Dihydropyrimidinase deficiency (Dihydropyrimidinase deficiency) - Gen DPYS.

Dihydropyrimidinase deficiency is a disorder that can cause neurological and gastrointestinal problems in some affected individuals. Others deficient dihydropyrimidinase no signs or symptoms related to the disease, and these individuals the disease can be diagnosed only by laboratory tests.

Neurological abnormalities that occur more frequently in affected individuals include mental retardation, seizures and hypotonia. In addition, affected individuals may have microcephaly and autistic behaviors that affect communication and social interaction. Meanwhile, gastrointestinal problems associated include gastroesophageal reflux and cyclic vomiting. Similarly, these individuals may have atrophy of the villi lining the small intestine, which can lead to difficulty absorbing nutrients from food and therefore to growth retardation.

People deficient dihydropyrimidinase, including those without symptoms, may be vulnerable to severe and potentially fatal toxic reactions to certain drugs called fluoropyrimidine used for the treatment of malignancies. Common examples of these drugs are 5-fluorouracil and capecitabine. These drugs can not be decomposed effectively and may accumulate to toxic levels in the body, leading to drug reactions, including gastrointestinal problems, blood disorders, and other signs and symptoms.

This process is due to mutations in the gene DPYS, located on the long arm of chromosome 8 (8q22). This gene encodes the enzyme dihydropyrimidinase, involved in degradation of pyrimidines, basic components of DNA and RNA. Specifically, dihydropyrimidinase enzyme is involved in the second step of the three step process that degrades pyrimidines. This step opens the ring structures of the 5,6-dihydrothymine and 5,6-dihydrouracil molecules. A further breakdown of these molecules leads to other molecules such as alanine beta-aminoisobutyric acid and which is believed to play a role in the nervous system. Beta-aminoisobutyric acid production increases leptin protein, which helps protect brain cells from damage caused by toxins, inflammation and other factors. Meanwhile, it is believed the beta-alanine is involved in synaptic transmission and control of the neurotransmitter dopamine. In addition, the dihydropyrimidinase enzyme also helps break down certain drugs called fluoropyrimidine used to treat neoplasms.

They have identified at least 23 mutations in the gene in people DPYS deficient dihydropyrimidinase. These genetic changes reduce or eliminate the function of the enzyme dihydropyrimidinase greatly. As a result, the enzyme is unable to initiate the decomposition of 5,6-dihydrothymine and 5,6-dihydrouracil, so that excessive amounts of these molecules in blood and cerebrospinal fluid build up and released into the urine. The relationship between the inability to break 5,6- and 5,6-dihydrouracil dihydrothymine and the specific characteristics of the disease is unclear. If this step is not completed in the decomposition of pyrimidines also prevents the final step of the process generating beta-aminoisobutyric acid and beta-alanine. A reduction in the production of these molecules may impair their function in the nervous system, leading to neurological problems in some people with dihydropyrimidinase deficiency. Furthermore, because fluoropyrimidine drugs are broken down by the same three step process that pyrimidines deficiency dihydropyrimidinase enzyme can lead to the accumulation of drugs that cause toxicity. However, it is unknown why some people with dihydropyrimidinase deficiency do not develop health problems related to the disease. Other genetic and environmental factors likely to help determine the effects of this disease.

This disease is inherited in an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.

Tests in IVAMI: in IVAMI perform detection of mutations associated with deficiency dihydropyrimidinase, by complete PCR amplification of exons DPYS 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).