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J Inherit Metab Dis. 2016 Jan;39(1):3-16. doi: 10.1007/s10545-015-9896-7. Epub 2015 Nov 5.

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

Author information

1
Department of General Pediatrics, Division of Neuropediatrics and Pediatric Metabolic Medicine, University Hospital Heidelberg, 69120, Heidelberg, Germany.
2
Institute of Human Genetics, Technische Universität München, 81675, Munich, Germany.
3
Institute of Human Genetics, Helmholtz Zentrum München, 85764, Neuherberg, Germany.
4
Institute of Pathology, University Hospital Heidelberg, 69120, Heidelberg, Germany.
5
Children's Hospital Reutlingen, 72764, Reutlingen, Germany.
6
Department of Pediatrics, University Hospital Center Zagreb and University of Zagreb, School of Medicine, 10000, Zagreb, Croatia.
7
Liver Unit, Birmingham Children's Hospital, Birmingham, B4 6NH, UK.
8
Institute of Human Genetics, University Hospital Heidelberg, 69120, Heidelberg, Germany.
9
Department of Neuroradiology, University Hospital Heidelberg, 69120, Heidelberg, Germany.
10
Ophthalmology Department, University Hospital Heidelberg, 69120, Heidelberg, Germany.
11
Children's Hospital Karlsruhe, 76133, Karlsruhe, Germany.
12
Children's Hospital St. Elisabeth, 56564, Neuwied, Germany.
13
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
14
Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine-University Düsseldorf, 40225, Duesseldorf, Germany.
15
University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, 15224, USA.
16
Department of Pathology, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15224, USA.
17
Division of Human Genetics, Innsbruck Medical University, 6020, Innsbruck, Austria.
18
Inborn Errors of Metabolism, Pediatric Intensive Care Unit, University Hospital of Nantes, 44093, Nantes, France.
19
Department of Pediatrics, University Hospital Würzburg, 97080, Wuerzburg, Germany.
20
Clinic for Pediatric Kidney-, Liver- and Metabolic Diseases, Hannover Medical School, 30625, Hannover, Germany.
21
Department of General Pediatrics, Division of Neuropediatrics and Pediatric Metabolic Medicine, University Hospital Heidelberg, 69120, Heidelberg, Germany. georg.hoffmann@med.uni-heidelberg.de.

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.

PMID:
26541327
DOI:
10.1007/s10545-015-9896-7
[Indexed for MEDLINE]

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