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  1. Pyrimidines and purines are the building blocks of DNA and RNA and are thus required for the retention and transmission of genetic information. In addition they function in the formation of coenzymes and active intermediates in carbohydrate and phospholipid metabolism. Purines and pyrimidines have two routes for nucleotide formation, the de novo pathway, which begins with ribose phosphate, amino acids, CO2, and ammonia; and the salvage pathway, which takes free bases and nucleosides back to nucleotides. De novo and salvage pathways are balanced and connected through the enzymes, which degrade the nucleotides to β-amino acids, CO2, and ammonia.

  2. In contrast to the well-known defects of purine metabolism, most of the seven defects of pyrimidine metabolism are recently discovered: hereditary orotic aciduria (UMP synthase deficiency; MIM 25890, 25892), pyrimidine 5′-nucleotidase deficiency (MIM 26612), dihydropyrimidine dehydrogenase deficiency (MIM 27427), dihydropyrimidinase (dihydropyrimidinuria, MIM), ureidopropionase deficiency, thymidine phosphorylase deficiency, and pyrimidine 5′-superactivity. Purine metabolism has an easily recognizable, easily measurable endpoint in uric acid. There is no equivalent compound in pyrimidine metabolism.

  3. The first defect, hereditary orotic aciduria, is in the de novo synthetic pathway. This autosomal recessive disorder results from a severe deficiency of the last two activities in the pathway, orotate phosphoribosyltransferase and orotidine-5′-monophosphate decarboxylase. Although orotic aciduria was thought to be unique because of the loss of two enzymes, it is now known that these activities reside in separate domains of a single polypeptide coded by a single gene. This bifunctional protein, uridine-5′-monophosphate synthase, has been purified, the amino acid sequence determined by cDNA sequencing, and the gene localized to chromosome 3q13. Two point mutations resulting in amino acid substitutions and loss of enzyme activity have been identified in one orotic aciduria patient.

  4. There are 15 known patients with hereditary orotic aciduria. All have had a macrocytic hypochromic megaloblastic anemia and orotic acid crystalluria. Thirteen have been treated with uridine with good effect in the majority. Five young adults remain well but require continued therapy. One adult has not received uridine therapy and is well despite persisting anemia. Other features have included renal tract obstruction by crystals, cardiac malformations, and strabismus. Infections have been a problem in some, associated with various abnormalities of in vitro tests of immune function. One patient had severe congenital abnormalities. Mild intellectual impairment has been an inconstant feature prior to treatment. The progressive neurologic deterioration in one young adult may be unrelated to the metabolic error.

  5. The other disorders involve defects in the pyrimidine degradative pathway. Deficiency of pyrimidine-5′-nucleotidase causes hemolytic anemia, possibly due to accumulation in erythrocytes of pyrimidine nucleotides, mostly uridine triphosphate (UTP) and cytidine triphosphate (CTP). The disorder is transmitted in an autosomal recessive manner, and there is no specific treatment available. Pyrimidine 5′-nucleotidase superactivity has been described in four unrelated patients with developmental delay and neurologic abnormalities. The patients were treated with uridine with good effect. Deficiency of dihydropyrimidine dehydrogenase causes an increase in blood and urine levels of uracil and thymine. This deficiency is detected in a variety of clinical situations including pediatric metabolic screens for neurologic and other problems and adverse reactions to 5-fluorouracil, and is also found in asymptomatic relatives of detected patients. The enzyme deficiency is transmitted in an autosomal recessive manner, and there is some doubt whether there is a causal relationship between the deficiency and the symptoms. Dihydropyrimidinase deficiency (dihydropyrimidinuria) results in a large excretion of dihydrouracil and dihydrothymine. Four Dutch patients have been ascertained following investigation of neurologic and other problems and five asymptomatic Japanese patients by population screening. One patient has been reported with N-carbamyl-β-aminoaciduria due to a deficiency of ureidopropionase. The patient presented with choreoathetosis, hypotonia, and microcephaly. A deficiency of thymidine phosphorylase has been described in patients with juvenile mitochondrial neurogastrointestinal encephalomyopathy (MNGIE).

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