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.
Competing interests: None declared
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Acknowledgements
We express our special thanks to Kazuko Honda, Sachio Yamamoto (staff of Kanazawa University) and Tohru Noguchi (former staff) for their outstanding technical assistance. This work has been supported by the Japan Heart Foundation and Astellas/Pfizer Grant for Research on Atherosclerosis Update.
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Take-Home Message
Extreme hypercholesterolaemia is exacerbated by breastfeeding in the infantile case with sitosterolaemia.
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We hereby certify that this paper, which consists of unpublished original observations, is not under consideration for publication elsewhere. This manuscript has been read and approved by all coauthors. Atsushi Nohara and Horoshi Mabuchi has received research grants from MSD K.K., Sanofi K.K., Shionogi & Co., Ltd., Kowa Co., Ltd., Astellas Pharma Inc., AstraZeneca K.K., Keiai-Kai Medical Corp. and Biopharm of Japan Co. Hayato Tada, Mutsuko Takata, Kunihiro Matsunami, Atsushi Imamura, Misayo Matsuyama, Hirotake Sawada, Hiroyuki Nunoi, Tetsuo Konno, Kenshi Hayashi, Akihiro Inazu and Junji Kobayashi have no financial or other relations that could lead to a conflict of interest. Masa-aki Kawashiri has received payments for lectures from Shionogi & Co., Ltd., Daiichi-Sankyo Co., Ltd., Astellas Pharma Inc., AstraZeneca K.K., Kissei Pharmaceutical Co., Ltd., Bayer Yakuhin, Ltd. and Kyowa Hakko Kirin, Co., Ltd. Masakazu Yamagishi has received research grants from MSD K.K., Astellas Pharma Inc., Daiichi-Sankyo Co., Ltd. and Otsuka Pharmaceutical Co., Ltd., and he has received payments for lectures from Astellas Pharma Inc., Daiichi-Sankyo Co., Ltd., Shionogi & Co., Ltd. and Kowa Co., Ltd. All coauthors agreed to submit this article to the Journal of Inherited Metabolic Disease. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. Informed consents were obtained from all patients or their parents (if the subject was an infant) when they visited Kanazawa University Hospital for being included in the study.
Author Contributions
Hayato Tada: designed research and performed research and wrote paper. Masa-aki Kawashiri: designed research and wrote paper. Mutsuko Takata: collected data and drafted paper. Kunihiro Matsunami: collected data and drafted paper. Atsushi Imamura: collected data and drafted paper. Misayo Matsuyama: collected data and drafted paper. Hirotake Sawada: collected data and drafted paper. Hiroyuki Nunoi: collected data and drafted paper. Tetsuo Konno: collected data and drafted paper. Kenshi Hayashi: collected data and drafted paper. Atsushi Nohara: collected data and drafted paper. Akihiro Inazu: collected data and drafted paper. Junji Kobayashi: collected data and drafted paper. Hiroshi Mabuchi: collected data and drafted paper. Masakazu Yamagishi: designed research and wrote paper.
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Tada, H. et al. (2015). Infantile Cases of Sitosterolaemia with Novel Mutations in the ABCG5 Gene: Extreme Hypercholesterolaemia is Exacerbated by Breastfeeding. In: Zschocke, J., Baumgartner, M., Morava, E., Patterson, M., Rahman, S., Peters, V. (eds) JIMD Reports, Volume 21. JIMD Reports, vol 21. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2014_404
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DOI: https://doi.org/10.1007/8904_2014_404
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