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Published in: BMC Neurology 1/2018

Open Access 01-12-2018 | Research article

Acquired modification of sphingosine-1-phosphate lyase activity is not related to adrenal insufficiency

Authors: Gulin Sunter, Ece Oge Enver, Azad Akbarzade, Serap Turan, Pinar Vatansever, Dilek Ince Gunal, Goncagul Haklar, Abdullah Bereket, Kadriye Agan, Tulay Guran

Published in: BMC Neurology | Issue 1/2018

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Abstract

Background

Congenital sphingosine-1-phosphate (S1P) lyase deficiency due to biallelic mutations in SGPL1 gene has recently been described in association with primary adrenal insufficiency and steroid-resistant nephrotic syndrome. S1P lyase, on the other hand, is therapeutically inhibited by fingolimod which is an oral drug for relapsing multiple sclerosis (MS). Effects of this treatment on adrenal function has not yet been evaluated. We aimed to test adrenal function of MS patients receiving long-term fingolimod treatment.

Methods

Nineteen patients (14 women) with MS receiving oral fingolimod (Gilenya®, Novartis) therapy were included. Median age was 34.2 years (range; 21.3–44.6 years). Median duration of fingolimod treatment was 32 months (range; 6–52 months) at a dose of 0.5 mg/day. Basal and ACTH-stimulated adrenal steroid measurements were evaluated simultaneously employing LC-MS/MS based steroid panel. Basal steroid concentrations were also compared to that of sex- and age-matched healthy subjects. Cortisol and 11-deoxycortisol, 11-deoxycorticosterone and dehydroepiandrosterone were used to assess glucocorticoid, mineralocorticoid and sex steroid producing pathways, respectively.

Results

Basal ACTH concentrations of the patients were 20.8 pg/mL (6.8–37.8 pg/mL) (normal range; 5–65 pg/mL). There was no significant difference in the basal concentrations of cortisol, 11-deoxycortisol, 11-deoxycorticosterone and dehydroepiandrosterone between patients and controls (p = 0.11, 0.058, 0.74, 0.15; respectively). All patients showed adequate cortisol response to 250 mcg IV ACTH stimulation (243 ng/mL, range; 197–362 ng/mL). There was no significant correlation between duration of fingolimod treatment and basal or ACTH-stimulated cortisol or change in cortisol concentrations during ACTH stimulation test (p = 0.57, 0.66 and 0.21, respectively).

