An integrated approach to the diagnosis and prospective management of partial ornithine transcarbamylase deficiency.

Ornithine transcarbamylase deficiency (OTCD) is the most common inherited urea cycle disorder, and is transmitted as an X-linked trait. Female OTCD heterozygotes exhibit wide clinical severities, ranging from being apparently asymptomatic to having the profound neurologic impairment observed in affected males. However, clinical and laboratory diagnosis of partial OTCD during asymptomatic periods is difficult, and correlation of phenotypic severity with either DNA mutation and/or in vitro enzyme activity is imprecise. Provocative testing, including protein load and allopurinol challenge used in the diagnosis of OTCD females, is not without risk and subject to both false positives and negatives. Although definitive when successful, DNA-based diagnosis is unable to detect mutations in all cases. We have previously used the ratio of isotopic enrichments of [(15)N]urea/[(15)N]glutamine ((15)N-U/G) derived from physiologic measurements of ureagenesis by stable isotope infusion as a sensitive index of in vivo urea cycle activity. We have now applied this method in combination with traditional biochemical testing to aid in the diagnosis of a symptomatic OTCD female in whom mutation in the ornithine transcarbamylase (OTC) gene was not found. The (15)N-U/G ratio in this patient showed that she had severe reduction of in vivo urea cycle activity on par with affected male subjects. This was correlated with partially deficient OTC activity in her liver, degree of orotic aciduria, and history of suspected recurrent hyperammonemic episodes before age 3. The measurement of in vivo urea cycle activity in combination with traditional biochemical indices optimizes a diagnostic approach to the at-risk partial OTCD patient, especially in those in whom molecular testing is unproductive. Together they contribute to the risk versus benefit considerations regarding the pursuit of medical therapy versus surgical, ie, orthotopic liver transplantation (OLT) therapy. The decision to resort to OLT in females with partial OTC activity is controversial, requiring consideration of phenotypic severity, failure of medical therapy, access to tertiary care centers experienced in the management of acute hyperammonemia, and social factors. In this patient, the use of in vivo and in vitro measures of urea cycle activity in conjunction with a consideration of her clinical history and medical-social situation led to a decision for OLT.