Recurrent acute liver failure due to NBAS deficiency: phenotypic spectrum, disease mechanisms, and therapeutic concepts

Christian Staufner, Tobias B. Haack, Marlies G. Köpke, Beate K. Straub, Stefan Kölker, Christian Thiel, Peter Freisinger, Ivo Baric, Patrick J. McKiernan, Nicola Dikow, Inga Harting, Flemming Beisse, Peter Burgard, Urania Kotzaeridou, Dominic Lenz, Joachim Kühr, Urban Himbert, Robert W. Taylor, Felix Distelmaier, Jerry Vockley, Lina Ghaloul‐Gonzalez, John A. Ozolek, Johannes Zschocke, Alice Kuster, Anke Dick, Anib M. Das, Thomas Wieland, Caterina Terrile, Tim M. Strom, Thomas Meitinger, Holger Prokisch, Georg F. Hoffmann

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). The phenotype and medical history of 14 individuals with NBAS deficiency was studied in detail and functional studies were performed on patients' fibroblasts. 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. 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.