Thompson & Thompson Genetics in Medicine, 8th Edition

Case 45. Thiopurine S-Methyltransferase Deficiency (TPMT Polymorphisms, MIM 610460)

Autosomal Semidominant


• Pharmacogenetics

• Precision medicine

• Cancer and immunosuppression chemotherapy

• Ethnic variation

Major Phenotypic Features

• Age at onset: Deficiency is present at birth, manifestation requires drug exposure

• Myelosuppression

• Increased risk for brain tumor in thiopurine methyltransferase–deficient patients with acute lymphoblastic leukemia receiving brain irradiation

History and Physical Findings

J.B. is a 19-year-old man with long-standing ulcerative colitis. Because he has been refractory to steroid treatment, his physician prescribed azathioprine at a standard dose of 2.5 mg/kg/day. After a few weeks, J.B. developed severe leukopenia. The physician measured thiopurine methyltransferase activity in the red cells and found it to be normal. The physician remembered that J.B. had received a red blood cell transfusion 3 weeks previously and decided to determine his TPMT genotype. J.B. was found to be a compound heterozygote for the TPMT*2 and -*3A alleles. Consequently, he should have been started and maintained on 6% to 10% of the standard dose of azathioprine.


Disease Etiology and Incidence

Thiopurine methyltransferase (TPMT) is the enzyme responsible for phase II metabolism of 6-mercaptopurine (6-MP) and 6-thioguanine by catalyzing S-methylation and thus inactivating these compounds (see Chapter 18). Azathioprine, a commonly used immunosuppressant, is activated by conversion to 6-MP, and so its metabolism is also affected by TPMT activity. These agents are used as immunosuppressants for various systemic inflammatory diseases, such as inflammatory bowel disease and lupus, and to prevent the rejection of solid tumor transplants. 6-MP is also a component in standard treatment of acute lymphoblastic leukemia. Approximately 10% of whites carry at least one slow metabolizer variant that causes accumulation of high levels of toxic metabolites, which can cause fatal hematopoietic toxicity (Fig. C-45). One in 300 whites is homozygous for an allele that causes complete deficiency of TPMT activity (MIM 610460). Deficiency is much less common in other ethnic groups.


FIGURE C-45 Genetic polymorphism of thiopurine S-methyltransferase (TPMT) and its role in determining response to thiopurine medications (azathioprine, mercaptopurine, and thioguanine). The upper left panel depicts the predominant TPMT mutant alleles causing autosomal semidominant inheritance of TPMT activity in humans. As depicted in the adjacent top three panels, when uniform (conventional) dosages of thiopurine medications are given to all patients, TPMT homozygous mutant patients accumulate 10-fold higher cellular concentrations of the active thioguanine nucleotides (TGNs); heterozygous patients accumulate approximately twofold higher TGN concentrations. These differences translate into a significantly higher frequency of toxicity (far right panels). As depicted in the bottom left three panels, when genotype-specific dosing is used, similar cellular TGN concentrations are achieved, and all three TPMT phenotypes can be treated without acute toxicity. 6MP, 6-Mercaptopurine; RBC, red blood cell. See Sources & Acknowledgments.

Phenotype and Natural History

Toxicity from thiopurines was first recognized in patients receiving 6-MP for acute lymphoblastic leukemia. Although patients with 6-MP toxicity had a risk for life-threatening leukopenia, those who survived were noted to have longer periods of leukemia-free survival. Among TPMT-deficient patients with acute lymphoblastic leukemia, there was an increased risk for radiation-induced brain tumors and of chemotherapy-induced acute myelogenous leukemia. Fifteen different mutations in the TPMT gene have been associated with decreased activity in red cell assay. The wild-type allele is TPMT*1. TPMT*2 is a missense mutation that results in an alanine to proline substitution at codon 80 (Ala80Pro), which has only been seen in whites. Approximately 75% of affected whites have the TPMT*3A allele, in which two mutations are present in cis: Tyr240Cys and Ala154Thr. The TPMT*3C allele contains only the Tyr240Cys mutation and is found in 14.8% of Ghanaians and 2% of Chinese, Koreans, and Japanese. The Ala154Thr mutation has not been seen in isolation and presumably occurred on a chromosome that already carried the Tyr240Cys allele after the European migration.

Testing for the TPMT mutations by polymerase chain reaction is inexpensive and accurate and can prevent azathioprine toxicity by allowing dose adjustment before starting therapy. TPMT testing is the standard of care for acute lymphoblastic leukemia and has a favorable cost-benefit analysis for inflammatory bowel disease. Because TPMT activity is measured in red cells, false negatives are common in patients who have received transfusions as long as 3 months before testing, therefore direct genotyping of a DNA is preferred.


Patients with complete TPMT deficiency should receive 6% to 10% of the standard dose of thiopurine medications. Heterozygous patients may start at the full dose but should have a dose reduction to half within 6 months or as soon as any myelosuppression is observed. The effect of TPMT polymorphism is an instructive example of the clinical importance of pharmacogenetics in personalized medicine (see Chapter 18).

Inheritance Risk

The a priori risk of a white individual carrying a TPMT deficiency allele is approximately 10%. In other ethnic groups, it is 2% to 5%. Because this is a simple semi-dominant trait, siblings of heterozygous individuals have a 50% chance of being heterozygous. Siblings of a deficient individual have a 25% chance of being deficient and a 50% chance of being heterozygous. Children of heterozygous carriers have a 25% chance of being deficient, and all children of deficient individuals will be heterozygous carriers if the other parent is *1*1 homozygote.

Questions for Small Group Discussion

1. VKORC1 polymorphisms account for significant variation in warfarin metabolism. Name several conditions in which warfarin therapy is commonly used.

2. The P450 enzymes encoded by the CYP genes are important to drug metabolism. Which CYP genes metabolize selective serotonin reuptake inhibitors? Does this result in toxicity or decreased effect?

3. Why do humans have genes for drug metabolism?

4. Suggest explanations for ethnic variation in these genes.


Relling MV, Gardner EE, Sandborn WJ, et al. Clinical pharmacogenetics implementation consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther. 2011;89:387–391.

Scott SA. Personalizing medicine with clinical pharmacogenetics. Genet Med. 2011;13:987–995.