ESPE Abstracts

Backgrounds: Sitosterolemia is an inborn error of sterol metabolism caused by pathogenic variation of ABCG5 or ABCG8. It is characterized by increased plant sterol levels, xanthomas, and accelerated atherosclerosis; however, it is likely to be underdiagnosed in the clinical field. This study aims to describe the genetic variance of clinically confirmed patients with sitosterolemia and analyze the clinical spectrum according to genetic variance.

Methods: Nine children and adolescents including 2 previously reported siblings and 7 unrelated patients with sitosterolemia were enrolled. All patients were clinically diagnosed and confirmed with elevated plasma sitosterol levels (serum sitosterol measured by gas chromatography-mass spectrometry > 1.7 mg/dL). Whole-exome sequencing (WES) was performed to analyze the cholesterol-associated genes in 7 patients and their parents.

Results: The median age at diagnosis was 5.8 (1.2–13.0) years. All patients (n=9) showed hypercholesterolemia and seven patients (78%) showed xanthomas at initial diagnosis. Total cholesterol and sitosterol levels at diagnosis were 461.3 (203.0–811.3) mg/dL and 7.5 (2.2–16.5 mg/dl, reference range: 0.3-1.0 mg/dL). In WES analysis, variances in ABCG5 or ABCG8 were noted in all patients (2 patients with homozygous mutations and 5 with compound heterozygous variants). Eight sequence variances, including 4 pathogenic and 4 variants of unknown significance (VUS) were observed, and frequently observed pathogenic variances were c.1336C>T in ABCG5(n=4) and c.904+1G>A in ABCG5(n=4). In addition, c.694+5G>C, VUS in ABCG8 was observed in 2 unrelated patients. Most patients showed dramatic clinical responses to low cholesterol, low plant sterol diet, and cholestyramine or ezetimibe treatment, although their sitosterol levels are still elevated (2.7(1.8–5.8) mg/dL).

Conclusion: In this study, we described clinical characteristics and genetic variations in Korean patients with sitosterolemia. The earliest presentations were cutaneous xanthomas and/or hypercholesterolemia. Plant sterol assay should be considered in young children with severe hypercholesterolemia showing dramatic improvement to dietary modification and/or cholestyramine treatment. Genetic analysis also seems to be helpful for the diagnosis of sitosterolemia, especially in infants in whom the plant sterol levels are not high enough.