Abstract
Background
Acute liver failure (ALF) in infancy and childhood is a life-threatening emergency and in about 50 % the etiology remains unknown. Recently biallelic mutations in NBAS were identified as a new molecular cause of ALF with onset in infancy, leading to recurrent acute liver failure (RALF).
Methods
The phenotype and medical history of 14 individuals with NBAS deficiency was studied in detail and functional studies were performed on patients’ fibroblasts.
Results
The phenotypic spectrum of NBAS deficiency ranges from isolated RALF to a multisystemic disease with short stature, skeletal dysplasia, immunological abnormalities, optic atrophy, and normal motor and cognitive development resembling SOPH syndrome. Liver crises are triggered by febrile infections; they become less frequent with age but are not restricted to childhood. Complete recovery is typical, but ALF crises can be fatal. Antipyretic therapy and induction of anabolism including glucose and parenteral lipids effectively ameliorates the course of liver crises. Patients’ fibroblasts showed an increased sensitivity to high temperature at protein and functional level and a disturbed tethering of vesicles, pointing at a defect of intracellular transport between the endoplasmic reticulum and Golgi.
Conclusions
Mutations in NBAS cause a complex disease with a wide clinical spectrum ranging from isolated RALF to a multisystemic phenotype. Thermal susceptibility of the syntaxin 18 complex is the basis of fever dependency of ALF episodes. NBAS deficiency is the first disease related to a primary defect of retrograde transport. Identification of NBAS deficiency allows optimized therapy of liver crises and even prevention of further episodes.
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Acknowledgments
The authors thank Lena Pawella, Elisabeth Specht-Delius, Eva Eiteneuer, Marion Hahne, Zlata Antoni, Lena Protzmann, and Sabine Schäfer for excellent technical assistance. Human control tissues were provided by the Tissue Bank of the National Center for Tumor Diseases (NCT, Heidelberg, Germany) in accordance with the ethics committee of the University of Heidelberg. J. Vockley was funded in part by PHS grant NIH R01-DK78775. Part of the work was funded by a grant of the DFG to B.K. Straub (STR 1160/1-2). This study was supported by the German Bundesministerium für Bildung und Forschung (BMBF) through the German Network for mitochondrial disorders (mitoNET, 01GM1113C to T.M. and H.P.) and through the E-Rare project GENOMIT (01GM1207 for T.M. and H.P.). T.B.H. was supported by the BMBF through the Juniorverbund in der Systemmedizin “mitOmics” (FKZ 01ZX1405C).
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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000.
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Communicated by: Bruce A Barshop
Christian Staufner, Tobias B. Haack, Holger Prokisch and Georg F. Hoffmann contributed equally to this work.
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Staufner, C., Haack, T.B., Köpke, M.G. et al. Recurrent acute liver failure due to NBAS deficiency: phenotypic spectrum, disease mechanisms, and therapeutic concepts. J Inherit Metab Dis 39, 3–16 (2016). https://doi.org/10.1007/s10545-015-9896-7
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DOI: https://doi.org/10.1007/s10545-015-9896-7