Thiopurines, Poor Metabolism of, 1 (THPM1)

External Ids:

MedlinePlus Genetics: ⁴² 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 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.

MalaCards based summary: Thiopurines, Poor Metabolism of, 1, also known as thiopurine s-methyltransferase deficiency, is related to autoimmune hepatitis and neutropenia. An important gene associated with Thiopurines, Poor Metabolism of, 1 is TPMT (Thiopurine S-Methyltransferase), and among its related pathways/superpathways are Metabolism and Metapathway biotransformation Phase I and II. Affiliated tissues include bone marrow, bone and skin, and related phenotypes are abnormality of metabolism/homeostasis and abnormality of blood and blood-forming tissues

OMIM®: ⁵⁷ THPM1 is an autosomal recessive trait associated with severe hematopoietic toxicity when patients are treated with standard doses of the antineoplastic agents 6-mercaptopurine (6MP) or 6-thioguanine (6TG), or the immunosuppressant azathioprine (AZA) (Lennard et al., 1989). The thiopurines are prodrugs that require extensive metabolism in order to exert their cytotoxic action. Azathioprine is nonenzymatically reduced to 6MP. 6MP and 6TG are activated by HPRT (308000) and subsequent steps to form cytotoxic thioguanine nucleotides (TGNs) which are incorporated into DNA and/or RNA, causing DNA-protein cross-links, single-strand breaks, interstrand cross-links, and sister chromatid exchange. TPMT functions mainly to inactivate these drugs; thus, a deficiency of TPMT results in increased conversion to toxic TGNs, which can result in myelosuppression (Coulthard and Hogarth, 2005). However, 6MP is unique in that it can also be converted via TPMT into a methyl-thioinosine 5-prime monophosphate (MeTIMP), a metabolite that inhibits de novo purine synthesis and likely contributes to the cytotoxic effect of 6MP (Vogt et al., 1993; Krynetski et al., 1995; Coulthard and Hogarth, 2005). (610460) (Updated 08-Dec-2022)

GARD: ¹⁹ Thiopurine S-methyltransferase deficiency is an autosomal recessive disorder that affects the body's ability to metabolize thiopurine drugs. Thiopurine S-methyltransferase (TPMT) is an enzyme that the body uses to break down thiopurine drugs. Thiopurine S-methyltransferase deficiency patients have a genetic change in either one or both copies of the TPMT gene that causes reduced enzyme activity and difficulties breaking down thiopurine drugs. Affected individuals are at a high risk of experiencing bone marrow damage if they take thiopurine drugs. Many patients recover from the bone marrow damage once thiopurine drug use is stopped. When the bone marrow is damaged, infections can cause health problems.

Disease Ontology: ¹¹ An inherited metabolic disease that is characterized by significantly reduced activity of an enzyme that helps the body process drugs called thiopurines.

Clinical features from OMIM®:

Search Clinical Trials, NIH Clinical Center for Thiopurines, Poor Metabolism of, 1