Cognitive and Behavioural Outcomes of Paediatric Liver Transplantation for Ornithine Transcarbamylase Deficiency

  • Louise CroweEmail author
  • Vicki Anderson
  • Winita Hardikar
  • Avihu Boneh
Research Report
Part of the JIMD Reports book series (JIMD, volume 43)


Ornithine Trans-Carbamylase (OTC) deficiency is the most common disorder of the urea cycle. Cognitive impairments in skills such as attention and executive function have been reported in individuals with OTC deficiency who are managed with medication. In some cases, children undergo liver transplantation (LTx) to correct the metabolic defect. The metabolic and medical outcomes of LTx are generally good. However, little is known about the impacts on cognition. In this study, four children (three female) completed detailed neuropsychological batteries prior to (n = 6) and following LTx (n = 8 assessments). Children’s age at assessment ranged from 3 to 11 years. The battery included standardised, age-referenced measures of intellectual ability (IQ), attention, memory and educational ability. Additionally, parent measures of behaviour and executive function were administered. Generally, there was little change in overall IQ following LTx. Memory and academic skills were at expected levels for the three female patients and gains were made after LTx. Children showed ongoing impairments in attention and parent rated executive function. In conclusion, the immediate effect of LTx on cognition may not appear beneficial in the short-term and impairments in IQ, attention and behaviour persisted after the procedure. However, LTx seems to enable stabilisation to premorbid function in the longer term.


Children Cognition Liver transplantation Ornithine Trans-Carbamylase (OTC) deficiency 


