Summary
A 10-year-old Arabic boy of consanguineous parents has suffered eight episodes of acute liver failure with haemolysis triggered by intercurrent febrile illnesses. The first crisis occurred at 9 months of age, after which diabetes mellitus developed. By the age of 6 years, short stature, mild myopathy and later skeletal epiphyseal dysplasia also became evident. His psychosocial development and educational achievements have remained within normal limits. While there were no clear biochemical indicators of a mitochondrial disorder, an almost complete deficiency of complex I of the respiratory chain was demonstrated in liver but not in fibroblast or muscle samples. Molecular analysis of the eukaryotic translation initiation factor 2α kinase gene (EIF2AK3) demonstrated a homozygous mutation, compatible with a diagnosis of Wolcott–Rallison syndrome (WRS). This patient’s course adds a new perspective to the presentation of WRS caused by mutations in the EIF2AK3 gene linking it to mitochondrial disorders: recoverable and recurrent acute liver failure. The findings also illustrate the diagnostic difficulty of mitochondrial disease as it cannot be excluded by muscle or skin biopsy in patients presenting with liver disease. The case also further complicates the decision-making process for liver transplantation in cases of acute liver failure in the context of a possible mitochondrial disorder. Such patients may be more likely to recover spontaneously if a mitochondrial disorder underlies the liver failure, yet without neurological features liver transplantation remains an option.
Similar content being viewed by others
References
Bernier FP, Boneh A, Dennett X, Chow CW, Cleary MA, Thorburn DR (2002) Diagnostic criteria for respiratory chain disorders in adults and children. Neurology 59(9): 1406–1411. doi:10.1001/archneur.59.9.1406.
Bhaduri BR, Mieli-Vergani G (1996) Fulminant hepatic failure: pediatric aspects. Semin Liver Dis 16(4): 349–355.
Brickwood S, Bonthron DT, Al-Gazali LI, et al (2003) Wolcott–Rallison syndrome: pathogenic insights into neonatal diabetes from new mutation and expression studies of EIF2AK3. J Med Genet 40(9): 685–689. doi:10.1136/jmg.40.9.685.
Dart RC, Bailey E (2007) Does therapeutic use of acetaminophen cause acute liver failure? Pharmacotherapy 27(9): 1219–1230. doi:10.1592/phco.27.9.1219.
Debray FG, Mitchell GA, Allard P, Robinson BH, Hanley JA, Lambert M (2007) Diagnostic accuracy of blood lactate-to-pyruvate molar ratio in the differential diagnosis of congenital lactic acidosis. Clin Chem 53(5): 916–921. doi:10.1373/clinchem.2006.081166.
Delepine M, Nicolino M, Barrett T, Golamaully M, Lathrop GM, Julier C (2000) EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nat Genet 25: 406–409. doi:10.1038/78085.
Dhawan A, Cheeseman P, Mieli-Vergani G (2004) Approaches to acute liver failure in children. Pediatr Transplant 8: 584–588. doi:10.1111/j.1399-3046.2004.00292.x.
Dubern B, Broue P, Dubuisson, C, et al (2001) Orthotopic liver transplantation for mitochondrial respiratory chain disorders: a study of 5 children. Transplantation 71: 633–637. doi:10.1097/00007890-200103150-00009.
Fischer JC, Ruitenbeek W, Trijbels JM, et al (1986) Estimation of NADH oxidation in human skeletal muscle mitochondria. Clin Chim Acta 155(3): 263–273. doi:10.1016/0009-8981(86)90246-9.
Gordon N (2006) Alpers syndrome: progressive neuronal degeneration of children with liver disease. Dev Med Child Neurol 48: 1001–1003. doi:10.1017/S0012162206002209.
Jacob DA, Neumann UP, Bahra M, et al (2006) Long-term follow-up after recurrence of primary biliary cirrhosis after liver transplantation in 100 patients. Clin Transplant 20: 211–220. doi:10.1111/j.1399-0012.2005.00471.x.
