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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 Kido
  • Shirou Matsumoto
  • Hiroshi Mitsubuchi
  • Fumio Endo
  • Kimitoshi Nakamura
Original Article
  • 103 Downloads

Abstract

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.

Keywords

Ammonia liver transplantation neurodevelopmental outcome urea cycle disorder 

Abbreviations

AGD

arginase 1 deficiency

ALD

arginosuccinate lyase deficiency

ASD

arginosuccinate synthetase deficiency

CPSD

carbamoyl phosphate synthetase 1 deficiency

LT

liver transplantation

OTCD

ornithine transcarbamylase deficiency

UCD

urea cycle disorder

Notes

Acknowledgements

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.

Funding

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)

References

  1. Bachmann C (2003) Outcome and survival of 88 patients with urea cycle disorders: a retrospective evaluation. Eur J Pediatr 162:410–416.  https://doi.org/10.1007/s00431-003-1188-9 CrossRefGoogle Scholar
  2. Bachmann C (2005) Long-term outcome of urea cycle disorders. Acta Gastroenterol Belg 68:466–468PubMedGoogle Scholar
  3. Batshaw ML, MacArthur RB, Tuchman M (2001) Alternative pathway therapy for urea cycle disorders: twenty years later. J Pediatr 138(Suppl 1):S46–S54CrossRefGoogle Scholar
  4. Brusilow SW (1991) Phenylacetylglutamine may replace urea as a vehicle for waste nitrogen excretion. Pediatr Res 29:147–150.  https://doi.org/10.1203/00006450-199102000-00009 CrossRefPubMedGoogle Scholar
  5. Brusilow SW, Valle DL, Batshaw M (1979) New pathways of nitrogen excretion in inborn errors of urea synthesis. Lancet 2:452–454CrossRefGoogle Scholar
  6. Chisuwa H, Hashikura Y, Nakazawa Y et al (2001) Fatal hemophagocytic syndrome after living-related liver transplantation: a report of two cases. Transplantation 72:1843–1846CrossRefGoogle Scholar
  7. Enns GM, Berry SA, Berry GT et al (2007) Survival after treatment with phenylacetate and benzoate for urea-cycle disorders. N Engl J Med 356:2282–2292.  https://doi.org/10.1056/NEJMoa066596 CrossRefPubMedGoogle Scholar
  8. Feillet F, Leonard JV (1998) Alternative pathway therapy for urea cycle disorders. J Inherit Metab Dis 21(Suppl 1):101–111CrossRefGoogle Scholar
  9. Karasu Z, Kilic M, Cagirgan S et al (2003) Hemophagocytic syndrome after living-related liver transplantation. Transplant Proc 35:1482–1484CrossRefGoogle Scholar
  10. Kasahara M, Sakamoto S, Horikawa R et al (2014) Living donor liver transplantation for pediatric patients with metabolic disorders: the Japanese multicenter registry. Pediatr Transplant 18:6–15.  https://doi.org/10.1111/petr.12196 CrossRefPubMedGoogle Scholar
  11. Kido J, Nakamura K, Mitsubuchi H et al (2012) Long-term outcome and intervention of urea cycle disorders in Japan. J Inherit Metab Dis 35:777–785.  https://doi.org/10.1007/s10545-011-9427-0 CrossRefPubMedGoogle Scholar
  12. Kido J, Matsumoto S, Momosaki K et al (2017a) Liver transplantation may prevent neurodevelopmental deterioration in high-risk patients with urea cycle disorders. Pediatr Transplant 21. doi:  https://doi.org/10.1111/petr.12987 CrossRefGoogle Scholar
  13. Kido J, Kawasaki T, Mitsubuchi H et al (2017b) Hyperammonemia crisis following parturition in a female patient with ornithine transcarbamylase deficiency. World J Hepatol 9:343–348.  https://doi.org/10.4254/wjh.v9.i6.343 CrossRefPubMedPubMedCentralGoogle Scholar
  14. Kölker S, Garcia-Cazorla A, Valayannopoulos V et al (2015a) The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation. J Inherit Metab Dis 38:1041–1457.  https://doi.org/10.1007/s10545-015-9839-3 CrossRefPubMedGoogle Scholar
