Disorders of purine and pyrimidine metabolism

The disorders of purine and pyrimidine metabolism are unusual in their variety of clinical presentations and in the mechanisms by which these presentations result from the fundamental mutations. In the most common of the hyperuricemic metabolic disorders, deficiency of hypoxanthine phosphoribosyl transferase, the fundamental deficiency in the activity of an enzyme of purine salvage leads to enormous overactivity of de novo pathway of purine synthesis and purine overproduction. In the other hyperuricemic disorder, that of phosphoribosylpyrophosphate synthetase, mutation leads not to deficient activity, but superactivity of the enzyme in an early stage of the synthetic pathway leading to overproduction. A number of disorders of purine metabolism lead to immunodeficiency; these include adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency. Marked susceptibility to infection is also seen in disorders of pyrimidine metabolism, classically in orotic aciduria, but also in pyrimidine nucleotide depletion syndrome. Orotic aciduria is a disorder of pyrimidine nucleotide synthesis, UMP synthetase deficiency, in which a single gene mutation can cause deficiency of two enzyme activities, orotic phosphoribosyltransferase and orotidine monophosphate decarboxylase which reside in a single protein. Pyrimidine degradation defects, dihydropyrimidine dehydrogenase and dihydropyrimidinase deficiencies leading to developmental delay are detected by analysis of the urine for pyrimidines and dihydropyrimidines. The recent discovery of aminoimidazolecarboxamideriboside deficiency points up the utility of simple colorimetric tests in bringing to light disorders of metabolism. Adenylosuccinatelyase deficiency and molybdenum cofactor deficiency illustrate the same point.