Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle defect. The clinical presentation in female manifesting carriers varies both in onset and severity. We report on a female with insulin dependent diabetes mellitus and recurrent episodes of hyperammonemia. Since OTC activity measured in a liver biopsy sample was within normal limits, OTC deficiency was initially excluded from the differential diagnoses of hyperammonemia. Due to moderately elevated homocitrulline excretion, hyperornithinemia-hyperammonemia-homocitrullinuria-syndrome was suggested, but further assays in fibroblasts showed normal ornithine utilization. Later, when mutation analysis of the OTC gene became available, a known pathogenic missense mutation (c.533C>T) in exon 5 leading to an exchange of threonine-178 by methionine (p.Thr178Met) was detected. Skewed X-inactivation was demonstrated in leukocyte DNA. In the further clinical course the girl developed marked obesity. By initiating physical activities twice a week, therapeutic control of both diabetes and OTC deficiency improved, but obesity persisted. In conclusion, our case confirms that normal hepatic OTC enzyme activity measured in a single liver biopsy sample does not exclude a clinical relevant mosaic of OTC deficiency because of skewed X-inactivation. Mutation analysis of the OTC gene in whole blood may be a simple way to establish the diagnosis of OTC deficiency. The joint occurrence of OTC deficiency and diabetes in a patient has not been reported before.
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Glycosylated hemoglobin A
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We thank Prof. Vivian E. Shih for the 14C-ornithine incorporation measurements in fibroblasts.
The authors declare that they have no competing interests.
SCG was involved in the treatment of the patient and drafted the manuscript with KOS. PVL was responsible for the X-inactivation studies and critically revised the manuscript. BW was responsible for the enzyme studies and critically revised the manuscript. WL was involved in the diagnostic work-up of the patient, responsible for most of the biochemical analyses and critically revised the manuscript. JOS was also involved in the biochemical investigations and critically revised the manuscript. KOS was involved in the diagnostic work-up and the long-term treatment of the patient. He drafted the manuscript together with SCG. All authors read and approved the final manuscript.
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Grünert, S.C., Villavicencio-Lorini, P., Wermuth, B. et al. Ornithine transcarbamylase deficiency combined with type 1 diabetes mellitus - a challenge in clinical and dietary management. J Diabetes Metab Disord 12, 37 (2013). https://doi.org/10.1186/2251-6581-12-37
- Ornithine transcarbamylase deficiency
- Ornithine carbamoyltransferase deficiency
- OTC deficiency
- Urea cycle disorder
- Insulin-dependent diabetes mellitus