SCYL1 deficiency and intrafamilial variability: Two cases from Kuwait

Biallelic pathogenic variants in SCYL1 have been reported in 22 individuals to date. Also referred to as CALFAN syndrome (cholestasis, acute liver failure, and neurodegeneration), this condition is characterized by recurrent episodic acute liver failure (ALF) with low-GGT cholestasis and variable neurological manifestations. SCYL1 deficiency disrupts intracellular vesicular trafficking, leading to hepatopathy and, in some cases, abnormal glycosylation.

We report two Kuwaiti siblings homozygous for a pathogenic splice site variant in SCYL1(NM_020680.4):c.1386 + 1G > A p.?. The younger sibling, an 8-year-old female presented at 16 months with ALF, hepatosplenomegaly, global developmental delay, hypotonia, and gait instability. During liver crises, she demonstrated biochemical features including low-GGT cholestasis, coagulopathy, and transient glycosylation abnormalities. Liver biopsy revealed peri-sinusoidal fibrosis and mild steatosis. She experienced two additional ALF episodes at 26 months and 3 years, both resolving completely. Follow-up biochemical testing at age 5.5 years showed normalization of glycosylation patterns following hepatic recovery. In contrast, her 9-year-old brother, who carries the same homozygous variant, remains asymptomatic, with normal development, liver function and imaging.

To our knowledge, this is the first description of an asymptomatic individual homozygous for a pathogenic SCYL1 variant. Our findings highlight striking intrafamilial variability in SCYL1-deficiency and emphasize the reversibility of glycosylation abnormalities and liver dysfunction upon clinical recovery.