Infantile Cases of Sitosterolaemia with Novel Mutations in the ABCG5 Gene: Extreme Hypercholesterolaemia is Exacerbated by Breastfeeding

Abstract

Few data exists regarding the clinical impact of breastfeeding in infantile sitosterolaemic cases. We report four Japanese infantile cases of sitosterolaemia, an extremely rare inherited disease characterised by increased serum levels of plant sitosterol, presenting with severe hypercholesterolaemia and systemic xanthomas exacerbated by breastfeeding. In these four cases, genetic analyses were performed for low-density lipoprotein (LDL) receptor, proprotein convertase subtilisin/kexin type 9 (PCSK9), LDL receptor adaptor protein 1 and ATP-binding cassette (ABC) subfamily G member 5 and 8 (ABCG5 and ABCG8) genes. We assessed their clinical manifestations, including responsiveness to a variety of treatments, especially to weaning from breastfeeding and use of ezetimibe. Two pairs of mutations in the ABCG5 gene in each case, including two novel mutations (c.130C>T or p.Ser44Ala and c.1813_1817delCTTTT or p.Pro558GlufsX14) and two known mutations (c.1306G>A or p.Arg389His and c.1336C>T or p.Arg446X), were identified. Significant reductions in cholesterol levels were obtained by means of weaning from breastfeeding alone. Substantial reductions in sitosterol levels, without any apparent side effects, were observed with ezetimibe. In conclusion, we have identified infantile Japanese sitosterolaemic subjects with extreme hypercholesterolaemia exacerbated by breastfeeding. Their unique response to weaning from breastfeeding, as well as to use of ezetimibe, could provide insights into the metabolic basis of sterols in humans.

A Rare Coincidence of Sitosterolemia and Familial Mediterranean Fever Identified by Whole Exome Sequencing

“…Her blood counts were within normal range. Her sitosterol levels could be reduced to 70 g/ml using 10 mg ezetimibe in accordance with a previous report 2) . We also reduction in LDL cholesterol, we suspected her condition to be sitosterolemia, and thus measured her serum sitosterol.…”

“…Serum levels of total cholesterol, triglycerides, and HDL cholesterol were determined enzymatically 6) . Serum levels of sterols, including sitosterol, lathosterol, and campesterol, were determined using gas-liquid chromatography-mass spectrometry as previously described 2) .…”

“…nosed with sitosterolemia 15) . The clinical features of sitosterolemia includes xanthomas, premature atherosclerosis, and increased serum levels of plant sterols 1,2) . In addition, they may exhibit extreme hypercholesterolemia induced by breastfeeding in accordance with our previous findings in infantile cases with sitosterolemia 2) .…”

“…The clinical features of sitosterolemia includes xanthomas, premature atherosclerosis, and increased serum levels of plant sterols 1,2) . In addition, they may exhibit extreme hypercholesterolemia induced by breastfeeding in accordance with our previous findings in infantile cases with sitosterolemia 2) . Separately, FMF, which is characterized by recurrent, self-limiting episodes of fever, affects more than 100,000 patients, primarily in the Mediterranean Basin 16) .…”

“…Sitosterolemia (OMIM #210250) caused by mutations in either of two genes ATP-binding cassette (ABC) sub-family G members 5 and 8 (ABCG5 and ABCG8) is an extremely rare autosomal recessive disorder of sterol metabolism characterized by increased absorption and decreased biliary excretion of plant sterols and cholesterol, resulting in prominently elevated serum levels of plant sterols such as sitosterol and campesterol 1,2) . Subjects suffering from sitosterolemia primarily present tendinous and tuberous xanthomas and premature coronary atherosclerosis resembling familial hypercholesterolemia (FH) 3) .…”