Pediatric Crohn's disease (CD) carries a higher
genetic susceptibility and an increased risk of a more aggressive disease course than adult CD. Treatment of CD is based on
immunomodulatory drugs, such as thiopurines. The
enzyme mainly involved in
drug metabolism is
thiopurine S-methyltransferase (TPMT). An increased concentration of
drug metabolites can cause adverse
drug effects, such as myelosuppression and hepatotoxicity; therefore, assessing the activity of TPMT is essential both before and during treatment. TPMT genotyping result is not affected by previous
thiopurine dose and currently is the primary component of TPMT activity and disease monitoring. Until now, more than 40 allelic variants of the TPMT gene have been reported, with most of them having an uncertain or no
enzyme function. In this article, we report the first case of a novel TPMT allele, TPMT*45, that was identified in a Korean girl with CD whose findings suggested decreased TPMT activity. This newly observed variant is caused by a single nucleotide polymorphism resulting in
nonsense mutation (c.676C>T, p.R226*) and the partial loss of
amino acids in the TPMT
protein. Initially, the patient began
azathioprine at a standard dosage (1.5 mg/kg/day), and her laboratory results, including red blood cell (RBC) TPMT activity (6-
methylmercaptopurine 2.68 nmol/mL/h and
6-methylmercaptopurine riboside 4.82 nmol/mL/h) along with
thiopurine metabolite levels (
6-thioguanine nucleotides 479.3 pmol/8×108 RBC), suggested an
enzyme deficiency. The
thiopurine dose was reduced to half (0.7 mg/kg/day), and the follow-up metabolite results as well as the associated inflammatory markers were continuously within reference ranges. Along with an improvement in the patient's subjective reports and clinical symptoms, the patient demonstrated a good treatment response to the adjusted dose. The results of our report illustrate the importance of TPMT genotyping and pharmacogenetic-based
thiopurine dose adjustment. Further research should focus on the functional characterization and impact on this novel allele's treatment effect.