also significantly augmented, reflecting an increased inflammatory response. We also evaluated whether bezafibrate (BEZ) pretreatment could prevent the alterations induced by D2HG. BEZ normalized most of the D2HG-induced deleterious effects. Therefore, bioenergetics and redox status disruption caused by D2HG, associated with neuronal death, glial reactivity, and increased inflammatory response, may potentially represent pathomechanisms of brain damage in D-2-HGA. Finally, it is proposed that BEZ may be potentially used as therapy for D-2-HGA.

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2024-07-03 | A multiomics approach reveals evidence for phenylbutyrate as a potential treatment for combined D,L-2- hydroxyglutaric aciduria.

To identify therapies for combined D, L-2-hydroxyglutaric aciduria (C-2HGA), a rare genetic disorder caused by recessive variants in the SLC25A1 gene. Patients C-2HGA were identified and diagnosed by whole exome sequencing and biochemical genetic testing. Patient derived fibroblasts were then treated with phenylbutyrate and the functional effects assessed by metabolomics and RNA-sequencing. In this study, we demonstrated that C-2HGA patient derived fibroblasts exhibited impaired cellular bioenergetics. Moreover, Fibroblasts form one patient exhibited worsened cellular bioenergetics when supplemented with citrate. We hypothesized that treating patient cells with phenylbutyrate (PB), an FDA approved pharmaceutical drug that conjugates glutamine for renal excretion, would reduce mitochondrial 2-ketoglutarate, thereby leading to improved cellular bioenergetics. Metabolomic and RNA-seq analyses of PB-treated fibroblasts demonstrated a significant decrease in intracellular 2-ketoglutarate, 2-hydroxyglutarate, and in levels of mRNA coding for citrate synthase and isocitrate dehydrogenase. Consistent with the known action of PB, an increased level of phenylacetylglutamine in patient cells was consistent with the drug acting as 2-ketoglutarate sink. Our pre-clinical studies suggest that citrate supplementation has the possibility exacerbating energy metabolism in this condition. However, improvement in cellular bioenergetics suggests phenylbutyrate might have interventional utility for this rare disease.

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