Dihydropyrimidine dehydrogenase deficiency

DPD deficiency is caused by mutations in the _DPYD _gene. This gene provides instructions for making an enzyme called dihydropyrimidine dehydrogenase (DPD), which is involved in the breakdown of molecules called uracil and thymine. Uracil and thymine are building blocks of DNA, RNA, and molecules that serve as energy sources in cells.

Mutations in the DPYD gene result in reduced amounts of working DPD enzyme, interfering with the breakdown of uracil and thymine in cells. This results in excessive amounts of uracil and thymine in the blood, urine, and the fluid that surrounds the brain and spinal cord. It is currently poorly understood exactly how this cascade of events causes the signs and symptoms of the condition, or why only some infants with DPYD gene mutations have symptoms.

DPD deficiency may be diagnosed in various ways. In infants with early neurological symptoms such as seizures or microcephaly, or people who are suspected to have DPYD gene mutations, specific types of laboratory testing can detect elevated levels of uracil and/or thymine in plasma or urine. In addition, testing is available to look for the levels of the DPD enzyme. Genetic testing can also be helpful for diagnosis.

There is a breath test available that can measure DPD enzyme activity. In addition, there is evidence that genetic testing can identify many people with DPYD gene mutations. This may be important for screening people prior to receiving 5-FU chemotherapy.

Dihydropyrimidine dehydrogenase (DPD) deficiency is inherited in an autosomal recessive manner. This means that in affected individuals, both copies of the DPYD gene in each cell (one inherited from each parent) have mutations. The mutations that cause DPD deficiency vary widely in severity; therefore, some people with 2 mutated copies of the gene may have signs and symptoms of the condition, while others may be asymptomatic. However, all individuals with 2 mutations are at risk for toxic reactions to fluoropyrimidine drugs.

Individuals who carry one mutated copy of the disease-causing gene (including most parents of affected individuals) are referred to as carriers. Carriers typically do not have signs and symptoms of the condition. However, people with one mutated copy of the DPYD gene may still experience toxic reactions to fluoropyrimidine drugs.

When 2 carriers for the same autosomal recessive condition have children, each child has a 25% (1 in 4) risk to have the condition, a 50% (1 in 2) risk to be a carrier like each parent, and a 25% risk to not have the condition and not be a carrier. A child of one carrier parent has a 50% risk to also be a carrier.

Severe dihydropyrimidine dehydrogenase (DPD) deficiency, with its early-onset neurological symptoms, is a rare disorder. Its prevalence is unknown.

However, between 2 and 8 percent of the general population may be at risk for toxic reactions to fluoropyrimidine drugs, such as 5-FU, caused by either total or partial DPD deficiency which does not show any symptoms.

Currently, no specific treatment exists for the severe form of dihydropyrimidine dehydrogenase deficiency. Treatment is aimed at managing the symptoms. Symptoms usually remain the same throughout the person's life.