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

Dominic Lenz, Patricia McClean, Aydan Kansu, Penelope E Bonnen, Giusy Ranucci, Christian Thiel, Beate K Straub, Inga Harting, Bader Alhaddad, Bianca Dimitrov, Urania Kotzaeridou, Daniel Wenning, Raffaele Iorio, Ryan W Himes, Zarife Kuloğlu, Emma L Blakely, Robert W Taylor, Thomas Meitinger, Stefan Kölker, Holger Prokisch, Georg F Hoffmann, Tobias B Haack, Christian Staufner, Dominic Lenz, Patricia McClean, Aydan Kansu, Penelope E Bonnen, Giusy Ranucci, Christian Thiel, Beate K Straub, Inga Harting, Bader Alhaddad, Bianca Dimitrov, Urania Kotzaeridou, Daniel Wenning, Raffaele Iorio, Ryan W Himes, Zarife Kuloğlu, Emma L Blakely, Robert W Taylor, Thomas Meitinger, Stefan Kölker, Holger Prokisch, Georg F Hoffmann, Tobias B Haack, Christian Staufner

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.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1. Genetic structure of SCYL1 and…
Figure 1. Genetic structure of SCYL1 and proof of pathogenicity in case of missense variants.
(a) Genetic structure ofSCYL1 including novel and previously reported mutations. (b). Biallelic SCYL1 mutations lead to reduced protein levels of SCYL1; western blot for SCYL1. CDS, coding DNA sequence.
Figure 2. SCYL1 deficiency causes microvesicular steatosis,…
Figure 2. SCYL1 deficiency causes microvesicular steatosis, fibrosis, and disorganized Golgi apparatus.
(a) Hematoxylin and eosin (H&E) stained liver biopsy shows hepatocytes with light-colored cytoplasm, incomplete cirrhosis (1, 3), CK7-positive ductular proliferations (2), and mild microvesicular steatosis as demonstrated by immunostains against plin2 (4). Antibodies against scyl1 stain diffusely the cytoplasm (5), but in contrast to control patients, no dot-like staining pattern is observed (6). (b) In transmission electron microscopy, enlarged Golgi cisternae are detected (1–6, arrows delineate margins). (7) and (8) show normal Golgi apparatus in a control patient. bc, bile canaliculus; gly, glycogen; rER, rough endoplasmic reticulum.
Figure 3. Brefeldin A (BFA) assay showing…
Figure 3. Brefeldin A (BFA) assay showing delayed retrograde transport.
Control and patients’ fibroblasts (F1:II.2 and F2:II.5) were incubated for 0–10 min with BFA. Cells were fixed and analyzed by immunofluorescence for localization of Golgi marker GM130 (red). The cell nucleus (blue) was stained with DAPI. The white arrows indicate signal degradation of GM130 already after 5 min BFA treatment in the control cells in contrast to the patients’ fibroblasts. Bar: 10 μm.

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