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

Abstract

PurposeBiallelic mutations in SCYL1 were recently identified to cause 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.MethodsWe aimed at identifying 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.ResultsSeven 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.ConclusionSCYL1 deficiency can cause recurrent low GGT cholestatic liver dysfunction in conjunction with a variable neurological phenotype. Similar to NBAS deficiency, it’s a member of the emerging group of congenital disorders of intracellular trafficking causing hepatopathy.

Variant in SCYL1 gene causes aberrant splicing in a family with cerebellar ataxia, recurrent episodes of liver failure, and growth retardation

“…Mouse strain SCYL1 mdf /SCYL1 mdf has also shown dorsoventral flattening of the pelvis by 3 months of age [10]. In our case, the patient's aunt had short stature, a symptom which was also reported in Lenz et al's recent publication [2]. We also performed whole-exome sequencing for the aunt to ensure that there was no dual diagnosis, which could explain her skeletal manifestation.…”

“…Variability in phenotype has been reported in other cases. While one of the families reported by Schmidt et al was mostly affected by debilitating ataxia due to cerebellar dysfunction, our patient's aunt was mainly afflicted with motor deterioration due to progressive weakness of the limbs, and families described by Lenz et al as well as our proband suffered primarily from recurrent and severe episodes of hepatic failure [1,2]. Variability in phenotype might be partially explained by the location of the mutation in the gene, as early variants have been suggested to cause a wider and more severe phenotype of the syndrome [2].…”

“…Growth parameters improved following percutaneous endoscopic gastrostomy (PEG) insertion. Only one of the previously reported patients underwent liver transplantation [2]. Our patient's liver functions stabilized, hence liver transplantation was not performed.…”

“…Skeletal manifestation may represent another phenotype of the SCYL1 variants, as latest reports of patients described multiple skeletal anomalies including short stature, lumbar lordosis, and an abnormal anatomy of bones [2,9]. Mouse strain SCYL1 mdf /SCYL1 mdf has also shown dorsoventral flattening of the pelvis by 3 months of age [10].…”

“…The phenotype is characterized by recurrent episodes of liver failure resolving during early childhood and hepatic fibrosis. Patients also suffer from neurological symptoms, such as gait disturbances and tremor, as well as peripheral neuropathy and cognitive disability [1,2]. SCYL1 is a catalytically inactivated protein kinase found in eukaryotic cells and an accessory protein in coatomer I (COPI)-mediated retrograde trafficking from the Golgi apparatus to the endoplasmic reticulum (ER) [3].…”