Abstract
The molecular basis of gastrointestinal intolerances in a severe case of Niemann-Pick type C disease was analyzed in an intestinal biopsy specimen. The enzyme activities of intestinal sucrase-isomaltase and maltase-glucoamylase are reduced in the patient, while that of lactase is comparable to the control. The association of SI with lipid rafts is reduced in the patient’s biopsy as a consequence of altered composition of membrane microdomains. As association with lipid rafts influences the intracellular transport and the enzyme activities of sucrase-isomaltase and maltase-glucoamylase, these data explain reduced carbohydrate digestion in the intestinal lumen and delineate the effect of deficient cholesterol and sphingolipid homeostasis in development of gastrointestinal symptoms in NPC patients.
Competing interests: None declared
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Aguilera-Romero A, Gehin C, Riezman H (2014) Sphingolipid homeostasis in the web of metabolic routes. Biochim Biophys Acta 1841:647–656
Alfalah M, Jacob R, Naim HY (2002) Intestinal dipeptidyl peptidase IV is efficiently sorted to the apical membrane through the concerted action of N- and O-glycans as well as association with lipid microdomains. J Biol Chem 277:10683–10690
Amiri M, Naim HY (2012) Miglustat-induced intestinal carbohydrate malabsorption is due to the inhibition of alpha-glucosidases, but not beta-galactosidases. J Inherit Metab Dis 35:949–954
Amiri M, Naim HY (2014) Long term differential consequences of miglustat therapy on intestinal disaccharidases. J Inherit Metab Dis 37:929–937
Banikazemi M, Ullman T, Desnick RJ (2005) Gastrointestinal manifestations of Fabry disease: clinical response to enzyme replacement therapy. Mol Genet Metab 85:255–259
Bernstein DL, Bialer MG, Mehta L, Desnick RJ (2010) Pompe disease: dramatic improvement in gastrointestinal function following enzyme replacement therapy. A report of three later-onset patients. Mol Genet Metab 101:130–133
Cox T, Lachmann R, Hollak C et al (2000) Novel oral treatment of Gaucher’s disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis. Lancet 355:1481–1485
Dahlqvist A (1968) Assay of intestinal disaccharidases. Anal Biochem 22:99–107
Hauri HP, Sterchi EE, Bienz D, Fransen JA, Marxer A (1985) Expression and intracellular transport of microvillus membrane hydrolases in human intestinal epithelial cells. J Cell Biol 101:838–851
Jacob R, Naim HY (2001) Apical membrane proteins are transported in distinct vesicular carriers. Curr Biol 11:1444–1450
Jacob R, Zimmer KP, Schmitz J, Naim HY (2000) Congenital sucrase-isomaltase deficiency arising from cleavage and secretion of a mutant form of the enzyme. J Clin Invest 106:281–287
Lindner R, Naim HY (2009) Domains in biological membranes. Exp Cell Res 315:2871–2878
Maiuri L, Raia V, Potter J et al (1991) Mosaic pattern of lactase expression by villous enterocytes in human adult-type hypolactasia. Gastroenterology 100:359–369
Nichols BL, Avery S, Sen P, Swallow DM, Hahn D, Sterchi E (2003) The maltase-glucoamylase gene: common ancestry to sucrase-isomaltase with complementary starch digestion activities. Proc Natl Acad Sci U S A 100:1432–1437
Parkinson-Lawrence EJ, Shandala T, Prodoehl M, Plew R, Borlace GN, Brooks DA (2010) Lysosomal storage disease: revealing lysosomal function and physiology. Physiology (Bethesda) 25:102–115
Patterson MC, Vanier MT, Suzuki K et al (2001) Niemann-Pick disease type C: a lipid trafficking disorder. In: Scriver CR, Beaudet AL, Sly WS et al (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 3611–3634
Rosenbaum AI, Maxfield FR (2011) Niemann-Pick type C disease: molecular mechanisms and potential therapeutic approaches. J Neurochem 116:789–795
Wetzel G, Heine M, Rohwedder A, Naim HY (2009) Impact of glycosylation and detergent-resistant membranes on the function of intestinal sucrase-isomaltase. Biol Chem 390:545–549
Acknowledgements
The authors would like to thank the patient and her family as well as the Clinic of Pediatrics of the University Hospital Bonn, Germany, for donating the biopsy.
During the course of this work Hadeel Shammas was recipient of a Ph.D. scholarship from the German Academic Exchange Service (DAAD), Bonn, Germany.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Additional information
Communicated by: Alberto B Burlina, M.D.
Appendices
Take-Home Message
Gastrointestinal symptoms observed in NPC patients can be due to reduced enzyme activities and lipid raft association of major intestinal disaccharidases.
Compliance with Ethics Guidelines
Conflict of Interest
Mahdi Amiri, Eva-Maria Kuech, Hadeel Shammas, Gabi Wetzel and Hassan Y. Naim declare that they have no conflict of interest.
Informed Consent
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 2000 (5). Informed consent was obtained from the patient for being included in the study.
Details on the Contributions of Individual Authors
Mahdi Amiri, Eva-Maria Kuech, Hadeel Shammas and Gabi Wetzel have equally contributed to designing and performing the experiments, analyzing the data and drafting the manuscript. Hassan Y. Naim has designed the concept of the study and written the final manuscript.
Rights and permissions
Copyright information
© 2015 SSIEM and Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Amiri, M., Kuech, EM., Shammas, H., Wetzel, G., Naim, H.Y. (2015). The Pathobiochemistry of Gastrointestinal Symptoms in a Patient with Niemann-Pick Type C Disease. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 25. JIMD Reports, vol 25. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2015_454
Download citation
DOI: https://doi.org/10.1007/8904_2015_454
Received:
Revised:
Accepted:
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-49667-1
Online ISBN: 978-3-662-49668-8
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)