Detecting DPD deficiency A small number of genetic variants have been repeatedly associated with DPD deficiency, such as IVS14+1G>A mutation in intron 14 coupled with exon 14 deletion (a.k.a. DPYD*2A), 496A>G in exon 6; 2846A>T in exon 22 and T1679G (a.k.a. DPYD*13) in exon 13. However, testing patients for these allelic variants usually show high specificity (i.e., bearing the mutation means that severe toxicity will occur indeed) but very low sensitivity (i.e., not bearing the mutation does not mean that there is no risk for severe toxicities). Alternatively, phenotyping DPD using ex-vivo enzymatic assay or surrogate testing (i.e., monitoring physiological dihydrouracil to uracil ratio in plasma) has been presented as a possible upfront strategy to detect DPD deficiency. 5-FU test dose (i.e., preliminary administration of a small dose of 5-FU with pharmacokinetics evaluation) has been proposed as another possible alternative strategy to secure the use of fluoropyrimidine drugs. Although DPYD pre-treatment screening has been proven to improve drug safety for DPYD*2A carriers by the Food and Drug Administration, the current (version 2016) European Society for Medical Oncology (ESMO) guidelines do not “routinely recommend” upfront genotyping of DPYD*2A before the administration of 5‐FU in metastatic CRC (mCRC) patients.
Dihydropyrimidine dehydrogenase deficiency
Purine nucleoside phosphorylase deficiency
Adenine phosphoribosyltransferase deficiency
Dihydrofolate reductase deficiency
Methylenetetrahydrofolate reductase deficiency
Enolase deficiency
Ribose-5-phosphate isomerase deficiency
Glutaminase deficiency