Dihydropyrimidine dehydrogenase deficiency

A rare metabolic disorder affecting pyrimidine metabolism

Dihydropyrimidine dehydrogenase deficiency (DPD deficiency) is a rare metabolic disorder that affects the body's ability to break down pyrimidine bases, which are components of DNA and RNA. This condition is caused by a deficiency in the enzyme dihydropyrimidine dehydrogenase (DPD), which is crucial for the catabolism of the pyrimidines uracil and thymine.

Pathophysiology

DPD is the initial and rate-limiting enzyme in the catabolic pathway of pyrimidines. It catalyzes the reduction of uracil and thymine to dihydrouracil and dihydrothymine, respectively. In individuals with DPD deficiency, these pyrimidines accumulate in the body, leading to various clinical manifestations. The deficiency can be complete or partial, with the latter being more common.

Genetics

DPD deficiency is inherited in an autosomal recessive manner. The condition is caused by mutations in the DPYD gene, which provides instructions for making the DPD enzyme. More than 50 different mutations in the DPYD gene have been identified in individuals with DPD deficiency. The most common mutation is IVS14+1G>A, which leads to a splicing defect and a nonfunctional enzyme.

Clinical Manifestations

The clinical presentation of DPD deficiency can vary widely, ranging from asymptomatic individuals to those with severe neurological problems. Symptoms may include:

• Developmental delay
• Intellectual disability
• Seizures
• Microcephaly
• Motor skill impairment

In some cases, individuals may also experience increased sensitivity to certain medications, particularly fluoropyrimidines such as 5-fluorouracil (5-FU) and capecitabine, which are used in cancer treatment. Patients with DPD deficiency are at risk of severe toxicity when treated with these drugs.

Diagnosis

Diagnosis of DPD deficiency can be challenging due to the variability in symptoms. It is often suspected in patients who experience severe toxicity to fluoropyrimidine drugs. Diagnostic methods include:

• Measurement of uracil and dihydrouracil levels in plasma
• Genetic testing for mutations in the DPYD gene
• Enzyme activity assays in peripheral blood mononuclear cells

Management

There is no specific treatment for DPD deficiency. Management focuses on avoiding drugs that can cause toxicity in affected individuals, particularly fluoropyrimidines. Genetic counseling is recommended for affected families to understand the inheritance pattern and risks for future pregnancies.

Related pages

• Metabolic disorder
• Pyrimidine metabolism
• Autosomal recessive disorder
• 5-fluorouracil