Dihydropyrimidine Dehydrogenase Deficiency

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Dihydropyrimidine Dehydrogenase Deficiency is caused by problems in the DPYD gene which is needed to produce the dihydropyrimidine dehydrogenase (DPD) enzyme. The enzyme is used to break down uracil and thymine which form part of our genetic makeup and are needed to produce the main source of energy for the body’s cells.A problem in the DPYD gene means that not enough enzyme is produced, and this prevents uracil and thymine from being broken down properly. Therefore, these molecules build up in the blood, urine and fluid surrounding the brain and spinal cord.

There can either be a partial deficiency or a complete deficiency of the DPD enzyme. A partial deficiency means that some, but not all, of the enzyme is produced. In these cases, you may have been unaware of the condition having had no symptoms. The complete deficiency causes symptoms which start in infancy.

It is important to note that the DPD enzyme also plays an important role in breaking down fluoropyrimidine drugs such as fluorouracil (5FU) and capecitabine (Xeloda). These are chemotherapy drugs commonly used in the treatment of different types of cancer. If you have a partial or a complete deficiency of the DPD enzyme, the chemotherapy drugs build up and cause severe side effects which can be life-threatening. This is called Fluoropyrimidine Toxicity.

A complete deficiency of the DPD enzyme is rare. The exact incidence is unknown. However around 2 to 8% of the general population have a partial deficiency.

Symptoms of the complete deficiency first begin in infancy. Severity varies. Symptoms may include:

• Epilepsy
• Intellectual disability
• A small head (microcephaly)
• A delay in reaching developmental milestones
• High muscle tone (hypertonia)
• Autistic behaviours
• Exaggerated reflexes

Some rarer symptoms that have been reported include an enlarged liver and spleen (hepatosplenomegaly) and eye problems such as involuntary eye movements (nystagmus) or the eyes pointing in different directions (strabismus).

If you have a partial deficiency, there are no signs or symptoms.

Fluoropyrimidine Toxicity

If you have either a partial or a complete deficiency of the DPD enzyme you are susceptible to having a severe reaction to Fluoropyrimidine drugs. Symptoms of Fluoropyrimidine toxicity often occur after the first few doses of the medication. Symptoms include:

• Inflammation and ulceration of the gastrointestinal tract.
• Diarrhoea
• Mouth sores
• Abdominal pain
• Feeling or being sick
• A reduced level of white blood cells (neutropenia) which increases your risk of infections

A reduced level of platelets in the blood (thrombocytopenia) which causes blood clotting problems, abnormal bleeding, breathlessness, hair loss, and a severe skin reaction which leads to peeling or blistering of the skin

Not everyone who has a reaction to Fluoropyrimidine medications has this disorder. Discuss any reactions with your doctor.

A partial deficiency can only be diagnosed through specialised tests on the blood and urine. It is not currently routinely tested for prior to chemotherapy treatment using the Fluoropyrimidine drugs. Research is ongoing into the development of a breath test and genetic testing.

Treatment is currently based on treating and managing the specific symptoms that are present and providing support to you and your family. There is currently no cure for the condition. Research is ongoing into methods of routinely screening for the partial deficiency prior to the use of Fluoropyrimidine drugs.

Humans have chromosomes composed of DNA. Genes are pieces of DNA that carry the genetic instruction. Each chromosome may have several thousand genes. We inherit particular chromosomes from the egg of the mother and sperm of the father. The genes on those chromosomes carry the instructions that determine a person’s characteristics, which are a combination of the parents.

This is an inherited condition. There is nothing that could have been done to prevent it.

Everyone has a pair of genes that make the DPD enzyme. If you have this disorder, neither of these genes works correctly. One non-working gene is inherited from each parent. Parents of those with DPD Deficiency are carriers of the condition. Carriers do not have the disorder because the other gene of this pair is working correctly

When both parents are carriers, in each pregnancy the risk to the baby is as follows:

• 25% chance (1 in 4) of inheriting the disorder
•  50% chance (1 in 2) for the baby to be a carrier
• 25% chance (1 in 4) for the baby to have two working genes and neither have the disorder nor be a carrier

All information accurately referenced by Metabolic Support UK, however, should you require access to our references, please contact us by email: contact@metabolicsupportuk.org