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The allopurinol load test lacks specificity for primary urea cycle defects but may indicate unrecognized mitochondrial disease
Author(s) -
Bonham J. R.,
Guthrie P.,
Downing M.,
Allen J. C.,
Tanner M. S.,
Sharrard M.,
Rittey C.,
Land J. M.,
Fensom A.,
O'Neill D.,
Duley J. A.,
Fairbanks L. D.
Publication year - 1999
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1023/a:1005406205548
Subject(s) - urea cycle , allopurinol , creatinine , medicine , ornithine , endocrinology , excretion , urinary system , gastroenterology , orotic acid , urea , biology , pathology , biochemistry , amino acid , arginine
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 excretion detected by routine organic acid analysis (group A), and 17 for clinical reasons suggesting a urea cycle defect (group B). The allopurinol load test proved positive in 13 of 16 patients from group A, mean peak orotate 64.0μmol/mmol creatinine (upper limit of reference range, 13.2) and 11 of 17 patients from group B, mean peak orotate 41.0μmol/mmol creatinine (upper limit of reference range, 13.2). Thorough investigation of these patients including urinary and plasma amino acid analysis and, in 17 cases, liver biopsy for histology and measurement of ornithine carbamyltransferase (OCT) and carbamyl‐phosphate synthetase (CPS) activity failed to identify any evidence of a urea cycle disorder. However, muscle biopsies performed in 11 patients showed some evidence of mitochondrial disease in four cases, two defined on the basis of reduced respiratory chain enzyme activity and two on the basis of mtDNA abnormalities. These findings indicate that an increased excretion of orotate in sick children may not be uncommon and that a positive allopurinol load test result may not indicate a specific inherited urea cycle defect. In addition, these results raise the interesting possibility that defective ureagenesis may be a feature of mitochondrial disease in some individuals.