Gene/phenotype/disorder under study
IDH2, ISOCITRATE DEHYDROGENASE, NADP(+), 2 (OMIM *147650); D-2-HYDROXYGLUTARIC ACIDURIA 2; D2HGA2 (OMIM # 613657)
Abstract
D-2-Hydroxyglutaric Aciduria type 2 is a rare metabolic syndrome caused by the recurrent variant NM_002168.4 (IDH2): c.419G>A, p.(Arg140Gln) resulting in neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. The variant is also cancer-associated due to epigenetic, growth-promoting effects leading to chromatin hypermethylation and blocked differentiation. A small cohort of affected individuals is currently treated with the specific IDH2 -R140Q inhibitor enasidenib under the European AcSé-ESMART cancer trial (NCT02813135), ARM I with positive visual, motor developmental and cardiac outcomes.
IDH2 is an enzyme that bridges cellular metabolism and epigenetic regulation (Nayarisseri et al., 2024). Kernytsky et al (2015) showed that in a TF-1 IDH2 R140Q erythroleukemia model system, the IDH2 R140Q-induced histone and DNA hypermethylation was reversed by enasidenib inhibition.
We are interested in performing genome methylation profiling in affected individuals and, where possible, before and/or after treatment, to investigate the possibility of a treatment episignature/biomarker and the pathogenetic mechanism of the condition.
Supported by a grant from the Norwegian National Centre for Rare Diagnoses (#43066) and the Research Council of Norway (#358387).
Coordinating clinicians
Sofia Douzgou Houge – sofia.douzgou.houge@helse-bergen.no
Omar Hikmat (on behalf of METABERN)
Institution
Haukeland University Hospital and University of Bergen, Norway
Specific requirements beyond clinical data and genotype data sharing:
1- Re-analysis of DNA samples: Yes (Genome Methylation Profiling, pre- and/or post-treatment)
2- Resampling of patients: Yes (if treated with enasidenib)
3- Linked to a translational/basic research project: No