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Developmental Outcomes with Early Orthotopic Liver Transplantation For Developmental Outcomes With Early Orthotopic Liver Transplantation for Infants With Neonatal-Onset Urea Cycle Defects and a Female Patient With Late-Onset Ornithine Transcarbamylase Deficiency Kim L. McBride, MD*; Geoffrey Miller, MD‡; Susan Carter, BSN*࿣; Saul Karpen, MD, PhD‡; John Goss, MD§; and Brendan Lee, MD, PhD*࿣ ABSTRACT. Urea cycle defects (UCDs) typically nherited disorders of the urea cycle are character- present with hyperammonemia, the duration and peak ized by high ammonia levels and altered amino levels of which are directly related to the neurologic acid metabolism. There are 6 well-characterized outcome. Liver transplantation can cure the underlying I urea cycle defects (UCDs), ie, N-acetylyglutamate defect for some conditions, but the preexisting neuro- synthase, carbamoyl phosphate synthase (CPS), X- logic status is a major factor in the final outcome. Mul- linked ornithine transcarbamylase (OTC), arginosuc- ticenter data indicate that most of the children who re- cinate synthase, arginosuccinate lyase, and arginase ceive transplants remain significantly neurologically deficiencies. Arginase deficiency is not typical of the impaired. We wanted to determine whether aggressive other UCDs, because it presents not with hyperam- metabolic management of ammonia levels after early monemia but with spastic diplegia. Presentation of referral/transfer to a metabolism center and early liver transplantation would result in better neurologic out- the other UCDs can be quite variable, from cata- comes. We report on 5 children with UCDs, ie, 2 male strophic neonatal illness and acute episodic enceph- patients with X-linked ornithine transcarbamylase defi- alopathy in childhood or adulthood to chronic neu- 1 ciency and 2 male patients with carbamoyl phosphate rologic disorders. synthase deficiency, all of whom had neonatal presenta- Neonates with UCDs typically have a normal birth tions and underwent orthotopic liver transplantation be- weight and an uneventful initial peripartum period. fore 1 year of age, and 1 female patient with partial They present within hours to days after birth with a X-linked ornithine transcarbamylase deficiency that was catastrophic illness, starting with poor feeding, leth- intractable to medical therapy, who underwent trans- argy, vomiting, and tachypnea and then progressing plantation at 35 months of age. Developmental testing rapidly to coma attributable to hyperammonemia. with the Griffiths scale was performed on 3 occasions Rapid treatment is required for survival, with neu- each, 12 months apart, up to 45 months after transplan- rologic and overall outcomes being related to the tation. Full-scale indices for 3 children who underwent level and duration of hyperammonemia.2,3 Prompt early transplantation showed average developmental reduction of ammonia levels through hemodialysis quotients of 67. All 5 children had metabolic cures. There and pharmacologic therapy that directs nitrogen were no deaths (30-month survival rate: 100%). One child waste to alternate pathways has reduced mortality is currently listed for repeat transplantation because of rates at 1 year of age from 86% to 8%. However, bile duct stenosis and cirrhosis. We conclude that early one-half of the survivors still die before entering liver transplantation and aggressive metabolic manage- school, and 80% to 100% of the remainder have se- ment improve early neurologic outcomes for children 4,5 with UCDs, but longer follow-up monitoring is needed. vere developmental disabilities. There are no data Pediatrics 2004;114:e523–e526. URL: www.pediatrics.org/ to suggest that treatments, overall outcomes, and cgi/doi/10.1542/peds.2004-0198; urea cycle defect, liver neurologic outcomes differ between CPS and OTC transplantation, ornithine transcarbamylase deficiency, deficiency. development, outcome. Long-term management of cases of UCDs requires strict dietary protein restriction, administration of sodium phenylbutyrate to stimulate alternate path- ABBREVIATIONS. UCD, urea cycle defect; CPS, carbamoyl phos- ways of nitrogen disposal, and prompt recognition phate synthase; OTC, ornithine transcarbamylase; EBV, Epstein- Barr virus; OLT, orthotopic liver transplantation. and treatment of intercurrent illnesses to prevent catabolism and hyperammonemia. Frequent epi- sodes of recurrent hyperammonemia have negative effects on neurologic outcomes but are a common problem because of the difficulties with long-term From the Departments of *Molecular and Human Genetics, ‡Pediatrics, and 2 §Surgery and ࿣Howard Hughes Medical Institute, Baylor College of Medi- dietary and pharmacologic management. cine, Houston, Texas. Orthotopic liver transplantation (OLT) is an alter- Accepted for publication May 