Liver transplantation in infantile Navajo neurohepatopathy
Danielle Romero1, Noelle H. Ebel1, Alice Huang1, Megan Brown1, Greg M. Enns2, Carlos Esquivel1,3, Clark A. Bonham1,3.
1Pediatric Liver and Intestine Transplant, Lucile Packard Children's Hospital Stanford, Palo Alta, CA, United States; 2Medical Genetics, Lucile Packard Children's Hospital Stanford, Palo Alto, CA, United States; 3Surgery - Abdominal Transplantation, Lucile Packard Children's Hospital Stanford, Palo Alto, CA, United States
Introduction: Navajo Neurohepatopathy (NNH) is a rare, autosomal recessive mitochondrial DNA depletion syndrome that affects up to 1 in 1600 births in Navajo communities where incidence is highest. NNH typically presents during infancy and can present with clinical heterogeneity, even in the same family. Challenges arise when these infants present in acute liver failure at a time when extrahepatic manifestations are not yet present or are challenging to assess. Liver transplantation has historically been avoided due to potential rapid progression of neurologic disease. We describe the longest period of follow-up post liver transplantation for an infant with acute liver failure from NNH.
Methods: In this case report, we describe our institution’s experience with an infant with NNH without severe extrahepatic manifestations, who presented in acute liver failure.
Discussion: An ex-term female infant was diagnosed with homozygous p.R50Q mutations in the MPV17 gene consistent with NNH during a work-up at 3 months of age for cholestasis. Her development was otherwise normal. At 10 months of age she developed acute liver failure. Her neurologic exam at that time was normal in the setting of hyperammonemia, and a brain MRI showed restricted diffusion throughout her white matter. Given absence of neurologic progression of the NNH, known phenotypic variability, and the mortality risk of acute liver failure, this patient was listed for liver transplantation with a natural Pediatric End-Stage Liver Disease (PELD) of 29. Her pre-transplant course was complicated by hypoglycemia, adrenal insufficiency and fluid overload. She underwent whole liver transplantation with choledocholedochostomy 18 days after listing with a natural PELD of 52 at the time of transplantation. Her post-operative course was uncomplicated. She received induction with basiliximab and steroids, and was discharged 8 days post-transplantation on tacrolimus monotherapy. She developed mild acute cellular rejection at 6 weeks post-transplantation treated with a steroid taper. At 10 weeks post-transplantation she was noted to have a biliary anastomotic stricture and underwent surgical biliary revision. She is now 15 months post-transplant (2 years old) with formal neurologic assessment demonstrating normal development.
Conclusion: Controversies remain regarding liver transplantation for NNH. In this infant who presented in acute liver failure with known NNH, a thorough pre-transplant evaluation process included multi-disciplinary consultations from Neurology and Metabolic Genetics. Phenotypes within families may be variable, with variable and slow neurologic progression. Acute liver failure from NNH carries a high mortality without transplant. We report an excellent 1-year post-transplant outcome and the longest post-transplant follow-up with no progression of disease in this rare patient population.
[1] Baumann, M., Schreiber, H., Schlotter‐Weigel, B., Löscher, W. N., Stucka, R., Karall, D., ... & Glaeser, D. (2019). MPV17 mutations in juvenile‐and adult‐onset axonal sensorimotor polyneuropathy. Clinical genetics, 95(1), 182-186.
[2] De Greef, E., Christodoulou, J., Alexander, I. E., Shun, A., O’Loughlin, E. V., Thorburn, D. R., ... & Stormon, M. O. (2011). Mitochondrial respiratory chain hepatopathies: role of liver transplantation. A case series of five patients. JIMD Reports-Case and Research Reports, 5-11.
[3] El-Hattab, A. W., Li, F. Y., Schmitt, E., Zhang, S., Craigen, W. J., & Wong, L. J. C. (2010). MPV17-associated hepatocerebral mitochondrial DNA depletion syndrome: new patients and novel mutations. Molecular genetics and metabolism, 99(3), 300-308.
[4] Karadimas, C. L., Vu, T. H., Holve, S. A., Chronopoulou, P., Quinzii, C., Johnsen, S. D., ... & Bonilla, E. (2006). Navajo neurohepatopathy is caused by a mutation in the MPV17 gene. The American Journal of Human Genetics, 79(3), 544-548.
[5] Lee, W. S., & Sokol, R. J. (2007). Liver disease in mitochondrial disorders. Seminars in liver disease, 27 (3), 259-273.
[6] Lee, W. S., & Sokol, R. J. (2013). Mitochondrial hepatopathies: advances in genetics, therapeutic approaches, and outcomes. The Journal of pediatrics, 163(4), 942-948.
[7] Nogueira, C., de Souza, C. F., Husny, A., Derks, T. G., Santorelli, F. M., & Vilarinho, L. (2012). MPV17: fatal hepatocerebral presentation in a Brazilian infant. Molecular genetics and metabolism, 107(4), 764.
[8] Sasaki, K., Sakamoto, S., Uchida, H., Narumoto, S., Shigeta, T., Fukuda, A., ... & Kasahara, M. (2017). Liver transplantation for mitochondrial respiratory chain disorder: a single-center experience and excellent marker of differential diagnosis. Transplantation proceedings, (49), 1097-1102.
[9] Spinazzola, A., Viscomi, C., Fernandez-Vizarra, E., Carrara, F., D'Adamo, P., Calvo, S., ... & Parini, R. (2006). MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion. Nature genetics, 38(5), 570-575.
[10] Vu, T. H., Tanji, K., Holve, S. A., Bonilla, E., Sokol, R. J., Snyder, R. D., ... & De Vivo, D. (2001). Navajo neurohepatopathy: a mitochondrial DNA depletion syndrome?. Hepatology, 34(1), 116-120.
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