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IDH2 gene
Reviewed by Medicinsk Expert•Last updated: 2026-10-22•Gene

IDH2 gene

The IDH2 gene provides instructions for making an enzyme essential for energy production and cellular protection, and its mutations are linked to several metabolic and cancerous conditions.

Normal Function

The IDH2 gene provides instructions for making an enzyme called isocitrate dehydrogenase 2. This enzyme is found in mitochondria, which are the energy-producing centers within cells. Within mitochondria, the enzyme participates in reactions that produce energy for cell activities. Specifically, isocitrate dehydrogenase 2 normally converts a compound called isocitrate to another compound called 2-ketoglutarate. A series of additional enzymes further process 2-ketoglutarate to produce energy. The conversion reaction also produces a molecule called NADPH, which is necessary for many cellular processes and helps protect cells from potentially harmful molecules called reactive oxygen species.

Health Conditions Related to Genetic Changes

2-hydroxyglutaric aciduria

At least two mutations in the IDH2 gene have been found to cause a type of 2-hydroxyglutaric aciduria known as D-2-hydroxyglutaric aciduria (D-2-HGA) type II. This condition has a variety of signs and symptoms that result primarily from progressive damage to the brain beginning early in life.

The mutations that cause D-2-HGA type II are present in all of an affected person's cells. These mutations prevent isocitrate dehydrogenase 2 from carrying out its usual activity, the conversion of isocitrate to 2-ketoglutarate. Instead, the altered enzyme takes on a new, abnormal function: the production of a compound called D-2-hydroxyglutarate. Because the genetic changes lead to an enzyme with a new function, they are classified as "gain-of-function" mutations.

In people with D-2-HGA type II, D-2-hydroxyglutarate builds up abnormally in cells. At high levels, this compound can damage cells and lead to cell death. Brain cells appear to be the most vulnerable to the toxic effects of this compound. Some people with this form of the disorder also have a weakened and enlarged heart (cardiomyopathy).

Maffucci syndrome

Mutations in the IDH2 gene can cause Maffucci syndrome, a disorder that primarily affects the bones and skin. It is characterized by:

  • Enchondromas: Noncancerous (benign) growths of cartilage that develop in the bones.
  • Hemangiomas: Red or purplish growths in the skin consisting of tangles of abnormal blood vessels.

The mutations associated with Maffucci syndrome are somatic, meaning they occur during a person's lifetime and are not inherited. These mutations occur in a single cell during early development, leading to mosaicism, where only some of the body's cells carry the mutation. These are gain-of-function mutations that result in the production of D-2-hydroxyglutarate.

Ollier disease

Mutations in the IDH2 gene can also cause Ollier disease, a disorder similar to Maffucci syndrome but without the blood vessel abnormalities. Like Maffucci syndrome, these are somatic gain-of-function mutations resulting in mosaicism.

Cytogenetically normal acute myeloid leukemia

Mutations in the IDH2 gene have been identified in some people with a form of blood cancer known as cytogenetically normal acute myeloid leukemia (CN-AML). Nearly 20 percent of people with CN-AML have a mutation in the IDH2 gene.

These somatic mutations change single protein building blocks (amino acids) in the isocitrate dehydrogenase 2 enzyme. These gain-of-function mutations cause the enzyme to abnormally produce D-2-hydroxyglutarate. Studies suggest that an increase in D-2-hydroxyglutarate may interfere with cell fate determination, causing immature blood cells to become cancerous and divide uncontrollably.

Other cancers

Somatic mutations in the IDH2 gene have been associated with other forms of cancer, including primary myelofibrosis and brain tumors called gliomas. These mutations are gain-of-function mutations that lead to the abnormal production of D-2-hydroxyglutarate, which likely blocks the maturation of cells, resulting in the overproduction of immature cells and the formation of tumors.

Frequently Asked Questions

Sudden worsening of seizures, loss of consciousness, severe vomiting, rapid breathing, or a marked increase in muscle tone can signal a metabolic crisis. Immediate evaluation in an emergency department for blood gas, lactate, and D‑2‑hydroxyglutarate levels, and prompt initiation of supportive care (IV fluids, seizure control) are essential.
Experimental therapies such as small‑molecule inhibitors of the mutant IDH2 enzyme (e.g., enasidenib) have shown promise in reducing D‑2‑hydroxyglutarate concentrations in clinical trials, but they are not yet standard of care for pediatric metabolic disease. Supportive measures include a low‑protein diet, supplementation with riboflavin, and antioxidants to mitigate oxidative stress, all under specialist supervision.
Diagnosis usually starts with clinical suspicion based on neurologic regression, seizures, or developmental delay, followed by metabolic testing of plasma and urine for elevated D‑2‑hydroxyglutarate. Confirmation is achieved by sequencing the IDH2 gene from a blood sample to identify pathogenic variants.
Carriers of a heterozygous IDH2 gain‑of‑function mutation are usually asymptomatic but have a 50 % chance of transmitting the variant to each offspring. Prenatal or pre‑implantation genetic testing can be offered to assess fetal status, and adult carriers should be monitored for late‑onset conditions such as certain leukemias that are also linked to IDH2 mutations.
Source: MedlinePlus, National Library of Medicine

MedlinePlus brings together authoritative health information from the National Library of Medicine (NLM), the National Institutes of Health (NIH), and other government agencies and health-related organizations.

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