  1. Bachmann C, Braissant O, Villard A, Boulat O, Henry H (2004) Ammonia toxicity to the brain and creatine. Mol Genet Metab 81:S52–S57CrossRefGoogle Scholar
  2. Braissant O (2010) Current concepts in the pathogenesis of urea cycle disorders. Mol Genet Metab 100:S3–S12CrossRefGoogle Scholar
  3. Braissant O, Henry H, Villard AM et al (2002) Ammonium-induced impairment of axonal growth is prevented through glial creatine. J Neurosci 22:9810–9820CrossRefGoogle Scholar
  4. Brusilow S, Horwich A (2000) Urea cycle enzymes. In: Scriver CR, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 1909–1963Google Scholar
  5. Cohen M (1997) Manual for the children’s memory scale. Psychological Corporation, San AntonioGoogle Scholar
  6. Compas B, Jaser S, Dunn M, Rodriguez E (2012) Coping with chronic illness in childhood and adolescence. Annu Rev Clin Psychol 8:455–480CrossRefGoogle Scholar
  7. Ewing-Cobbs L, Barnes MA, Fletcher J (2003) Early brain injury in children: development and reorganization of cognitive function. Dev Neuropsychol 24:669–704CrossRefGoogle Scholar
  8. Fouladi M, Chintagumpala M, Laningham F et al (2004) White matter lesions detected by magnetic resonance imaging after radiotherapy and high-dose chemotherapy in children with medulloblastoma or primitive neuroectodermal tumor. J Clin Oncol 22:4551–4560CrossRefGoogle Scholar
  9. Gioia G, Espy K, Isquith P (1996) Behavior rating inventory of executive function-preschool version (BRIEF-P). Harcourt Assessment, San AntonioGoogle Scholar
  10. Gioia G, Isquith P, Guy G, Kenworthy K (2003) Behavior rating inventory of executive function. Harcourt Assessment, San AntonioGoogle Scholar
  11. Gropman A, Batshaw M (2004) Cognitive outcome in urea cycle disorders. Mol Genet Metab 81:58–62CrossRefGoogle Scholar
  12. Gyato K, Wray J, Huang Z, Yudkoff M, Batshaw M (2004) Metabolic and neuropsychological phenotype in women heterozygous for ornithine transcarbamylase deficiency. Ann Neurol 55:80–86CrossRefGoogle Scholar
  13. Hermenegildo C, Montoliu C, Llansola M et al (1998) Chronic hyperammonemia impairs the glutamate-nitric oxide-cyclic GMP pathway in cerebellar neurons in culture and in the rat in vivo. Eur J Neurosci 10:3201–3209CrossRefGoogle Scholar
  14. Kim IK, Niemi A-K, Krueger C et al (2013) Liver transplantation for urea cycle disorders in pediatric patients: a single-center experience. Pediatr Transplant 17:158–167CrossRefGoogle Scholar
  15. Korkman M, Kirk U, Kemp S (2007) NEPSY-II, 2nd edn. Pearson, San AntonioGoogle Scholar
  16. Krivitzky L, Babikian T, Lee HS, Thomas NH, Burk-Paull KL, Batshaw M (2009) Intellectual, adaptive, and behavioral functioning in children with urea cycle disorders. Pediatr Res 66:96–101CrossRefGoogle Scholar
  17. Maestri N, Brusilow S, Clissold D, Bassett S (1996) Long-term treatment of girls with ornithine transcarbamylase deficiency. N Engl J Med 335:855–859CrossRefGoogle Scholar
  18. Manly T, Robertson I, Anderson V, Nimmo-Smith I (1998) Test of everyday attention for children (TEA-Ch). Thames Valley Test Company, SuffolkGoogle Scholar
  19. McCullough BA, Yudkoff M, Batshaw ML, Wilson JM, Raper SE, Tuchman M (2000) Genotype spectrum of ornithine transcarbamylase deficiency: correlation with the clinical and biochemical phenotype. Am J Med Genet 93:313–319CrossRefGoogle Scholar
  20. Reynolds C, Kamphaus R (2010) Behavior assessment system for children-second edition, manual. Pearson, BloomingtonGoogle Scholar
  21. Scantlebury N, Mabbott D, Janzen L et al (2011) White matter integrity and core cognitive function in children diagnosed with sickle cell disease. J Pediatr Hematol Oncol 33:163–171CrossRefGoogle Scholar
  22. Sorensen L, Neighbors K, Martz K, Zelko F, Bucuvalas J, Alonso E, Studies of Pediatric Liver Transplantation (SPLIT) Research Group and the Functional Outcomes Group (FOG) (2014) Longitudinal study of cognitive and academic outcomes after pediatric liver transplantation. J Pediatr 165:65–72CrossRefGoogle Scholar
  23. Stevenson T, Millan MT, Wayman K et al (2009) Long-term outcome following pediatric liver transplantation for metabolic disorders. Pediatr Transplant 14:268–275CrossRefGoogle Scholar
  24. Wechsler D (2002) Wechsler preschool and primary scale of intelligence, 3rd edn. Psychological Corporation, San AntonioGoogle Scholar
  25. Wechsler D (2003) Wechsler intelligence scale for children, 4th edn. Harcourt Assessment, San AntonioGoogle Scholar
  26. Wilkinson G (2006) Wide-range achievement test, 4th edn. Harcourt Assessment, San AntonioGoogle Scholar

Copyright information

© Society for the Study of Inborn Errors of Metabolism (SSIEM) 2018

Authors and Affiliations

  • Louise Crowe
    • 1
    • 2
    • 3
    Email author
  • Vicki Anderson
    • 1
    • 2
    • 3
    • 4
  • Winita Hardikar
    • 4
    • 5
  • Avihu Boneh
    • 4
    • 6
    • 7
  1. 1.School of Psychological SciencesUniversity of MelbourneParkvilleAustralia
  2. 2.Child NeuropsychologyMurdoch Children’s Research InstituteMelbourneAustralia
  3. 3.Department of PsychologyRoyal Children’s HospitalMelbourneAustralia
  4. 4.Department of PaediatricsUniversity of MelbourneParkvilleAustralia
  5. 5.Department of Gastroenterology and NutritionRoyal Children’s HospitalMelbourneAustralia
  6. 6.Metabolic ResearchMurdoch Children’s Research Institute, Royal Children’s HospitalMelbourneAustralia
  7. 7.Department of Metabolic MedicineRoyal Children’s HospitalMelbourneAustralia

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