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Creatine metabolism in urea cycle defects

  • SSIEM Symposium 2011
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Creatine (Cr) and phosphocreatine play an essential role in energy storage and transmission. Maintenance of creatine pool is provided by the diet and by de novo synthesis, which utilizes arginine, glycine and s-adenosylmethionine as substrates. Three primary Cr deficiencies exists: arginine:glycine amidinotransferase deficiency, guanidinoacetate methyltransferase deficiency and the defect of Cr transporter SLC6A8. Secondary Cr deficiency is characteristic of ornithine-aminotransferase deficiency, whereas non-uniform Cr abnormalities have anecdotally been reported in patients with urea cycle defects (UCDs), a disease category related to arginine metabolism in which Cr must be acquired by de novo synthesis because of low dietary intake. To evaluate the relationships between ureagenesis and Cr synthesis, we systematically measured plasma Cr in a large series of UCD patients (i.e., OTC, ASS, ASL deficiencies, HHH syndrome and lysinuric protein intolerance). Plasma Cr concentrations in UCDs followed two different trends: patients with OTC and ASS deficiencies and HHH syndrome presented a significant Cr decrease, whereas in ASL deficiency and lysinuric protein intolerance Cr levels were significantly increased (23.5 vs. 82.6 μmol/L; p < 0.0001). This trend distribution appears to be regulated upon cellular arginine availability, highlighting its crucial role for both ureagenesis and Cr synthesis. Although decreased Cr contributes to the neurological symptoms in primary Cr deficiencies, still remains to be explored if an altered Cr metabolism may participate to CNS dysfunction also in patients with UCDs. Since arginine in most UCDs becomes a semi-essential aminoacid, measuring plasma Cr concentrations might be of help to optimize the dose of arginine substitution.

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Authors and Affiliations

  1. Division of Metabolism and Research Unit of Metabolic Biochemistry, Bambino Gesù Children’s Hospital, IRCCS, Piazza S. Onofrio 4, 00165, Rome, Italy

    Sara Boenzi, Anna Pastore, Diego Martinelli, Arianna Boiani & Carlo Dionisi-Vici

  2. Laboratory of Metabolic Biochemistry, Bambino Gesù Children’s Hospital, IRCCS, Piazza S. Onofrio 4, 00165, Rome, Italy

    Bianca Maria Goffredo & Cristiano Rizzo

  3. Division of Metabolism, Bambino Gesù Children’s Hospital, IRCCS, Piazza S. Onofrio, 4, 00165, Rome, Italy

    Carlo Dionisi-Vici

Authors
  1. Sara Boenzi
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  2. Anna Pastore
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  3. Diego Martinelli
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  4. Bianca Maria Goffredo
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  5. Arianna Boiani
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  6. Cristiano Rizzo
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  7. Carlo Dionisi-Vici
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Corresponding author

Correspondence to Carlo Dionisi-Vici.

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Communicated by: Eva Morava

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Boenzi, S., Pastore, A., Martinelli, D. et al. Creatine metabolism in urea cycle defects. J Inherit Metab Dis 35, 647–653 (2012). https://doi.org/10.1007/s10545-012-9494-x

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  • DOI: https://doi.org/10.1007/s10545-012-9494-x

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