Thiopurines, Poor Metabolism Of, 1; Thpm1

Description

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 (OMIM ) 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). Genetic Heterogeneity of Poor Thiopurine MetabolismSee also THPM2 (OMIM ), caused by variation in the NUDT15 gene (OMIM ) on chromosome 13q14.

Clinical Features

• Abnormality of metabolism/homeostasis
• Autoimmunity
• Leukemia
• Pancytopenia
• Bone marrow hypocellularity
• Pancreatitis
• Leukopenia
• Glomerulonephritis
• Abnormality of blood and blood-forming tissues
• Acute lymphoblastic leukemia