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

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). M...

Full description

Saved in:

Bibliographic Details
Published in:	Journal of inherited metabolic disease Vol. 39; no. 1; pp. 3 - 16
Main Authors:	Staufner, Christian, Haack, Tobias B., Köpke, Marlies G., Straub, Beate K., Kölker, Stefan, Thiel, Christian, Freisinger, Peter, Baric, Ivo, McKiernan, Patrick J., Dikow, Nicola, Harting, Inga, Beisse, Flemming, Burgard, Peter, Kotzaeridou, Urania, Lenz, Dominic, Kühr, Joachim, Himbert, Urban, Taylor, Robert W., Distelmaier, Felix, Vockley, Jerry, Ghaloul-Gonzalez, Lina, Ozolek, John A., Zschocke, Johannes, Kuster, Alice, Dick, Anke, Das, Anib M., Wieland, Thomas, Terrile, Caterina, Strom, Tim M., Meitinger, Thomas, Prokisch, Holger, Hoffmann, Georg F.
Format:	Journal Article
Language:	English
Published:	Dordrecht Springer Netherlands 01-01-2016 Blackwell Publishing Ltd Springer Verlag
Subjects:	Adolescent Adult Biochemistry Child Child, Preschool Female Fibroblasts - pathology Human Genetics Human health and pathology Humans Infant Internal Medicine Life Sciences Liver - pathology Liver Cirrhosis - genetics Liver Cirrhosis - pathology Liver Failure, Acute - genetics Liver Failure, Acute - pathology Male Medicine Medicine & Public Health Metabolic Diseases Mutation - genetics Neoplasm Proteins - deficiency Pediatrics Phenotype Rapid Communication Recurrence Young Adult Acute Liver Failure Snare Complex Skeletal Dysplasia Urea Cycle Disorder Digitonin pattern mutations form gene
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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.
Bibliography:	The online version of this article (doi:10.1007/s10545‐015‐9896‐7) contains supplementary material, which is available to authorized users. Christian Staufner, Tobias B. Haack, Holger Prokisch and Georg F. Hoffmann contributed equally to this work. Communicated by: Bruce A Barshop Electronic Supplementary Material ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0141-8955 1573-2665
DOI:	10.1007/s10545-015-9896-7