  15. Kölker S, Valayannopoulos V, Burlina AB et al (2015b) The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2: the evolving clinical phenotype. J Inherit Metab Dis 38:1059–1074.  https://doi.org/10.1007/s10545-015-9840-x CrossRefPubMedGoogle Scholar
  16. Krivitzky L, Babikian T, Lee HS et al (2009) Intellectual, adaptive, and behavioral functioning in children with urea cycle disorders. Pediatr Res 66:96–101.  https://doi.org/10.1203/PDR.0b013e3181a27a16 CrossRefPubMedPubMedCentralGoogle Scholar
  17. Langendonk JG, Roos JC, Angus L et al (2012) A series of pregnancies in women with inherited metabolic disease. J Inherit Metab Dis 35:419–424.  https://doi.org/10.1007/s10545-011-9389-2 CrossRefPubMedGoogle Scholar
  18. Leonard JV (2001) The nutritional management of urea cycle disorders. J Pediatr 138(Suppl 1):S40–S44CrossRefGoogle Scholar
  19. Maestri N, Brusilow SW, Clissold DB, Bassett SS (1996) Long-term treatment of girls with ornithine transcarbamylase deficiency. N Engl J Med 335:855–859.  https://doi.org/10.1056/NEJM199609193351204 CrossRefPubMedGoogle Scholar
  20. Nagasaka H, Yorifuji T, Murayama K et al (2006) Effects of arginine treatment on nutrition, growth and urea cycle function in seven Japanese boys with late-onset ornithine transcarbamylase deficiency. Eur J Pediatr 165:618–624.  https://doi.org/10.1007/s00431-006-0143-y CrossRefPubMedGoogle Scholar
  21. Nagata N, Matsuda I, Oyanagi K (1991a) Estimated frequency of urea cycle enzymopathies in Japan. Am J Med Genet 39:228–229.  https://doi.org/10.1002/ajmg.1320390226 CrossRefPubMedGoogle Scholar
  22. Nagata N, Matsuda I, Matsuura T et al (1991b) Retrospective survey of urea cycle disorders: part 2. Neurological outcome in forty-nine Japanese patients with urea cycle enzymopathies. Am J Med Genet 40:477–481.  https://doi.org/10.1002/ajmg.1320400421 CrossRefPubMedGoogle Scholar
  23. Nassogne MC, Héron B, Touati G, Rabier D, Saudubray JM (2005) Urea cycle defects: management and outcome. J Inherit Metab Dis 28:407–414.  https://doi.org/10.1007/s10545-005-0303-7 CrossRefPubMedGoogle Scholar
  24. Nicolaides P, Liebsch D, Dale N, Leonard J, Surtees R (2002) Neurological outcome of patients with ornithine carbamoyltransferase deficiency. Arch Dis Child 86:54–56CrossRefGoogle Scholar
  25. Posset R, Garcia-Cazorla A, Valayannopoulos V et al (2016) Age at disease onset and peak ammonium level rather than interventional variables predict the neurological outcome in urea cycle disorders. J Inherit Metab Dis 39:661–672.  https://doi.org/10.1007/s10545-016-9938-9 CrossRefGoogle Scholar
  26. Schaefer F, Straube E, Oh J, Mehls O, Mayatepek E (1999) Dialysis in neonates with inborn errors of metabolism. Nephrol Dial Transplant 14:910–918CrossRefGoogle Scholar
  27. Seminara J, Tuchman M, Krivitzky L et al (2010) Establishing a consortium for the study of rare diseases: The Urea Cycle Disorders Consortium. Mol Genet Metab 100(Suppl1):S97–S105.  https://doi.org/10.1016/j.ymgme.2010.01.014 CrossRefPubMedPubMedCentralGoogle Scholar
  28. Summar ML, Barr F, Dawling S et al (2005) Unmasked adult-onset urea cycle disorders in the critical care setting. Crit Care Clin 21(Suppl 4):S1–S8.  https://doi.org/10.1016/j.ccc.2005.05.002 CrossRefPubMedGoogle Scholar
  29. Uchino T, Endo F, Matsuda I (1998) Neurodevelopmental outcome of long-term therapy of urea cycle disorders in Japan. J Inherit Metab Dis 21:151–159CrossRefGoogle Scholar

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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