Metabolic Brain Disease

, Volume 33, Issue 5, pp 1517–1523 | Cite as

Early liver transplantation in neonatal-onset and moderate urea cycle disorders may lead to normal neurodevelopment

  • Jun KidoEmail author
  • Shirou Matsumoto
  • Hiroshi Mitsubuchi
  • Fumio Endo
  • Kimitoshi Nakamura
Original Article


Urea cycle disorders (UCDs) are inherited metabolic diseases that lead to hyperammonemia. Neurodevelopmental outcomes of patients with UCDs depend on the maximum ammonia concentration (MAC) in the blood during onset. MAC ≥360 μM is a marker of poor neurodevelopmental outcomes. We investigated the neurodevelopmental outcomes and MAC at onset for 177 patients with UCDs in Japan (median age, 8 years and 2 months; range, 10 days–72 years), including 57 patients with male ornithine transcarbamylase (OTCD), 59 patients with female OTCD, 23 patients with carbamoyl-phosphate synthetase 1 deficiency (CPSD), 28 patients with arginosuccinate synthetase deficiency, 9 patients with arginosuccinate lyase deficiency (ALD), and 1 patient with arginase 1 deficiency. Neurodevelopmental outcomes of patients with CPSD and ALD were poor because most had neonatal onset with blood MAC ≥300 μM at onset. Although OTCD, particularly female late-onset OTCD, has good neurodevelopmental outcomes among those with UCDs, it is not necessarily a mild disease with good long-term outcomes. Patients with severe UCDs and MAC ≥300 μM at onset should undergo liver transplantation (LT). Moreover, this study suggested that if the onset of UCD began during the neonatal period, then even UCD patients with MAC <300 μM at onset should undergo LT to protect the brain.


Ammonia liver transplantation neurodevelopmental outcome urea cycle disorder 



arginase 1 deficiency


arginosuccinate lyase deficiency


arginosuccinate synthetase deficiency


carbamoyl phosphate synthetase 1 deficiency


liver transplantation


ornithine transcarbamylase deficiency


urea cycle disorder



This study was supported in part by a grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology. We thank all 668 institutions, especially the 87 institutions that kindly provided useful clinical information regarding patients with urea cycle disorders, for their assistance. We are extremely grateful to Drs. Toshihiro Ohura, Masaki Takayanagi, Masafumi Matsuo, Makoto Yoshino, Yosuke Shigematsu, Tohru Yorifuji, Mureo Kasahara, and Reiko Horikawa, who comprise the pediatric research group of the Ministry of Health, Labor, and Welfare, for generously providing help and advice when we conducted the questionnaire survey.

Author Contributions

Kido J and Nakamura K designed the report. Kido J, Matsumoto S, Mitsubuchi H, and Endo F collected the patients’ clinical and laboratory data. Kido J and Nakamura K analyzed the data. Kido J wrote the paper.


This study was funded in part by a grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology.

Compliance with ethical standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

11011_2018_259_MOESM1_ESM.pptx (93 kb)
Supplemental Fig.1 Long-term outcomes and blood maximum ammonia concentration (MAC) of neonatal and late onset CPSD, ASD, and ALD. a. Long-term outcomes for neonatal and late onset CPSD, ASD, and ALD. Neonatal onset CPSD, N = 20; late onset CPSD, N = 3; neonatal onset ASD, N = 21; late onset ASD, N = 7; neonatal onset ALD, N = 8; late onset ALD, N = 1. b. Blood MAC at onset for neonatal and late onset CPSD, ASD, and ALD. Neonatal onset CPSD, N = 19; late onset CPSD, N = 2; neonatal onset ASD, N = 19; late onset ASD N = 6; neonatal onset ALD, N = 8; late onset ALD, N = 1. (PPTX 92.7 kb)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pediatrics, Graduate School of Medical SciencesKumamoto UniversityKumamoto PrefectureJapan

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