Dataset Information

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

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.

SUBMITTER: Lenz D

PROVIDER: S-EPMC5989927 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Publications

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

Lenz Dominic D McClean Patricia P Kansu Aydan A Bonnen Penelope E PE Ranucci Giusy G Thiel Christian C Straub Beate K BK Harting Inga I Alhaddad Bader B Dimitrov Bianca B Kotzaeridou Urania U Wenning Daniel D Iorio Raffaele R Himes Ryan W RW Kuloğlu Zarife Z Blakely Emma L EL Taylor Robert W RW Meitinger Thomas T Kölker Stefan S Prokisch Holger H Hoffmann Georg F GF Haack Tobias B TB Staufner Christian C

Genetics in medicine : official journal of the American College of Medical Genetics 20180208 10

<h4>Purpose</h4>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.<h4>Methods</h4>We aimed to identify patients with SCYL1 variants within an exome- ...[more]

PMID: 29419818

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Project description:Background and aimsSerum levels of γ-glutamyl-transpeptidase(γ-GT) were associated with liver disease severity and metabolic alterations, which in turn are able to affect hepatic damage. In patients with nonalcoholic fatty liver disease (NAFLD), genotype 1 chronic hepatitis C (G1CHC) and chronic hepatitis B (CHB), we assessed the link between liver fibrosis and γ-GT serum levels, and we evaluated if normal or high γ-GT serum levels affect the association between insulin resistance (IR) and severity of liver fibrosis.Methods843 consecutive patients with chronic liver disease (CLD)(193 NAFLD, 481 G1CHC, 169 CHB) were evaluated by liver biopsy (Kleiner and Scheuer scores) and clinical and metabolic measurements. IR was diagnosed if HOMA>3. A serum γ-GT concentration of >36 IU/L in females and >61 IU/L in males was considered the threshold value for identifying high levels of γ-GT.ResultsBy multivariate logistic regression analysis, abnormal γ-GT serum levels were independently linked to severe liver fibrosis in patients with NAFLD (OR2.711,CI1.120-6.564,p = 0.02), G1CHC (OR3.461,CI2.138-5.603,p<0.001) and CHB (OR2.778,CI1.042-7.414,p = 0.04), together with IR and liver necroinflammation, and with a negative predictive value>80%. Interestingly, among patients with high or normal γ-GT values, even if IR prevalence was significantly higher in patients with severe fibrosis compared to those without, IR remained significantly associated with severe fibrosis in patients with abnormal γ-GT values only (OR4.150,CI1.079-15.970,p = 0.03 for NAFLD; OR2.250,CI1.211-4.181,p = 0.01 for G1CHC; OR3.096,CI2.050-34.220,p = 0.01 for CHB).ConclusionsIn patients with CLD, IR is independently linked to liver fibrosis only in patients with abnormal γ-GT values, without differences according to liver disease etiology, and suggesting a role of γ-GT as a marker of metabolic-induced liver damage. These data could be useful for the clinical and pharmacologic management of patients with CLD.

Project description:Gamma-glutamyl transferase (GGT) is a biomarker of inflammation, and is known to be associated with stroke and atrial fibrillation. Venous thromboembolism (VT), a not uncommon thrombotic disorder, shares similar mechanisms with other thrombotic disorders including these stroke and atrial fibrillation. Given these associations, we intended to investigate the potential association between variability in GGT and VT. The study included data from the National Health Insurance Service-Health Screening Cohort, comprising 1,085,105 participants with health examinations 3 or more times from 2003 to 2008. Variability indexes were the coefficient of variation, standard deviation, and variability independent of the mean. The occurrence of venous thromboembolism (VT) was defined with more than one claim of the following ICD-10 codes: deep VT (I80.2-80.3), pulmonary thromboembolism (I26), intraabdominal venous thrombosis (I81, I82.2, I82.3), or other VT (I82.8, I82.9). To determine the relationship of quartiles of GGT with incident VT risk, Kaplan-Meier survival curve and logrank test were used. Cox's proportional hazard regression was used to investigate the risk of VT occurrence by GGT quartile (Q1-Q4). A total of 1,085,105 subjects were incorporated in the analysis, and the average follow-up was 12.4 years (interquartile range 12.2-12.6). VT occurred in 11,769 (1.08%) patients. The GGT level was measured 5,707,768 times in this stud. Multivariable analysis showed that GGT variability were positively associated with the occurrence of VT. Compared to the Q1, the Q4 showed an adjusted HR of 1.15 (95% CI 1.09-1.21, p < 0.001) when using coefficient of variation, 1.24 (95% CI 1.17-1.31, p < 0.001) when using standard deviation, and 1.10 (95% CI 1.05-1.16, p < 0.001) when using variability independent of the mean. Increased variability of GGT may be related to an increased risk of VT. Maintaining a stable GGT level would be beneficial in reducing the risk of VT.

Project description:BackgroundThe normalization of liver biochemical parameters usually reflects the histological response to treatment for nonalcoholic fatty liver disease (NAFLD). Researchers have not clearly determined whether different liver enzymes exhibit various metabolic changes during the follow-up period in patients with NAFLD.MethodsWe performed a retrospective analysis of patients with NAFLD who were receiving therapy from January 2011 to December 2019. Metabolism indexes, including glucose levels, lipid profiles, uric acid levels and liver biochemical parameters, were measured. Magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) and liver ultrasound were used to evaluate steatosis. All patients received recommendations for lifestyle modifications and guideline-recommended pharmacological treatments with indications for drug therapy for metabolic abnormalities.ResultsOverall, 1048 patients with NAFLD were included and received lifestyle modification recommendations and pharmaceutical interventions, including 637 (60.7%) patients with abnormal GGT levels and 767 (73.2%) patients with abnormal ALT levels. Patients with concurrent ALT and GGT abnormalities presented higher levels of metabolism indexes and higher liver fat content than those in patients with single or no abnormalities. After 12 months of follow-up, the cumulative normalization rate of GGT was considerably lower than that of ALT (38% vs. 62%, P < 0.001). Greater weight loss resulted in higher cumulative normalization rates of GGT and ALT. Weight loss (OR = 1.21, 95% CI 1.11-1.32, P < 0.001), ALT normalization (OR = 2.75, 95% CI 1.41-5.36, P = 0.01) and lower TG and HOMA-IR values (OR = 2.03, 95% CI 1.11-3.71, P = 0.02; OR = 2.04, 95% CI 1.07-3.89, P = 0.03) were independent protective factors for GGT normalization. Elevated baseline GGT (OR = 0.99, 95% CI 0.98-0.99, P = 0.01) was a risk factor.ConclusionsFor NAFLD patients with concurrently increased ALT and GGT levels, a lower normalization rate of GGT was observed, rather than ALT. Good control of weight and insulin resistance was a reliable predictor of GGT normalization.

Dataset Information

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

Purpose

Methods

Results

Conclusion

Publications

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

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