title: Recurrent acute liver failure due to NBAS deficiency: phenotypic spectrum, disease mechanisms, and therapeutic concepts.
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.
authors.affiliation: Department of General Pediatrics, Division of Neuropediatrics and Pediatric Metabolic Medicine, University Hospital Heidelberg, 69120, Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Staufner
authors.affiliation: Institute of Human Genetics, Technische Universität München, 81675, Munich, Germany.|Institute of Human Genetics, Helmholtz Zentrum München, 85764, Neuherberg, Germany.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Haack
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, 85764, Neuherberg, Germany.
authors.forename: Marlies G
authors.initials: MG
authors.lastname: Köpke
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, 69120, Heidelberg, Germany.
authors.forename: Beate K
authors.initials: BK
authors.lastname: Straub
authors.affiliation: Department of General Pediatrics, Division of Neuropediatrics and Pediatric Metabolic Medicine, University Hospital Heidelberg, 69120, Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kölker
authors.affiliation: Department of General Pediatrics, Division of Neuropediatrics and Pediatric Metabolic Medicine, University Hospital Heidelberg, 69120, Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Thiel
authors.affiliation: Children's Hospital Reutlingen, 72764, Reutlingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Freisinger
authors.affiliation: Department of Pediatrics, University Hospital Center Zagreb and University of Zagreb, School of Medicine, 10000, Zagreb, Croatia.
authors.forename: Ivo
authors.initials: I
authors.lastname: Baric
authors.affiliation: Liver Unit, Birmingham Children's Hospital, Birmingham, B4 6NH, UK.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: McKiernan
authors.affiliation: Institute of Human Genetics, University Hospital Heidelberg, 69120, Heidelberg, Germany.
authors.forename: Nicola
authors.initials: N
authors.lastname: Dikow
authors.affiliation: Department of Neuroradiology, University Hospital Heidelberg, 69120, Heidelberg, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Harting
authors.affiliation: Ophthalmology Department, University Hospital Heidelberg, 69120, Heidelberg, Germany.
authors.forename: Flemming
authors.initials: F
authors.lastname: Beisse
authors.affiliation: Department of General Pediatrics, Division of Neuropediatrics and Pediatric Metabolic Medicine, University Hospital Heidelberg, 69120, Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Burgard
authors.affiliation: Department of General Pediatrics, Division of Neuropediatrics and Pediatric Metabolic Medicine, University Hospital Heidelberg, 69120, Heidelberg, Germany.
authors.forename: Urania
authors.initials: U
authors.lastname: Kotzaeridou
authors.affiliation: Department of General Pediatrics, Division of Neuropediatrics and Pediatric Metabolic Medicine, University Hospital Heidelberg, 69120, Heidelberg, Germany.
authors.forename: Dominic
authors.initials: D
authors.lastname: Lenz
authors.affiliation: Children's Hospital Karlsruhe, 76133, Karlsruhe, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Kühr
authors.affiliation: Children's Hospital St. Elisabeth, 56564, Neuwied, Germany.
authors.forename: Urban
authors.initials: U
authors.lastname: Himbert
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.affiliation: Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine-University Düsseldorf, 40225, Duesseldorf, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Distelmaier
authors.affiliation: University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, 15224, USA.
authors.forename: Jerry
authors.initials: J
authors.lastname: Vockley
authors.affiliation: University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, 15224, USA.
authors.forename: Lina
authors.initials: L
authors.lastname: Ghaloul-Gonzalez
authors.affiliation: Department of Pathology, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15224, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Ozolek
authors.affiliation: Division of Human Genetics, Innsbruck Medical University, 6020, Innsbruck, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Zschocke
authors.affiliation: Inborn Errors of Metabolism, Pediatric Intensive Care Unit, University Hospital of Nantes, 44093, Nantes, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Kuster
authors.affiliation: Department of Pediatrics, University Hospital Würzburg, 97080, Wuerzburg, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Dick
authors.affiliation: Clinic for Pediatric Kidney-, Liver- and Metabolic Diseases, Hannover Medical School, 30625, Hannover, Germany.
authors.forename: Anib M
authors.initials: AM
authors.lastname: Das
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, 85764, Neuherberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, 85764, Neuherberg, Germany.
authors.forename: Caterina
authors.initials: C
authors.lastname: Terrile
authors.affiliation: Institute of Human Genetics, Technische Universität München, 81675, Munich, Germany.|Institute of Human Genetics, Helmholtz Zentrum München, 85764, Neuherberg, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: Institute of Human Genetics, Technische Universität München, 81675, Munich, Germany.|Institute of Human Genetics, Helmholtz Zentrum München, 85764, Neuherberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: Institute of Human Genetics, Technische Universität München, 81675, Munich, Germany.|Institute of Human Genetics, Helmholtz Zentrum München, 85764, Neuherberg, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: Department of General Pediatrics, Division of Neuropediatrics and Pediatric Metabolic Medicine, University Hospital Heidelberg, 69120, Heidelberg, Germany. georg.hoffmann@med.uni-heidelberg.de.
authors.forename: Georg F
authors.initials: GF
authors.lastname: Hoffmann
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D005347:Fibroblasts / Q000473:pathology; D006801:Humans; D007223:Infant; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics / Q000473:pathology; D017114:Liver Failure, Acute / Q000235:genetics* / Q000473:pathology*; D008297:Male; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000172:deficiency*; D010641:Phenotype; D012008:Recurrence; D055815:Young Adult
chemical_list: C117339:NBAS protein, human; D009363:Neoplasm Proteins