Abstract 9603: Extreme Hypercholesterolemia Exacerbated by Breast Feeding: Infantile Cases of Sitosterolemia With Novel Mutations in ABCG5 Gene
Background: Sitosterolemia is an extremely rare inherited disease characterized by increased levels of plant sterols such as sitosterol, the cause of which is ATP-binding cassette (ABC) sub-family G member 5 or member 8 (ABCG5 or ABCG8) gene mutations. It has been described that infantile sitosterolemic cases exhibit clinical manifestations resembling homozygous FH, including severe hypercholesterolemia, the mechanism of which still remains unclear. In the present study, we tried to determine the molecular diagnosis for 6 Japanese infantile cases with severe hypercholesterolemia and systemic xanthomas without any mutations in LDL receptor (LDLR), proprotein convertase subtilisin/kexin type 9 (PCSK9), and LDL receptor adaptor protein 1 (LDLRAP1) genes, then evaluated their clinical features, especially the responsiveness to variety of therapies, including statins, ezetimibe, colestimide, and weaning from breast feeding.
Methods and Results: We performed genetic analysis for ABCG5, and ABCG8 genes for those 6 cases, and identified 2 pairs of mutations in ABCG5 gene in each case, including 2 novel mutations (c.130C>T and c.1813_1817delCTTTT) and 2 known mutations (c.1306G>A and c .1336C>T). During their clinical courses, significant reduction of their LDL cholesterol levels could be obtained through their weaning alone (from 540 ± 164 mg/dl to 147 ± 60 mg/dl, p < 0.05). Also, a substantial reduction of their sitosterol levels were observed (from 90 ± 69 μg/ml to 52 ± 38 μg/ml, p < 0.05) using ezetimibe without any apparent side effects, although statins and colestimide did not have any effects on their sitosterol levels. Interestingly, their cutaneous xanthomas completely disappeared associated with the reductions of their cholesterol levels rather than those of sitosterol levels.
Conclusion: We have identified infantile Japanese sitosterolemic subjects with extreme hypercholesterolemia exacerbated by breast feeding. Their unique manner of responses to weaning as well as to ezetimibe could provide us novel insights into the metabolic basis for cholesterol and plant sterols in human.
Author Disclosures: H. Tada: None. M. Kawashiri: None. T. Konno: None. K. Hayashi: None. A. Nohara: None. A. Inazu: None. H. Mabuchi: None. M. Yamagishi: None.
- © 2014 by American Heart Association, Inc.