Dihydropyrimidine dehydrogenase deficiency is an
autosomal
An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosom ...
recessive
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
metabolic disorder
A metabolic disorder is a disorder that negatively alters the body's processing and distribution of macronutrients, such as proteins, fats, and carbohydrates. Metabolic disorders can happen when abnormal chemical reactions in the body alter t ...
in which there is absent or significantly decreased activity of
dihydropyrimidine dehydrogenase
In enzymology, a dihydropyrimidine dehydrogenase (NADP+) () is an enzyme that catalyzes the chemical reaction
:5,6-dihydrouracil + NADP+ \rightleftharpoons uracil + NADPH + H+
Thus, the two substrates of this enzyme are 5,6-dihydrouracil an ...
, an enzyme involved in the metabolism of
uracil
Uracil () (symbol U or Ura) is one of the four nucleobases in the nucleic acid RNA. The others are adenine (A), cytosine (C), and guanine (G). In RNA, uracil binds to adenine via two hydrogen bonds. In DNA, the uracil nucleobase is replaced b ...
and
thymine
Thymine () ( symbol T or Thy) is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidi ...
.
Individuals with this condition may develop life-threatening toxicity following exposure to
5-fluorouracil
Fluorouracil (5-FU), sold under the brand name Adrucil among others, is a cytotoxic chemotherapy medication used to treat cancer. By intravenous injection it is used for treatment of colorectal cancer, oesophageal cancer, stomach cancer, pan ...
(5-FU), a
chemotherapy
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothe ...
drug that is used in the treatment of cancer. Beside 5-FU, widely prescribed oral fluoropyrimidine
capecitabine
Capecitabine, sold under the brand name Xeloda among others, is a chemotherapy medication used to treat breast cancer, gastric cancer and colorectal cancer. For breast cancer it is often used together with docetaxel. It is taken by mouth.
Com ...
(Xeloda) could put DPD-deficient patients at risk of experiencing severe or lethal toxicities as well.
Genetics
DPD deficiency is inherited in an autosomal recessive manner.
[ This means the defective gene responsible for the disorder is located on an autosome, and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both ]carry
Carry or carrying may refer to:
People
*Carry (name)
Finance
* Carried interest (or carry), the share of profits in an investment fund paid to the fund manager
* Carry (investment), a financial term: the carry of an asset is the gain or cost of h ...
one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.
Diagnosis
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 United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
, the current (version 2016) European Society for Medical Oncology
The European Society for Medical Oncology (ESMO) is the leading professional organisation for medical oncology. With more than 25,000 members representing oncology professionals from over 160 countries worldwide, ESMO was founded in 1975.
''Anna ...
(ESMO) guidelines do not “routinely recommend” upfront genotyping of DPYD*2A before the administration of 5‐FU in metastatic CRC (mCRC) patients.
Management
Epidemiology
References
External links
*
{{Purine, pyrimidine, porphyrin, bilirubin metabolic pathology
Inborn errors of purine-pyrimidine metabolism
Autosomal recessive disorders