IDH2 – D-2-hydroxyglutaric aciduria

The IDH2 gene encodes mitochondrial NADP(+)-dependent isocitrate dehydrogenase 2, which catalyzes conversion of isocitrate to α-ketoglutarate. D-2-hydroxyglutaric aciduria (D-2-HGA) type II (MONDO:0010924) is a rare neurometabolic disorder characterized by supraphysiological accumulation of D-2-hydroxyglutarate, developmental delay, hypotonia, and seizures. Unlike type I D-2-HGA caused by bi-allelic loss-of-function variants in D2HGDH, type II arises from heterozygous gain-of-function variants in IDH2. The pathogenic lesions cluster at residue Arg140 and produce neomorphic enzyme activity. Detailed genetic and functional characterization supports a strong gene–disease association. This summary reviews the current evidence linking IDH2 and D-2-hydroxyglutaric aciduria type II.

In a cohort of 15 unrelated patients with type II D-2-HGA, heterozygous germline variants altering Arg140 to glycine or glutamine were identified ([PMID:20847235]). These variants include c.418C>G (p.Arg140Gly) and c.419G>A (p.Arg140Gln), each found recurrently across multiple families, indicating hotspots at codon 140. No additional segregation data are reported, consistent with dominant inheritance. Population studies confirm absence of these variants in control databases, underscoring rarity and specificity. Collectively, this series establishes heterozygous IDH2 Arg140 variants as the primary genetic cause of type II D-2-HGA. The inheritance pattern is autosomal dominant with likely full penetrance given biochemical phenotype.

Functional assays in patient-derived lymphoblasts demonstrate gain-of-function activity for IDH2(p.Arg140Gln) and IDH2(p.Arg140Gly) alleles, converting 2-ketoglutarate to D-2-HG at an 8-fold higher rate compared to controls ([PMID:21889589]). The ultra performance liquid chromatography-tandem mass spectrometry assay quantified D-2-HG accumulation and confirmed stable expression of the heterozygous mutation. These data provide direct biochemical evidence that Arg140 variants neomorphically produce the oncometabolite D-2-HG. Such functional concordance strongly supports pathogenicity of IDH2 Arg140 variants. Together with genetic findings, these experiments validate a gain-of-function mechanism.

Neomorphic IDH2 Arg140 variants confer enzymatic activity that leads to D-2-HG accumulation, central to pathogenesis of type II D-2-HGA. This oncometabolite competitively inhibits key α-KG-dependent dioxygenases, altering epigenetic and metabolic homeostasis in nerve and muscle cells. Although detailed in vivo D-2-HGA models are limited, data from IDH mutant glioma systems suggest comparable epigenetic signatures arise from mutant IDH activity. The mechanism is distinct from loss-of-function disorders, reinforcing genotype–phenotype concordance. Therapeutic strategies targeting D-2-HG production or its downstream effects could therefore be rationally designed.

These findings have direct implications for clinical practice. Genetic testing for Arg140 variants in IDH2 should be considered in patients with unexplained developmental delay, hypotonia, seizures, and elevated D-2-HG. Techniques such as targeted sequencing and mass spectrometry-based D-2-HG assays enable sensitive detection. Identification of IDH2 mutation confirms type II D-2-HGA, informs autosomal dominant risk counseling, and guides biochemical surveillance. On the horizon, small-molecule inhibitors of mutant IDH2 may reduce D-2-HG levels and ameliorate disease manifestations.

In summary, heterozygous gain-of-function variants in IDH2 at Arg140 underlie D-2-hydroxyglutaric aciduria type II and drive disease through neomorphic enzyme activity. Robust genetic evidence from 15 unrelated probands and concordant functional assays support a strong gene–disease association. No conflicting evidence has emerged to date. Autosomal dominant inheritance and a specific variant spectrum at codon 140 facilitate accurate molecular testing. Key Take-home: IDH2 Arg140 variants confer neomorphic D-2-HG production, enabling definitive diagnosis and opening avenues for mechanism-based treatment of type II D-2-hydroxyglutaric aciduria.

References

• Science • 2010 • IDH2 mutations in patients with D-2-hydroxyglutaric aciduria PMID:20847235
• Biochimica et biophysica acta • 2011 • A lymphoblast model for IDH2 gain-of-function activity in d-2-hydroxyglutaric aciduria type II: novel avenues for biochemical and therapeutic studies PMID:21889589

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