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Genet Med. 2018 Oct;20(10):1255-1265. doi: 10.1038/gim.2017.260. Epub 2018 Feb 8.

SCYL1 variants cause a syndrome with low γ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN).

Author information

1
Division of Neuropediatrics and Pediatric Metabolic Medicine, Department of General Pediatrics, University Hospital Heidelberg, Heidelberg, Germany.
2
Children's Liver Unit, Leeds Children's Hospital, Leeds, UK.
3
Division of Pediatric Gastroenterology, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey.
4
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
5
Department of Translational Medical Sciences, Section of Pediatrics, Liver Unit, University of Naples Federico II, Italy, Italy.
6
Division of Metabolism, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.
7
Institutes of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
8
Institute of Pathology and Tissue Bank of the, University Medical Center Mainz, Mainz, Germany.
9
Department of Neuroradiology, University Hospital Heidelberg, Heidelberg, Germany.
10
Institute of Human Genetics, Technische Universität München, Munich, Germany.
11
Department of Pediatrics, Section of Gastroenterology, Hepatology, and Nutrition, Texas Children's Hospital, Houston, Texas, USA.
12
Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
13
Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
14
Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
15
Division of Neuropediatrics and Pediatric Metabolic Medicine, Department of General Pediatrics, University Hospital Heidelberg, Heidelberg, Germany. Christian.Staufner@med.uni-heidelberg.de.

Abstract

PURPOSE:

Biallelic mutations in SCYL1 were recently identified as causing a syndromal disorder characterized by peripheral neuropathy, cerebellar atrophy, ataxia, and recurrent episodes of liver failure. The occurrence of SCYL1 deficiency among patients with previously undetermined infantile cholestasis or acute liver failure has not been studied; furthermore, little is known regarding the hepatic phenotype.

METHODS:

We aimed to identify patients with SCYL1 variants within an exome-sequencing study of individuals with infantile cholestasis or acute liver failure of unknown etiology. Deep clinical and biochemical phenotyping plus analysis of liver biopsies and functional studies on fibroblasts were performed.

RESULTS:

Seven patients from five families with biallelic SCYL1 variants were identified. The main clinical phenotype was recurrent low γ-glutamyl-transferase (GGT) cholestasis or acute liver failure with onset in infancy and a variable neurological phenotype of later onset (CALFAN syndrome). Liver crises were triggered by febrile infections and were transient, but fibrosis developed. Functional studies emphasize that SCYL1 deficiency is linked to impaired intracellular trafficking.

CONCLUSION:

SCYL1 deficiency can cause recurrent low-GGT cholestatic liver dysfunction in conjunction with a variable neurological phenotype. Like NBAS deficiency, it is a member of the emerging group of congenital disorders of intracellular trafficking causing hepatopathy.

KEYWORDS:

CALFAN syndrome; SCYL1; acute liver failure; congenital disorder of intracellular trafficking; low-GGT cholestasis

PMID:
29419818
PMCID:
PMC5989927
DOI:
10.1038/gim.2017.260
[Indexed for MEDLINE]
Free PMC Article

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