Kelly DA, McKiernan PJ (1998) Metabolic liver disease in the pediatric patient. Clin Liver Dis 2: 1–30. doi:10.1016/S1089-3261(05)70361-5.
Kollberg G, Moslemi A, Darin N, et al (2006) POLG1 mutations associated with progressive encephalopathy in childhood. J Neuropathol Exp Neurol 65: 758–768.
Lee WS, Sokol RJ (2007) Mitochondrial hepatopathies: advances in genetics and pathogenesis. Hepatology 45(6): 1555–1565. doi:10.1002/hep.21710.
Loeffen JL, Smeitink JA, Trijbels JM, et al (2000) Isolated complex I deficiency in children: clinical, biochemical and genetic aspects. Hum Mutat 15: 123–134. doi:10.1002/(SICI)1098-1004(200002)15:2<123::AID-HUMU1>3.0.CO;2-P.
Mert A, Tabak F, Ozturk R, Aktuglu Y, Ozaras R, Kanat M (2001) Acute viral hepatitis with severe hyperbilirubinemia and massive hemolysis in glucose-6-phosphate dehydrogenase deficiency. J Clin Gastroenterol 32(5): 461–462. doi:10.1097/00004836-200105000-00030.
Meyburg J, Hoffmann GF (2005) Liver transplantation for inborn errors of metabolism. Transplantation 80: S135–S137. doi:10.1097/01.tp.0000186905.10088.e5.
O’Brien PJ, Slaughter MR, Swain A, et al (2000) Repeated acetaminophen dosing in rats: adaptation of hepatic antioxidant system. Hum Exp Toxicol 19: 277–283. doi:10.1191/096032700678815918.
Puppi J, Tan N, Mitry RR, et al (2008) Hepatocyte transplantation followed by auxiliary liver transplantation—a novel treatment for ornithine transcarbamylase deficiency. Am J Transplant 8(2): 452–457.
Rake JP, van Spronsen FJ, Visser G, et al (2000) End-stage liver disease as the only consequence of a mitochondrial respiratory chain deficiency: no contra-indication for liver transplantation. Eur J Pediatr 159: 523–526. doi:10.1007/s004310051324.
Sarzi E, Goffart S, Serre V, et al (2007) Twinle helicase (PEO1) gene mutation causes mitochondrial DNA depletion. Ann Neurol 62(6): 579–587. doi:10.1002/ana.21207.
Senée V, Vattem KM, Deléphine M, et al (2004) Wolcott–Rallison syndrome. Diabetes 53: 1876–1883. doi:10.2337/diabetes.53.7.1876.
Sokol RJ, Treem WR (1999) Mitochondria and childhood liver diseases. J Pediatr Gastroenterol Nutr 28: 4–16. doi:10.1097/00005176-199901000-00005.
Squires RH Jr, Shneider BL, Bucuvalas J, et al (2006) Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group. J Pediatr 148(5): 652–658. doi:10.1016/j.jpeds.2005.12.051.
Stephenne X, Najimi M, Sibille C, Nassogne M, Smets F, Sokal EM (2006) Sustained engraftment and tissue enzyme activity after liver cell transplantation for argininosuccinate lyase deficiency. Gastroenterology 130: 1317–1323. doi:10.1053/j.gastro.2006.01.008.
Wolcott CD, Rallison ML (1972) Infancy-onset diabetes mellitus and multiple epiphyseal dysplasia. J Pediatr 80: 292–297. doi:10.1016/S0022-3476(72)80596-1.
Author information
Authors and Affiliations
Corresponding author
Additional information
Communicating editor: Bruce Barshop
Competing interests: None declared
References to electronic databases: Wolcott–Rallison syndrome: OMIM #226980.
Rights and permissions
About this article
Cite this article
Engelmann, G., Meyburg, J., Shahbek, N. et al. Recurrent acute liver failure and mitochondriopathy in a case of Wolcott–Rallison syndrome. J Inherit Metab Dis 31, 540–546 (2008). https://doi.org/10.1007/s10545-008-0867-0
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10545-008-0867-0