Dihydropyrimidine dehydrogenase (DPD) deficiency is a genetic condition where the body has reduced or absent activity of the DPD enzyme. This enzyme plays a role in breaking down certain substances within the body, including specific medications. When the DPD enzyme is deficient, these substances are not processed efficiently, which can lead to their accumulation. This inherited metabolic disorder can have varying degrees of severity among affected individuals.
Understanding Dihydropyrimidine Dehydrogenase Deficiency
The DPD enzyme, encoded by the DPYD gene, is responsible for the initial and rate-limiting step in the breakdown of pyrimidines, which are building blocks of DNA and RNA. Specifically, it converts uracil to 5,6-dihydrouracil and thymine to 5,6-dihydrothymine, preparing them for excretion or use in other cellular processes. A deficiency in this enzyme, caused by mutations in the DPYD gene, means that uracil and thymine cannot be broken down effectively, leading to their buildup in the blood, urine, and cerebrospinal fluid. The impact of these mutations can range from a complete absence of enzyme activity to a partial reduction, affecting how the body metabolizes naturally occurring pyrimidines and certain drugs with similar chemical structures.
Recognizing Symptoms and Diagnosis
The symptoms of DPD deficiency can vary widely, from individuals showing no outward signs to those experiencing severe neurological problems. In severe cases, often identified in infancy, symptoms may include recurrent seizures, intellectual disability, a small head size (microcephaly), increased muscle tone (hypertonia), and delayed motor skills. Some affected individuals also exhibit autistic behaviors that impact communication and social interaction.
Individuals with DPD deficiency, even those who are otherwise asymptomatic, are susceptible to severe and potentially life-threatening reactions if exposed to certain medications. These reactions can manifest as severe inflammation and ulceration of the gastrointestinal tract lining (mucositis), leading to mouth sores, abdominal pain, nausea, vomiting, and diarrhea. Other possible symptoms include low white blood cell counts (neutropenia), increasing infection risk, and low platelet counts (thrombocytopenia), which can cause abnormal bleeding. Diagnosis involves laboratory testing, such as measuring DPD enzyme activity in blood or checking for specific mutations in the DPYD gene. Blood tests can also measure the level of uracil, a substance broken down by DPD, or the ratio of dihydrouracil to uracil in plasma.
Medication Safety and Management
DPD deficiency significantly impacts the body’s ability to process certain chemotherapy drugs, particularly fluoropyrimidines like 5-fluorouracil (5-FU), capecitabine, and tegafur. These drugs are widely used to treat various cancers, including breast, colorectal, and gastric cancers. In individuals with DPD deficiency, the enzyme cannot adequately break down these medications, leading to their accumulation to toxic levels in the body.
This toxic buildup can cause severe adverse reactions, including myelosuppression (bone marrow suppression), severe diarrhea, mucositis, and hand-foot syndrome. The mortality rate associated with fluoropyrimidine toxicity in DPD-deficient patients can range from 0.2% to 1.0%. Given these risks, pre-treatment testing for DPD deficiency is recommended for all patients before administering fluoropyrimidine drugs.
For patients with a complete DPD deficiency, fluoropyrimidine medications must be avoided due to the high risk of fatal toxicity. If a partial DPD deficiency is identified, a reduced starting dose of these drugs should be considered to minimize severe side effects. Subsequent dose adjustments may be possible with careful monitoring. Healthcare providers should be informed of any DPD deficiency diagnosis to tailor treatment plans and provide supportive care for any adverse reactions that may occur.
Inheritance and Screening
DPD deficiency follows an autosomal recessive inheritance pattern. This means that an individual must inherit two mutated copies of the DPYD gene, one from each parent, to be affected with the condition. Parents who each carry one copy of the mutated gene typically do not show symptoms themselves but can pass the gene to their children.
Genetic counseling can help families understand the inheritance pattern and the implications for other family members. While testing for family members not receiving fluoropyrimidine chemotherapy is generally not offered, genetic testing can identify carriers. Population screening or targeted screening for DPD deficiency is particularly relevant in contexts where fluoropyrimidine drugs are frequently used, as it can identify at-risk individuals before treatment. The prevalence of partial DPD deficiency is estimated to affect 3-9% of Caucasian populations, while complete deficiency is much rarer, occurring in about 0.01-0.5% of Caucasian individuals.