Optimization of allopurinol challenge: Sample purification, protein intakecontrol, and the use of orotidine response as a discriminative variable improve performance of the test for diagnosing ornithine carbamoyltransferasedeficiency

Background: The diagnosis of heterozygosity for X-linked ornithine carbamoy ltransferase (OCT) deficiency has usually been based on measurement of the increase of orotate and orotidine excretion after an allopurinol load. We e xamined the choices of analyte, cutoff, and test conditions to obtain maxim al test accuracy. Methods: Urine orotate/orotidine responses to allopurinol load in 37 childr en (13 OCT-deficient and 24 non-OCT-deficient) and 24 women (7 at risk for carrier status and 17 not related to OCT-deficient children) were analyzed by liquid chromatography after sample purification by anion-exchange chroma tography. Diagnostic accuracy was evaluated by nonparametric ROC curves. Results: Sample purification was necessary to prevent interferences. Orotat e and orotidine excretion increased with increased protein intake during th e test. At a cutoff of 8 mmol orotidine/mol creatinine, sensitivity was 1.0 and specificity was 0.92 in mild forms of OCT deficiency. Results in monop lex carrier women may differ greatly from those expected because of the gen etics of this deficiency. Conclusions: Standardization of protein intake is required in the allopurin ol loading test. A negative response in the face of clinical suspicion shou ld be followed with a repeat test during a protein intake not <2.5 g.kg(-1) .day(-1). Measurements of orotidine provide better clinical sensitivity tha n measurements of orotate. (C) 1999 American Association for Clinical Chemi stry.