Dihydropyrimidine dehydrogenase deficiency ... (dihydropyrimidine dehydrogenase deficiency) - Gen DPYD            

Dihydropyrimidine dehydrogenase deficiency is a rare disease with a wide range of severity from individuals with other neurological individuals who show no signs or symptoms problems. In people with severe dihydropyrimidine dehydrogenase deficiency, the condition manifests in childhood. These individuals have neurological problems such as episodes of epilepsy, mental retardation, microcephaly, hypertonia, delayed development of motor skills such as walking, and autistic behaviors that affect communication and social interaction. Other affected individuals are asymptomatic. Individuals with asymptomatic dihydropyrimidine dehydrogenase deficiency can be identified only by laboratory tests.

People with dihydropyrimidine dehydrogenase deficiency, including those who have no symptoms, are vulnerable to a severe and potentially fatal toxic reaction certain fluoropyrimidine drugs called administered in the treatment of cancer. The most common examples of these drugs are 5-fluorouracil and capecitabine. These drugs do not decompose efficiently by people with dihydropyrimidine dehydrogenase deficiency and accumulate to toxic levels in the body. It may be severe inflammation and ulceration of the mucosa of the gastrointestinal tract (mucositis), which can lead to signs and symptoms including mouth sores, abdominal pain, bleeding, nausea, vomiting and diarrhea. Fluoropyrimidine toxicity can also cause neutropenia, which increases the risk of infections and thrombocytopenia. Redness, swelling, numbness, difficulty breathing, loss of hair and skin peeling on the palms of hands and soles of the feet may also appear. Although its prevalence is unknown, it is believed that between 2 and 8% of the population may be vulnerable to toxic fluoropyrimidines following the dihydropyrimidine dehydrogenase deficiency reactions.

This process is due to changes in the DPYD gene (dihydropyrimidine dehydrogenase), located on the short arm of chromosome 1 (1p22). This gene encodes the enzyme dihydropyrimidine dehydrogenase, which is involved in degradation of molecules called uracil and thymine. Uracil and thymine are pyrimidines, a type of nucleotide. Specifically, dihydropyrimidine dehydrogenase is involved in the first step in the degradation of pyrimidines. This enzyme converts 5,6-dihydrouracil uracil and thymine to 5,6-dihydrothymine. Molecules are created when break down pyrimidines are excreted by the body or used in other cellular processes.

There are more than 50 mutations in the gene DPYD in people with dihydropyrimidine dehydrogenase deficiency. These genetic changes interfere with the breakdown of uracil and thymine and result in excessive amounts of these molecules in blood, urine and cerebrospinal fluid. It is unclear how excess uracil and thymine are related to specific neurological problems that affect some people with dihydropyrimidine dehydrogenase deficiency. Mutations in the gene DPYD also interfere with the decomposition of drugs with similar structures pyrimidines such as 5-fluorouracil and capecitabine. Consequently, these drugs accumulate in the body and cause severe reactions can occur in persons with dihydropyrimidine dehydrogenase deficiency.

This process is inherited as an autosomal recessive pattern, which means that both copies of the gene in every cell have mutations. Depending on the severity of these mutations, individuals with two copies of the mutated gene in each cell DPYD can manifest signs and symptoms of the disorder, or may be generally asymptomatic, but at risk of toxic drug reactions fluoropyrimidine. The parents of an individual with an autosomal recessive disorder each carry one copy of the mutated gene, but usually show no signs and symptoms of the disease. However, people with a mutated copy of the gene in every cell DPYD can manifest toxic reactions to fluoropyrimidine.

Tests in IVAMI: in IVAMI perform detection of mutations associated with dihydropyrimidine dehydrogenase deficiency, by complete PCR amplification of the exons of the DPYD gene, and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).