Thiopurine S-methyltransferase (TPMT) deficiency is a condition characterized by significantly reduced activity of an enzyme that helps the body process drugs called thiopurines. These drugs, which include 6-thioguanine, 6-mercaptopurine, and azathioprine, inhibit (suppress) the body's immune system. Thiopurine drugs are used to treat some autoimmune disorders, including Crohn's disease and rheumatoid arthritis, which occur when the immune system malfunctions. These drugs are also used to treat several forms of cancer, particularly cancers of blood-forming tissue (leukemias) and cancers of immune system cells (lymphomas). Additionally, thiopurine drugs are used in organ transplant recipients to help prevent the immune system from attacking the transplanted organ.

A potential complication of treatment with thiopurine drugs is damage to the bone marrow (hematopoietic toxicity). Although this complication can occur in anyone who takes these drugs, people with TPMT deficiency are at highest risk. Bone marrow normally makes several types of blood cells, including red blood cells, which carry oxygen; white blood cells, which help protect the body from infection; and platelets, which are involved in blood clotting. Damage to the bone marrow results in myelosuppression, a condition in which the bone marrow is unable to make enough of these cells. A shortage of red blood cells (anemia) can cause pale skin (pallor), weakness, shortness of breath, and extreme tiredness (fatigue). Low numbers of white blood cells (neutropenia) can lead to frequent and potentially life-threatening infections. A shortage of platelets (thrombocytopenia) can cause easy bruising and bleeding.

Many healthcare providers recommend that patients' TPMT activity levels be tested before thiopurine drugs are prescribed. In people who are found to have reduced enzyme activity, the drugs may be given at a significantly lower dose or different medications can be used to reduce the risk of hematopoietic toxicity.

TPMT deficiency does not appear to cause any health problems other than those associated with thiopurine drug treatment.

TPMT deficiency results from changes in the TPMT gene. This gene provides instructions for making the TPMT enzyme, which plays a critical role in breaking down (metabolizing) thiopurine drugs. Once inside the body, these drugs are converted to toxic compounds that kill immune system cells in the bone marrow. The TPMT enzyme "turns off" thiopurine drugs by breaking them down into inactive, nontoxic compounds. Changes in the TPMT gene reduce the stability and activity of the TPMT enzyme. Without enough of this enzyme, the drugs cannot be "turned off," so they stay in the body longer and continue to destroy cells unchecked. The resulting damage to the bone marrow leads to potentially life-threatening myelosuppression.

Normal Function

The TPMT gene provides instructions for making an enzyme called thiopurine S-methyltransferase (TPMT). This enzyme carries out a specific chemical reaction called S-methylation of a group of molecules known as aromatic and heterocyclic sulphydryl compounds. This function is of particular interest because it is critical for breaking down (metabolizing) drugs called thiopurines. These drugs, which include 6-thioguanine, 6-mercaptopurine, and azathioprine, inhibit (suppress) the body's immune system. They are used to treat several forms of cancer and other disorders involving immune system malfunction, such as Crohn's disease and rheumatoid arthritis. Thiopurine drugs are also used in organ transplant recipients to help prevent the immune system from attacking the transplanted organ.

Once inside the body, thiopurine drugs are converted to toxic compounds that kill immune system cells in the bone marrow. The TPMT enzyme "turns off" thiopurine drugs by metabolizing them to inactive, nontoxic compounds.

Health Conditions Related to Genetic Changes

Thiopurine S-methyltransferase deficiency

Changes in the TPMT gene cause TPMT deficiency, which is a reduction in the activity of the TPMT enzyme. Without enough of this enzyme, the body cannot "turn off" thiopurine drugs by metabolizing them into inactive compounds. The drugs stay in the body longer and continue to destroy cells unchecked, which leads to bone marrow damage (hematopoietic toxicity). This damage causes myelosuppression, which is an inability of the bone marrow to make enough red blood cells, white blood cells, and platelets. A shortage of these cells can cause a variety of health problems, the most serious of which include abnormal bleeding and an increased risk of potentially life-threatening infections. Although hematopoietic toxicity can occur in anyone who takes thiopurine drugs, people with TPMT deficiency are at highest risk of this complication.

The TPMT gene can be classified as either low-activity or high-activity. When the gene is altered in a way that impairs the activity of the TPMT enzyme, it is described as low-activity. When the gene is unaltered and TPMT activity is normal, it is described as high-activity. Because two copies of the gene are present in each cell, each person can have two low-activity copies, one low-activity copy and one high-activity copy, or two high-activity copies. People with two low-activity copies of the TPMT gene in each cell have TPMT deficiency and are at the greatest risk of developing hematopoietic toxicity when treated with thiopurine drugs unless they are given much less than the usual dose. People with one high-activity copy and one low-activity copy have moderately reduced enzyme activity and are also at increased risk of this complication unless given a significantly lower dose of the drug. People with two high-activity copies have normal TPMT activity and do not have an increased risk of hematopoietic toxicity with thiopurine drug treatment.

More than 40 low-activity versions (alleles) of the TPMT gene have been found in people with TPMT deficiency. Each of these alleles includes one or more changes in the gene that reduce the stability and activity of the TPMT enzyme. Two particular alleles, TPMT*3A and TPMT*3C, underlie more than 90 percent of cases of the condition. Studies suggest that TPMT*3A is the most common low-activity allele in whites, while TPMT*3C is the most common low-activity allele in Asians, Africans, and African Americans.

Other Names for This Gene

• S-adenosyl-L-methionine:thiopurine S-methyltransferase
• thiopurine methyltransferase
• TPMT_HUMAN

Genomic Location

The activity of the TPMT enzyme is inherited in a pattern described as autosomal codominant. Codominance means that two different versions of the gene are active (expressed), and both versions influence the genetic trait.

The TPMT gene can be classified as either low-activity or high-activity. When the gene is altered in a way that impairs the activity of the TPMT enzyme, it is described as low-activity. When the gene is unaltered and TPMT activity is normal, it is described as high-activity. Because two copies of the gene are present in each cell, each person can have two low-activity copies, one low-activity copy and one high-activity copy, or two high-activity copies.

People with two low-activity copies of the TPMT gene in each cell have TPMT deficiency and are at the greatest risk of developing hematopoietic toxicity when treated with thiopurine drugs unless they are given much less than the usual dose. People with one high-activity copy and one low-activity copy have moderately reduced enzyme activity and are also at increased risk of this complication unless given a significantly lower dose of the drug. People with two high-activity copies have normal TPMT activity and do not have an increased risk of hematopoietic toxicity with thiopurine drug treatment.

Studies suggest that less than 1 percent of individuals in the general population have TPMT deficiency. Another 11 percent have moderately reduced levels of TPMT activity that increase their risk of hematopoietic toxicity with thiopurine drug treatment.