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 ProkischGeorg F Hoffmann, Tobias B Haack, Christian Staufner

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1255-1265
Number of pages11
JournalGenetics in Medicine
Volume20
Issue number10
DOIs
Publication statusPublished - Oct 2018

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Acute Liver Failure
Cholestasis
Transferases
Phenotype
Liver
Exome
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Cerebellar Ataxia
Liver Failure
Peripheral Nervous System Diseases
Atrophy
Liver Diseases
Fibrosis
Fever
Fibroblasts
Biopsy
Mutation
Infection

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SCYL1 variants cause a syndrome with low γ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN). / Lenz, Dominic; McClean, Patricia; Kansu, Aydan; Bonnen, Penelope E; Ranucci, Giusy; Thiel, Christian; Straub, Beate K; Harting, Inga; Alhaddad, Bader; Dimitrov, Bianca; Kotzaeridou, Urania; Wenning, Daniel; Iorio, Raffaele; Himes, Ryan W; Kuloğlu, Zarife; Blakely, Emma L; Taylor, Robert W; Meitinger, Thomas; Kölker, Stefan; Prokisch, Holger; Hoffmann, Georg F; Haack, Tobias B; Staufner, Christian.

In: Genetics in Medicine, Vol. 20, No. 10, 10.2018, p. 1255-1265.

Research output: Contribution to journalArticle

Lenz, D, McClean, P, Kansu, A, Bonnen, PE, Ranucci, G, Thiel, C, Straub, BK, Harting, I, Alhaddad, B, Dimitrov, B, Kotzaeridou, U, Wenning, D, Iorio, R, Himes, RW, Kuloğlu, Z, Blakely, EL, Taylor, RW, Meitinger, T, Kölker, S, Prokisch, H, Hoffmann, GF, Haack, TB & Staufner, C 2018, 'SCYL1 variants cause a syndrome with low γ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN)', Genetics in Medicine, vol. 20, no. 10, pp. 1255-1265. https://doi.org/10.1038/gim.2017.260
Lenz, Dominic ; McClean, Patricia ; Kansu, Aydan ; Bonnen, Penelope E ; Ranucci, Giusy ; Thiel, Christian ; Straub, Beate K ; Harting, Inga ; Alhaddad, Bader ; Dimitrov, Bianca ; Kotzaeridou, Urania ; Wenning, Daniel ; Iorio, Raffaele ; Himes, Ryan W ; Kuloğlu, Zarife ; Blakely, Emma L ; Taylor, Robert W ; Meitinger, Thomas ; Kölker, Stefan ; Prokisch, Holger ; Hoffmann, Georg F ; Haack, Tobias B ; Staufner, Christian. / SCYL1 variants cause a syndrome with low γ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN). In: Genetics in Medicine. 2018 ; Vol. 20, No. 10. pp. 1255-1265.
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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.",
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T1 - SCYL1 variants cause a syndrome with low γ-glutamyl-transferase cholestasis, acute liver failure, and neurodegeneration (CALFAN)

AU - Lenz, Dominic

AU - McClean, Patricia

AU - Kansu, Aydan

AU - Bonnen, Penelope E

AU - Ranucci, Giusy

AU - Thiel, Christian

AU - Straub, Beate K

AU - Harting, Inga

AU - Alhaddad, Bader

AU - Dimitrov, Bianca

AU - Kotzaeridou, Urania

AU - Wenning, Daniel

AU - Iorio, Raffaele

AU - Himes, Ryan W

AU - Kuloğlu, Zarife

AU - Blakely, Emma L

AU - Taylor, Robert W

AU - Meitinger, Thomas

AU - Kölker, Stefan

AU - Prokisch, Holger

AU - Hoffmann, Georg F

AU - Haack, Tobias B

AU - Staufner, Christian

PY - 2018/10

Y1 - 2018/10

N2 - 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.

AB - 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.

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DO - 10.1038/gim.2017.260

M3 - Article

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VL - 20

SP - 1255

EP - 1265

JO - Genetics in Medicine

JF - Genetics in Medicine

SN - 1098-3600

IS - 10

ER -