FV 697. Biallelic Mutations in SCYL1 Cause CALFAN-Syndrome (Cholestasis, Acute Liver Failure, and Neurodegeneration), A Congenital Disorder of Intracellular Trafficking with a Variable Neurological Phenotype

Background and Objectives: Biallelic mutations in SCYL1 were recently identified as the molecular cause of “spinocerebellar ataxia, autosomal recessive 21” within a study of patients with ataxia. SCYL1 is involved in retrograde transport scaffolding for key components of coat protein complex I coats and regulating Golgi morphology. Inborn errors of intracellular trafficking, such as NBAS deficiency, are an emerging group of diseases associated with a syndromal multisystemic phenotype mainly involving brain and liver. So far, very little is known regarding the phenotypic spectrum and pathomechanism of SCYL1 deficiency.

Methods: We aimed at identifying patients with SCYL1 variants within a whole exome sequencing study of individuals with infantile cholestasis or liver failure of unknown etiology. Deep clinical phenotyping was performed, including a detailed neurological work-up, laboratory, and metabolic analyses. Liver biopsies were studied by immunohistochemistry and transmission electron microscopy (TEM). Functional studies on patients’ fibroblasts including SCYL1 western blot, glycosylation studies, and analyses of endoplasmic reticulum stress were performed.

Results: Seven patients from five families with biallelic mutations in SCYL1 were identified: three individuals from two families are homozygous for a missense mutation, whereas the other individual is homozygous for nonsense mutations. All mutations are novel and pathogenicity of the missense mutation was proven by absent protein levels of SCYL1 in patients’ fibroblasts. The neurological phenotype was very variable, ranging from isolated secondary microcephaly to a combined developmental delay and peripheral neuropathy. No ataxia was observed in any subject in this study. The main clinical phenotype was recurrent cholestatic liver dysfunction triggered by febrile infections with onset within the first 2 years of life. TEM demonstrates disorganized Golgi morphology in hepatocytes. Functional studies emphasize that SCYL1 deficiency is linked to impair intracellular trafficking.

Conclusion: Biallelic mutations in SCYL1 cause a syndrome with low γ-glutamyltransferase cholestasis, acute liver failure, and neurodegeneration (CALFAN). In contrast to the previously reported patients with a primarily ataxic phenotype, our study of primarily hepatic patients demonstrated the variability of the neurological phenotype of SCYL1 deficiency. Neurodegeneration may be of late onset and can be mild with secondary microcephaly as the only abnormality in infancy. Similar to NBAS deficiency, it is a member of the emerging group of congenital disorders of intracellular trafficking causing multisystemic phenotypes and should be considered a differential diagnosis in previously unresolved diseases affecting brain and liver.