What Is an Isocitrate Dehydrogenase-2 (IDH2) Mutation?

The isocitrate dehydrogenase-2 (IDH2) mutation is associated with some types of cancer such as acute myeloid leukemia (AML), myelofibrosis, and brain cancer (glioma), as well as some genetic conditions. Drugs that target the effects of the IDH2 mutation have been developed to treat some of these conditions.

This mutation (change in genetic material) affects the gene that provides instructions for making the IDH enzyme found in the mitochondria of each cell. The mitochondria are the powerhouse of the cell. They make the energy to fuel a variety of cell functions.

Here's what to know about the IDH2 mutation, how it is affiliated with a few different conditions, and what it means for treatments.

Acute Myeloid Leukemia

The IDH2 mutation has been detected in about 8 percent to 19 percent of people with acute myeloid leukemia (AML). In AML, the blood-producing cells in the bone marrow become cancerous and fail to mature. This mutation tends to occur early on in cancer development.

The theory is that its cancer-related properties are due to a substance known as 2-hydroxyglutarate (2HG), which is produced in greater quantities because of the mutation. Because of 2HG, researchers think that cells with the mutation stay immature instead of becoming mature blood cells. The result is acute myeloid leukemia.

There is a treatment aimed at decreasing the amount of 2HG produced. The drug Idhifa (enasidenib) inhibits IDH2, thereby reducing 2HG levels. This can prod AML cells to differentiate and mature.

However, the mechanism of action here may not be fully understood. While almost all of those treated with enasidenib see a decrease in 2HG levels, not everyone treated with IDH2 inhibitors sees clinical improvements.

Still, the drug clearly has an effect in some cases. Enasidenib has had approximately a 40 percent overall response rate in relapsed and refractory cases.

Myelofibrosis

IDH2 mutations can also be connected to myelofibrosis. With this rare type of blood cancer, fibrous scar tissue replaces the usually soft spongy bone marrow. The result can be a type of chronic leukemia. Over time, the bone marrow becomes less able to produce normal blood cells.

At this point, the root cause of myelofibrosis has not yet been identified. While it's not inherited, it does involve gene mutations. About half of patients have a mutation in proteins known as Janus-associated kinases (JAKs).

With or without these JAK mutations, most people with this condition have overactive JAK signaling. Many also have an IDH2 mutation. Those with this IDH2 mutation tend not to do as well as those without it.

Some drugs being studied for myelofibrosis include:

• Ruxolitinib: This tamps down on the overactive JAK signaling to control blood cell production.
• Enasidenib: This inhibits the IDH2 enzyme and allows for the normal maturation of blood cells.

Maffucci Syndrome

Maffucci syndrome can be associated with an IDH2 mutation. This rare disorder involves cartilage growths, skin lesions with abnormal blood vessels (hemangiomas) that develop early in childhood, and skeletal deformities.

The first sign is often a cartilage overgrowth known as an enchondroma (a tumor in a bone) in one of the long bones of the body, weakening this and often causing a fracture.

This kind of mutation is not hereditary. The mutation occurs at some point during a person's own lifetime. This means that cells that arise from the mutated ones will also have this mutation. However, others will be unaffected. So this is not something that can be passed along from parent to child.

Maffucci syndrome happens in both males and females equally. Treatment revolves around addressing signs and symptoms of the disease but does not currently involve any related mutations.

Ollier Disease

Another disease that's connected to IDH2 is Ollier disease. It can resemble Maffucci syndrome as it is a skeletal disorder that can have abnormal bony development. It is different in one distinct way—it doesn't have skin lesions with abnormal blood vessels that are associated with Maffucci syndrome.

Still, both can be linked to the IDH2 gene. As in Maffucci syndrome, the IDH2 mutations are only found in some cells but not others. This again appears to be a mutation that occurs during a person's lifetime instead of being inherited.

Currently, treatment for Ollier disease is surgical and centers around correcting any skeletal deformities or replacing any joints when needed.

Gliomas

Mutations in IDH1 and IDH2 occur in most low-grade gliomas, as well as secondary high-grade cases of these brain tumors. Gliomas are the most common type of brain tumor, affecting about 20,000 people each year in the United States.

When IDH mutations are found, these cases actually tend to have a better prognosis than other cases. While this can affect either IDH1 or IDH2, the IDH2 mutations tend to be less common and don't occur together with IDH1.

The specific role that the mutated IDH enzyme produced by these gene mutations plays here is unclear. There's some thinking that this may be a direct driver of the cancer. Some point to the fact that those with Ollier's disease or Maffucci syndrome have hemangiomas and cartilaginous tumors and which are associated with an increased glioma risk.

But exactly how this mutation leads to glioma hasn't been determined. There is some thinking that the IDH gene is an oncogene and the resultant mutated IDH enzyme may be the cancer trigger, but this has not been conclusively shown as of yet. It's also possible that it's the mutated IDH gene itself that is triggering the cancer in the cells that harbor it.

Currently, the drug enasidenib has gone through phase 2 clinical trials to evaluate its safety in treating solid tumors including glioma.

Summary

IDH2 mutations appear linked to a variety of cancerous conditions such as AML, myelofibrosis, and gliomas, as well as disorders such as Maffucci syndrome and Ollier disease.

There's some thinking that conditions like cancer may be spurred by the IDH2 mutation, which may cause an increase in the substance 2HG that may interfere with the ability of some cells to mature. It's also possible that the IDH gene itself is triggering cancer development in the cells that harbor it.

A Word From Verywell

Knowing you have an IDH2 mutation at work in a condition can be empowering. By understanding a little better the role this may play, you are in a better position to know what's going on and possibly access any treatments as they emerge.