View source for Phenotype:TPMT poor metabolizer

A '''TPMT poor metabolizer''' (PM) is a person who carries two no-function ''TPMT'' alleles and therefore has little or no thiopurine S-methyltransferase activity. It is one of the three metabolizer phenotypes assigned from ''TPMT'' genotype, the others being the [[Phenotype:TPMT intermediate metabolizer|intermediate metabolizer]] and the [[Phenotype:TPMT normal metabolizer|normal metabolizer]]. TPMT has no rapid or ultrarapid phenotype. This page describes the poor-metabolizer phenotype; the enzyme itself, including the foundational pharmacogenetics history, is covered at [[Enzyme:TPMT]].

The clinical stake of this phenotype is unusually stark. A TPMT poor metabolizer given a standard dose of a thiopurine medicine will, with high probability, develop profound and potentially fatal bone-marrow suppression within weeks. Understanding why requires the inverted logic set out on the enzyme page: TPMT methylation is a competing route that draws thiopurine away from the pathway that forms the active, cytotoxic 6-thioguanine nucleotides. When TPMT activity is absent, less thiopurine is methylated away, more is converted to thioguanine nucleotides, those accumulate, and the bone marrow is the tissue that pays. The danger of TPMT deficiency is not failure to activate a medicine but loss of a competing detoxification route.

== Genotype basis ==
The poor-metabolizer phenotype is produced by a ''TPMT'' diplotype combining two no-function alleles. Four alleles account for nearly all clinically encountered loss of function:

* '''\*2''' (Ala80Pro), no function.
* '''\*3A''', no function, the most common loss-of-function allele in European-ancestry populations.
* '''\*3B''', no function, rare.
* '''\*3C''', no function, the most common loss-of-function allele in East Asian and African-ancestry populations.

Diplotypes such as ''\*3A/\*3A'', ''\*2/\*3A'', and ''\*3C/\*3C'' produce the poor-metabolizer phenotype. An adequate genotyping panel must cover all four alleles; the ancestry difference between ''\*3A'' and ''\*3C'' is described on the [[Enzyme:TPMT]] page.

== Population frequency ==
The TPMT poor-metabolizer phenotype is rare: roughly 1 person in 300 (about 0.3%) in European-ancestry populations, with broadly similar order-of-magnitude rarity elsewhere. It is rare precisely because it requires two no-function alleles; the intermediate-metabolizer phenotype, carrying one, is much more common.

== Clinical consequences ==
The thiopurine medicines, [[Azathioprine|azathioprine]], [[Mercaptopurine|mercaptopurine]], and [[Thioguanine|thioguanine]], are the entire clinical concern for TPMT, and the guidance for the poor metabolizer is uniform across them. The Clinical Pharmacogenetics Implementation Consortium recommends that a TPMT poor metabolizer receive a drastically reduced thiopurine dose, on the order of 10% of the standard dose and given three times weekly rather than daily, or that a non-thiopurine alternative be selected. Standard dosing in a poor metabolizer risks fatal myelosuppression and is not appropriate.<ref name="relling2019">Relling MV, Schwab M, Whirl-Carrillo M, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update. ''Clinical Pharmacology and Therapeutics''. 2019 May;105(5):1095-1105. PMID: 30447069.</ref>

Two further points belong with any account of the TPMT poor metabolizer. First, ''TPMT'' should not be tested alone: the parallel gene [[Enzyme:NUDT15|NUDT15]] produces the same thiopurine-myelosuppression phenotype, and its loss-of-function alleles have a nearly complementary ancestry distribution, so current best practice is to test both genes before starting a thiopurine. Second, co-prescription of [[Allopurinol|allopurinol]], a xanthine-oxidase inhibitor that removes another competing route of thiopurine metabolism, intensifies thiopurine toxicity in any patient and is a recognised cause of inadvertent myelosuppression when the interaction is overlooked.

== See also ==
* [[Enzyme:TPMT]], the enzyme, its history, and the inverted-logic explanation in full.
* [[Phenotype:TPMT intermediate metabolizer]], [[Phenotype:TPMT normal metabolizer]], the sibling phenotypes.
* [[Enzyme:NUDT15]] and [[Phenotype:NUDT15 poor metabolizer]], the parallel thiopurine-safety gene.
* [[Azathioprine]], [[Mercaptopurine]], [[Thioguanine]] (the entire clinical TPMT substrate set).
* [[:Category:Pharmacogenomic phenotypes]]

== References ==

<references/>

[[Category:Pharmacogenomic phenotypes]]