Pathomechanism of Fever‐Induced Liver Failure in
NBAS
Deficiency and Treatment Effect of
NAC
—Observations In Vitro and In Vivo
Tian Sun, Nicole Hammann, Lina Leghlam, Bianca Peters, Cigdem Arikan, Sarah M. Bedoyan, Qian Chen, Tal Dattner, Felix Distelmaier, Alexander Fichtner, Sven F. Garbade, Nedim Hadžić, Robert Hegarty, Andrea Hellwig, Marianne Hørby Jørgensen, Carolin Jentsch, Sabine Jung‐Klawitter, Martin Laass, Elke Lainka, Hannah Münch, Halise Neslihan Önenli Mungan, Moritz Niesert, Stephanie Oehrl, Begona Polo, Knut Schäkel, James E. Squires, Stefan Kölker, Georg F. Hoffmann, Christian Staufner, Dominic Lenz ABSTRACT
Background and Aims
Pathogenic variants in neuroblastoma amplified sequence ( NBAS ) gene causes infantile liver failure type 2 (IFLS2; MIM 616483), characterised by recurrent episodes of liver failure triggered by febrile infections. The underlying pathophysiological mechanisms remain incompletely understood. With this work we try to shed light on the pathomechanism and propose a potential therapeutic option.
Methods
For in vitro analyses, human skin fibroblasts were obtained from three individuals with ILFS2 and one healthy control. Cells were cultivated at 37°C or 40°C. Western blots were performed to assess NBAS protein and its interaction partners. Furthermore, immunofluorescence and electron microscopy were used to examine morphological changes associated with endoplasmic reticulum (ER) stress. Apoptosis was measured using flow cytometry. The effects of N ‐acetylcysteine (NAC) treatment were analysed not only in cultured fibroblasts but also in vivo retrospectively in 16 affected individuals.
Results
We demonstrate that elevated temperature induces ER stress in fibroblasts from individuals with NBAS variants, leading to increased reactive oxygen species (ROS) production and apoptosis. Treatment with the antioxidant NAC, an established therapeutic in acetaminophen‐induced liver failure, effectively mitigated oxidative stress and reduced apoptosis in vitro. In a retrospective clinical analysis, there was a trend that NAC treatment was associated with reduced severity of hepatic crises, suggesting a potential therapeutic benefit.
Conclusions
Our findings link fever‐induced ER stress, ROS accumulation, and apoptosis to the pathogenesis of liver failure in NBAS deficiency. NAC attenuates these cellular stress responses and may represent a promising supportive treatment option in NBAS‐associated liver failure.