INBORN-ERRORS OF PYRIMIDINE DEGRADATION - CLINICAL, BIOCHEMICAL AND MOLECULAR ASPECTS

The pyrimidines, uracil and thymine, are degraded in four steps. The f irst three steps of pyrimidine catabolism, controlled by enzymes share d by both pathways, result in the production of the neurotransmitter a mino acid beta-alanine from uracil and the nonfunctional (R)-(-)-beta- aminoisobutyrate from thymine. The fourth step is controlled by severa l aminotransferases, which have different affinities for beta-alanine, beta-aminoisobutyrate and GABA. Defects concerning the first three st eps all lead to a reduced production of beta-alanine; defects of the t ransaminases involving the metabolism of beta-alanine and GABA lead to accumulation of these neurotransmitter substances. In addition, other metabolites will accumulate or be reduced depending on the specific e nzyme defect. Analysis of the abnormal concentrations of these metabol ites in the body fluids is essential for the detection of patients wit h pyrimidine degradation defects. Clinically these disorders are often overlooked because symptomatology is highly aspecific. The growth in our knowledge concerning inborn errors of pyrimidine degradation has e mphasized the importance of the clinical awareness of these defects as a possible cause of neurological disease and a contraindication for t reatment of cancer patients with certain pyrimidine analogues. The var ious defects are discussed and attention is paid to clinical, genetic and diagnostic aspects.