The allopurinol load test lacks specificity for primary urea cycle defectsbut may indicate unrecognized mitochondrial disease

Thirty-three children ranging from 2 weeks to 12 years of age were selected for allopurinol loading, 16 on the basis of an increased urinary orotate e xcretion detected by routine organic acid analysis (group A) and 17 for cli nical reasons suggesting a urea cycle defect (group B). The allopurinol loa d test proved positive in 13 of 16 patients from group A, mean peak orotate 64.0 mu mol/mmol creatinine (upper limit of reference range, 13.2) and 11 of 17 patients from group B, mean peak orotate 41.0 mu mol/mmol creatinine (upper limit of reference range, 13.2). Thorough investigation of these pat ients including urinary and plasma amino acid analysis and, in 17 cases, li ver biopsy for histology and measurement of ornithine carbamyltransferase ( OCT) and carbamyl-phosphate synthetase (CPS) activity failed to identify an y evidence of a urea cycle disorder. However, muscle biopsies performed in 11 patients showed some evidence of mitochondrial disease in four cases, tw o defined on the basis of reduced respiratory chain enzyme activity and two on the basis of mtDNA abnormalities. These findings indicate that an incre ased excretion of orotate in sick children may not be uncommon and that a p ositive allopurinol load test result may not indicate a specific inherited urea cycle defect. In addition, these results raise the interesting possibi lity that defective ureagenesis may be a feature of mitochondrial disease i n some individuals.