13, 2004. native to medical therapy for severe UCDs. OLT doi:10.1542/peds.2004-0198 results show nearly complete metabolic correction Address correspondence to Brendan Lee, MD, PhD, One Baylor Plaza, Room 635E, Houston, TX 77030. E-mail: [email protected] and cessation, but not reversal, of neurologic defi- 6 PEDIATRICS (ISSN 0031 4005). Copyright © 2004 by the American Acad- cits. Originally, transplantation was avoided among emy of Pediatrics. children Ͻ12 months of age, because it was thought www.pediatrics.org/cgi/doi/10.1542/peds.2004-0198Downloaded from www.aappublications.org/news byPEDIATRICS guest on September Vol. 24, 114 2021 No. 4 October 2004 e523 that there were greater risks of death and morbidity. (increased liver transaminase levels, confirmed with Advances in surgical techniques and management of biopsy), which responded to augmentation of immu- immunosuppression now allow transplantation at an nosuppressive medication. None of the surviving earlier age, with mortality rates equal to those for patients has required readmission or additional ther- older children.7 We hypothesized that aggressive apy because of rejection. One of the 5 patients (pa- metabolic management and earlier transplantation tient 5) experienced biopsy-proven, mild, localized, might result in improved neurologic outcomes, be- posttransplant lymphoproliferative disorder. This cause of fewer episodes of hyperammonemia. was treated with tonsillectomy/adenoidectomy and autologous Epstein-Barr virus (EBV)-specific cyto- METHODS toxic T lymphocyte infusion, as part of an experimen- We retrospectively reviewed our experience with aggressive tal phase I trial (Epstein-Barr Virus Infections Lym- metabolic control of ammonia levels, strict dietary management, phoproliferative Disorders). All patients have and use of early (Ͻ12 months of age) OLT. All patients with neonatal-onset UCDs who underwent early OLT after January unrestricted diets and, with the exception of some 2000 were identified. An additional patient was enrolled prospec- with slightly low citrulline levels, have normal tively. One female patient with late-onset OTC deficiency was also plasma amino acid profiles. Results of the testing enrolled. As previously reported,8 that patient was selected for with Griffiths Mental Developmental Scales are pre- transplantation because of poor metabolic control. The decision to sented in Table 2. Neurologic examinations revealed perform transplantation in that case was made after a multifaceted attempt to characterize maximally the patient’s biological pheno- hypotonia for 1 patient (patient 3, with failure to type, as part of a multifaceted risk/benefit assessment.8 A chart thrive) and mild speech apraxia for the partially survey was performed to record details of initial presentation, OTC-deficient female patient (patient 5). subsequent hyperammonemic episodes, transplantation, and cur- rent medical status. After obtaining informed consent through an institutional review board-approved protocol, we prospectively DISCUSSION performed developmental testing. The children were evaluated by OLT has become a useful therapy for severe UCDs, an accredited tester using the Griffiths Mental Developmental particularly CPS deficiency and hemizygous male 9 10 Scales, which were restandardized in 1996. The mean Griffiths OTC deficiency.11–14 Many reports note the success score and each of the 5 subscales have a mean of 100 and a SD of 10.8. Development was compared with historical control findings of this therapy in providing metabolic control and reported in the literature. preventing additional episodes of hyperammone- mia, preserving neurologic function.12 When trans- RESULTS plantation is performed later, however, neurologic All patients have now been monitored for Ն30 compromise already exists and is not corrected. months after transplantation. Patient characteristics Our results with early OLT indicate that transplan- are noted in Table 1. All patients had gastrostomy tation is possible and neurologic outcomes are im- tubes placed shortly after diagnosis, to facilitate di- proved, compared with later transplantation. Histor- etary management. Patients who presented in the ical control findings obtained from the literature newborn period all underwent hemodialysis. A rare (findings for patients with UCDs who received liver blood type prevented 1 patient (patient 2) from un- transplants at Ͼ1 year of age) demonstrated gener- dergoing transplantation until 11 months of age. No ally poor outcomes. Maestri et al5 noted that 2 of 3 of deaths occurred among the liver transplant recipi- their transplanted patients were “profoundly de- ents, for a 30-month survival rate of 100%. One pa- layed,” whereas the other (who underwent early tient (patient 3) had hepatic artery thrombosis,
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