What are the other Names for this Condition? (Also known as/Synonyms)

• DPD Deficiency
• Hereditary Thymine-Uraciluria
• Familial Pyrimidinemia

What is Dihydropyrimidine Dehydrogenase Deficiency? (Definition/Background Information)

• Dihydropyrimidine Dehydrogenase (DPD) Deficiency is a condition in which the body cannot break down the nucleotides thymine and uracil
• DPD deficiency can have a wide range of severity; some individuals may have various neurological problems, while others have no signs and symptoms
• Signs and symptoms in severely affected individuals begin in infancy and may include seizures, intellectual disability, microcephaly, increased muscle tone (hypertonia), delayed motor skills, and autistic behavior
• All individuals with the condition, regardless of the presence or severity of symptoms, are at risk for severe, toxic reactions to drugs called fluoropyrimidines which are used to treat cancer
• Individuals with no symptoms may be diagnosed only by laboratory testing or after exposure to fluoropyrimidines
• Dihydropyrimidine Dehydrogenase Deficiency is caused by mutations in the DPYD gene and is inherited in an autosomal recessive manner

(Source: Dihydropyrimidine Dehydrogenase Deficiency; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Who gets Dihydropyrimidine Dehydrogenase Deficiency? (Age and Sex Distribution)

• Dihydropyrimidine Dehydrogenase Deficiency is a rare congenital disorder. The presentation of symptoms may occur at birth
• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Dihydropyrimidine Dehydrogenase Deficiency? (Predisposing Factors)

• A positive family history may be an important risk factor, since Dihydropyrimidine Dehydrogenase Deficiency is an inherited condition

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Dihydropyrimidine Dehydrogenase Deficiency? (Etiology)

Dihydropyrimidine Dehydrogenase 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 deficiencies (to various degrees) of functional DPD, 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.

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.

(Source: Dihydropyrimidine Dehydrogenase Deficiency; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Dihydropyrimidine Dehydrogenase Deficiency?

The signs and symptoms of Dihydropyrimidine Dehydrogenase Deficiency that are present occasionally (in 5-29% of the cases) may include:

• Agenesis of corpus callosum; condition causing absence of the corpus callosum, a part that connects the two halves of the brain
• Autism
• Cerebral atrophy; degeneration of the brain causing loss of nerve cells
• Coloboma; eye defect due to missing eye structure
• Delayed speech and language development
• Failure to thrive
• Growth delay
• Hyperactivity
• Hypertonia; increased muscle tone causing muscle stiffness

(Source: Dihydropyrimidine Dehydrogenase Deficiency; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How is Dihydropyrimidine Dehydrogenase Deficiency Diagnosed?

Dihydropyrimidine Dehydrogenase Deficiency may be diagnosed in various ways.

• In individuals with complete or profound DPD deficiency, laboratory testing can detect elevated levels of uracil and/or thymine in plasma or urine
• Partial DPD deficiency is more difficult to detect, which has led to the development of a radioenzymatic test for the DPD enzyme. This test has remained the gold standard for diagnosing DPD deficiency even after the development of genetic testing for the condition, because of the complexity of the DPYD gene and the presence of multiple DNA sequence variations present in most affected individuals
• Various types of cells and tissues can be examined this way. More recently, a rapid, noninvasive, and cost-effective breath test was developed. This test permits the evaluation of DPD activity (normal activity and partial or profound deficiency) before the administration of fluoropyrmidine drugs such as 5-FU

(Source: Dihydropyrimidine Dehydrogenase Deficiency; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the Possible Complications of Dihydropyrimidine Dehydrogenase Deficiency?

The complications of Dihydropyrimidine Dehydrogenase Deficiency may include:

• Agenesis of corpus callosum
• Autism
• Cerebral atrophy
• Failure to thrive

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Dihydropyrimidine Dehydrogenase Deficiency Treated?

• Currently, no treatment or cure exists for the inborn error of metabolism form of Dihydropyrimidine Dehydrogenase Deficiency
• Symptoms usually remain the same throughout the person's life

(Source: Dihydropyrimidine Dehydrogenase Deficiency; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How can Dihydropyrimidine Dehydrogenase Deficiency be Prevented?

Currently, Dihydropyrimidine Dehydrogenase Deficiency may not be preventable, since it is a genetic disorder.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are recommended.

What is the Prognosis of Dihydropyrimidine Dehydrogenase Deficiency? (Outcomes/Resolutions)

• The prognosis of Dihydropyrimidine Dehydrogenase Deficiency is dependent upon the severity of the signs and symptoms and associated complications, if any
• Individuals with mild conditions have better prognosis than those with severe symptoms and complications
• Typically, the prognosis may be assessed on a case-by-case basis

Additional and Relevant Useful Information for Dihydropyrimidine Dehydrogenase Deficiency:

The following DoveMed website link is a useful resource for additional information:

https://www.dovemed.com/diseases-conditions/rare-disorders/