Thiopurine methyltransferase deficiency

Evans WE, Horner M, Chu YQ et al. Altered mercaptopurine metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase-deficient child with acute lymphocytic leukemia. J Pediatr 1991 119 985-989. 

McBride KL, Gilchrist GS, Smithson WA et al. Severe 6-thioguanine-induced marrow aplasia in a child with acute lymphoblastic leukemia and inhibited thiopurine methyltransferase deficiency. J Pediatr Hematol Oncol 2000 22 441-445. Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet 1980 32 651-662. 

McLeod HL, Lin J-S, Scott EP, Pui C-H, Evans WE. Thiopurine methyltransferase activity in American white subjects and black subjects. Clin Pharmacol Ther 1994 55 15-20. McLeod HL, Miller DR, Evans WE. Azathioprine-induced myelosuppression in thiopurine methyltransferase deficient heart transplant recipient. Lancet 1993 1341 1151. 

Lennard L, Gibson BES, Nicole T, Lilleyman JS. Congenital thiopurine methyltransferase deficiency and 6-mer-captopurine toxicity during treatment for acute lymphoblastic leukaemia. Arch Dis Child 1993 69 577-579. 

Schutz E, Gummert J, Mohr F, Oel-lerich M. Azathioprine induced myelosuppression in thiopurine methyltransferase deficient heart transplant recipient. Lancet 1993 341 436. 

Lennard L, Lilleyman JS. Variable mercaptopurine metabolism and treatment outcome in childhood lymphoblastic leukemia. J Clin Oncol 1989 7 1816-1823. Erratum itv.JClin Oncol 1990 8 567. Lennard L, Lewis IJ, Michelagnoli M et al. Thiopurine methyltransferase deficiency in childhood lymphoblastic leukaemia 6-mercaptopurine dosage strategies. MedPediatr Oncol 1997 29 252-255. Lennard L, Van Loon JA, Weinshilboum RM. Pharmaeogenetics of acute azathioprine toxicity relationship to thiopurine methyltransferase genetic polymorphism. Clin Pharmacol Ther 1989 46 149-154. 

Lu Y, Kham SK, Tan PL et al. Arrayed primer extension a robust and reliable genotyping platform for the diagnosis of single gene disorders beta-thalassemia and thiopurine methyltransferase deficiency. Genet Test 2005 9 212-219. 

Lennard L, Gibson BE, Nicole T et al. Congenital thiopurine methyltransferase deficiency and... 

Andersen JB, Szumlanski C, Weinshilboum RM et al. Pharmacokinetics, dose adjustments, and 6-mercaptopurine/methotrexate drug interactions in two patients with thiopurine methyltransferase deficiency. Acta Paediatr 1998 87 108-111. 

Table 23.9, Thiopurine methyltransferase deficiency [Patients 27 (Europe)]...

Tauri disease Tay-Sachs disease Testicular feminization syndrome Tetrahydrobiopterin deficiency Thiopurine methyltransferase deficiency Thymidine phosphorylase deficiency Transcobalamin II deficiency Tricho-hepato-enteric syndrome Trimethylaminuria Tripeptidyl peptidase I deficiency Tryptophan-2,3-dioxygenase deficiency Tryptophanuria... 

May be attenuated by pretreatment with antiemetic, especially if drug is given intravenously. Can be severe in patients with thiopurine methyltransferase deficiency. 

Thiopurine S-methyltransferase deficiency two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians. Am J Hum Genet 1996 58 694-702. 

Molecular diagnosis of thiopurine-S-methyltransferase deficiency genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med 1997 126 608-614. 

Corominas, H., Domenech, M., Gonzalez, D., et al. (2000) Allelic variants of the thiopurine S-methyltransferase deficiency in patients with ulcerative colitis and in healthy controls. Am. J. Gastroenterol. 95, 2313-2317. 

Yates, C.R., Krynetski, E.Y., Loennechen, T., et al. (1997) Molecular diagnosis of thiopurine S-methyltransferase deficiency genetic basis for azathioprine and mercaptopurine intolerance. Ann. Intern. Med. 126, 608-614. 

Thiopurine methyltransferase methylates 6-mercaptopurine, a commonly used treatment for childhood acute lymphocytic leukemia, reducing its conversion to the active form of the drug. Approximately 10% of patients have intermediate enzyme activity, and 0.3% are deficient for TPMT activity. Intermediate activity patients have a greater incidence of thiopurine toxicity, whereas TPMT-deficient patients have severe or fatal hematological toxicity from 6-mercaptopurine therapy. In one study, patients deficient for TPMT tolerated only 7% of a 2.5-yr mercaptopurine treatment regimen. Patients with intermediate TPMT activity tolerated 65% of total weeks of therapy and patients with normal TPMT activity tolerated 84% of total weeks of therapy (3). 

Dose-related myelosuppression is the major adverse effect produced by 6-thioguanine. Patients deficient in thiopurine methyltransferase (TPMT), a cytosolic enzyme required for metabolism of 6-thioguanine, are at heightened risk. Other adverse effects include gastrointestinal complaints and elevations of liver transaminases. There have been rare reports of more serious he-patotoxicity, including acute hepatitis, acute cholestasis, and hepatic venoocclusive disease. 

Kaskas BA, Louis E, Hindorf U et al. Safe treatment of thiopurine S -methyltransferase deficient Crohn s disease patients with azathioprine. Gut 2003 52 140-142. 

The thiopurines are also metabolized by the enzyme thiopurine methyltransferase (TPMT), in which a methyl group is attached to the thiopurine ring. There is a pharmacogenetic syndrome in which there is partial or complete deficiency of this enzyme. Patients with this genotype are at increased risk for developing severe toxicities in the form of myelosuppression and gastrointestinal toxicity with mucositis and diarrhea. 

Evans WE, Hon YY, Bomgaars L, Coutre 8, Holdsworth M, Janco R, et al. Preponderance of thiopurine 8-methyltransferase deficiency and heterozygosity among patients intolerant to mercap-topurine or azathioprine. J Cfin Oncol 2001 19 2293-301. 

Evans, W. E., Y. Y. Hon, L. Bomgaars, S. Coutre, M. Holdsworth, R. Janco, D. Kalwinsky, et al. 2001. Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mecaptopurine and azathiopurine. J Clin Oncol 19 2293-301. 

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