Isocitrate Dehydrogenase – ILLUSTRATED MEDICAL COURSES

1. Overview of IDH

Gene Names: IDH1 and IDH2 (Isocitrate Dehydrogenase 1 and 2)
Normal Function:
- Catalyzes the conversion of isocitrate → α-ketoglutarate (α-KG) in the citric acid cycle
- Maintains normal cellular metabolism and redox balance

2. IDH Mutations

Hotspot mutations:
- IDH1: R132 (mostly R132H in gliomas)
- IDH2: R140, R172 (in AML)
Effect of mutation:
- Mutant IDH acquires neomorphic activity → converts α-KG → 2-hydroxyglutarate (2-HG)
- 2-HG is an oncometabolite → inhibits α-KG–dependent dioxygenases → blocks DNA/histone demethylation → epigenetic dysregulation and impaired differentiation

3. Tumors Associated with IDH Mutations

Tumor Type	Notes
Acute myeloid leukemia (AML)	IDH1 ~7–10%, IDH2 ~10–15%; leads to differentiation block
Gliomas	IDH1 R132H common in lower-grade gliomas (WHO grade II–III)
Cholangiocarcinoma	IDH1 mutations ~10–20% in intrahepatic cholangiocarcinoma
Other cancers	Rare in solid tumors

4. Clinical Implications

Prognostic:
- IDH mutations in AML often associated with intermediate prognosis
- IDH mutations in glioma → better prognosis than wild-type
Predictive:
- IDH mutations are targetable with specific inhibitors

5. Targeted Therapy

Drug	Target	Indication	Notes
Ivosidenib	IDH1	AML, cholangiocarcinoma	Oral inhibitor, differentiation therapy
Enasidenib	IDH2	AML	Oral inhibitor, induces differentiation of leukemic blasts
Vorasidenib	IDH1/2	Low-grade glioma	Crosses BBB

Mechanism:

Blocks mutant IDH enzyme → reduces 2-HG → restores normal epigenetic regulation → allows differentiation

6. Key Points

IDH mutations produce an oncometabolite (2-HG) → epigenetic dysregulation → tumor growth.
Mutations are actionable in AML, glioma, and cholangiocarcinoma.
Targeted therapy is mutation-specific: IDH1 inhibitors for IDH1, IDH2 inhibitors for IDH2.

Synonyms

IDH, IDH1, IDH2