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

Lookup NU author(s): Professor Robert Taylor


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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 spectrumof 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.

Publication metadata

Author(s): Staufner C, Haack TB, Kopke MG, Straub BK, Kolker S, Thiel C, Freisinger P, Baric I, McKiernan PJ, Dikow N, Harting I, Beisse F, Burgard P, Kotzaeridou U, Lenz D, Kuhr J, Himbert U, Taylor RW, Distelmaier F, Vockley J, Ghaloul-Gonzalez L, Ozolek JA, Zschocke J, Kuster A, Dick A, Das AM, Wieland T, Terrile C, Strom TM, Meitinger T, Prokisch H, Hoffmann GF

Publication type: Article

Publication status: Published

Journal: Journal of Inherited Metabolic Disease

Year: 2016

Volume: 39

Issue: 1

Pages: 3-16

Print publication date: 01/01/2016

Online publication date: 05/11/2015

Acceptance date: 28/09/2015

ISSN (print): 0141-8955

ISSN (electronic): 1573-2665

Publisher: Springer

DOI: 10.1007/s10545-015-9896-7


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Funder referenceFunder name
01GM1113CGerman Bundesministerium fur Bildung und Forschung (BMBF) through the German Network for mitochondrial disorders (mitoNET)
01GM1207German Bundesministerium fur Bildung und Forschung (BMBF) through the E-Rare project GENOMIT
FKZ 01ZX1405CBMBF through the Juniorverbund in der Systemmedizin "mitOmics"
NIH R01-DK78775PHS
STR 1160/1-2DFG