Conclusion

Modification and inhibition of S1P lyase activity by the long-term therapeutic use of fingolimod is not associated with adrenal insufficiency in adult patients with MS. This suggests that S1P lyase has potentially a critical role on adrenal development rather than the function of a fully mature adrenal gland.
Literature
1.
go back to reference Prasad R, Hadjidemetriou I, Maharaj A, Meimaridou E, Buonocore F, Saleem M, Hurcombe J, Bierzynska A, Barbagelata E, Bergadá I, Cassinelli H, Das U, Krone R, Hacihamdioglu B, Sari E, Yesilkaya E, Storr HL, Clemente M, Fernandez-Cancio M, Camats N, Ram N, Achermann JC, Van Veldhoven PP, Guasti L, Braslavsky D, Guran T, Metherell LA. Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome. J Clin Invest. 2017;127(3):942–53.CrossRefPubMedPubMedCentral Prasad R, Hadjidemetriou I, Maharaj A, Meimaridou E, Buonocore F, Saleem M, Hurcombe J, Bierzynska A, Barbagelata E, Bergadá I, Cassinelli H, Das U, Krone R, Hacihamdioglu B, Sari E, Yesilkaya E, Storr HL, Clemente M, Fernandez-Cancio M, Camats N, Ram N, Achermann JC, Van Veldhoven PP, Guasti L, Braslavsky D, Guran T, Metherell LA. Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome. J Clin Invest. 2017;127(3):942–53.CrossRefPubMedPubMedCentral
2.
go back to reference Lovric S, Goncalves S, Gee HY, Oskouian B, Srinivas H, Choi WI, Shril S, Ashraf S, Tan W, Rao J, Airik M, Schapiro D, Braun DA, Sadowski CE, Widmeier E, Jobst-Schwan T, Schmidt JM, Girik V, Capitani G, Suh JH, Lachaussée N, Arrondel C, Patat J, Gribouval O, Furlano M, Boyer O, Schmitt A, Vuiblet V, Hashmi S, Wilcken R, Bernier FP, Innes AM, Parboosingh JS, Lamont RE, Midgley JP, Wright N, Majewski J, Zenker M, Schaefer F, Kuss N, Greil J, Giese T, Schwarz K, Catheline V, Schanze D, Franke I, Sznajer Y, Truant AS, Adams B, Désir J, Biemann R, Pei Y, Ars E, Lloberas N, Madrid A, Dharnidharka VR, Connolly AM, Willing MC, Cooper MA, Lifton RP, Simons M, Riezman H, Antignac C, Saba JD, Hildebrandt F. Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency. J Clin Invest. 2017;127(3):912–28.CrossRefPubMedPubMedCentral Lovric S, Goncalves S, Gee HY, Oskouian B, Srinivas H, Choi WI, Shril S, Ashraf S, Tan W, Rao J, Airik M, Schapiro D, Braun DA, Sadowski CE, Widmeier E, Jobst-Schwan T, Schmidt JM, Girik V, Capitani G, Suh JH, Lachaussée N, Arrondel C, Patat J, Gribouval O, Furlano M, Boyer O, Schmitt A, Vuiblet V, Hashmi S, Wilcken R, Bernier FP, Innes AM, Parboosingh JS, Lamont RE, Midgley JP, Wright N, Majewski J, Zenker M, Schaefer F, Kuss N, Greil J, Giese T, Schwarz K, Catheline V, Schanze D, Franke I, Sznajer Y, Truant AS, Adams B, Désir J, Biemann R, Pei Y, Ars E, Lloberas N, Madrid A, Dharnidharka VR, Connolly AM, Willing MC, Cooper MA, Lifton RP, Simons M, Riezman H, Antignac C, Saba JD, Hildebrandt F. Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency. J Clin Invest. 2017;127(3):912–28.CrossRefPubMedPubMedCentral
3.
go back to reference Janecke AR, Xu R, Steichen-Gersdorf E, Waldegger S, Entenmann A, Giner T, Krainer I, Huber LA, Hess MW, Frishberg Y, Barash H, Tzur S, Schreyer-Shafir N, Sukenik-Halevy R, Zehavi T, Raas-Rothschild A, Mao C, Müller T. Deficiency of the sphingosine-1-phosphate lyase SGPL1 is associated with congenital nephrotic syndrome and congenital adrenal calcifications. Hum Mutat. 2017;38(4):365–72.CrossRefPubMedPubMedCentral Janecke AR, Xu R, Steichen-Gersdorf E, Waldegger S, Entenmann A, Giner T, Krainer I, Huber LA, Hess MW, Frishberg Y, Barash H, Tzur S, Schreyer-Shafir N, Sukenik-Halevy R, Zehavi T, Raas-Rothschild A, Mao C, Müller T. Deficiency of the sphingosine-1-phosphate lyase SGPL1 is associated with congenital nephrotic syndrome and congenital adrenal calcifications. Hum Mutat. 2017;38(4):365–72.CrossRefPubMedPubMedCentral
4.
go back to reference Vogt D, Stark H. Therapeutic strategies and pharmacological tools influencing S1P signaling and metabolism. Med Res Rev. 2017;37(1):3–51.CrossRefPubMed Vogt D, Stark H. Therapeutic strategies and pharmacological tools influencing S1P signaling and metabolism. Med Res Rev. 2017;37(1):3–51.CrossRefPubMed
5.
go back to reference Brinkmann V, Billich A, Baumruker T, Heining P, Schmouder R, Francis G, Aradhye S, Burtin P. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov. 2010;9(11):883–97.CrossRefPubMed Brinkmann V, Billich A, Baumruker T, Heining P, Schmouder R, Francis G, Aradhye S, Burtin P. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov. 2010;9(11):883–97.CrossRefPubMed
6.
go back to reference Bandhuvula P, Tam YY, Oskouian B, Saba JD. The immune modulator FTY720 inhibits sphingosine-1-phosphate lyase activity. J Biol Chem. 2005;280(40):33697–700.CrossRefPubMed Bandhuvula P, Tam YY, Oskouian B, Saba JD. The immune modulator FTY720 inhibits sphingosine-1-phosphate lyase activity. J Biol Chem. 2005;280(40):33697–700.CrossRefPubMed
7.
go back to reference Park SM, Angel CE, McIntosh JD, Brooks AE, Middleditch M, Chen CJ, Ruggiero K, Cebon J, Rod Dunbar P. Sphingosine-1-phosphate lyase is expressed by CD68+ cells on the parenchymal side of marginal reticular cells in human lymph nodes. Eur J Immunol. 2014;44(8):2425–36.CrossRefPubMed Park SM, Angel CE, McIntosh JD, Brooks AE, Middleditch M, Chen CJ, Ruggiero K, Cebon J, Rod Dunbar P. Sphingosine-1-phosphate lyase is expressed by CD68+ cells on the parenchymal side of marginal reticular cells in human lymph nodes. Eur J Immunol. 2014;44(8):2425–36.CrossRefPubMed
8.
go back to reference Stewart PM, Krone N. The adrenal cortex. In: Melmed S, Polonsky KS, Larsen PR, Kronenberg HM, editors. Williams textbook of endocrinology, vol. 1. 12th ed. Philadelphia: Saunders Elsevier; 2011. p. 479–544.CrossRef Stewart PM, Krone N. The adrenal cortex. In: Melmed S, Polonsky KS, Larsen PR, Kronenberg HM, editors. Williams textbook of endocrinology, vol. 1. 12th ed. Philadelphia: Saunders Elsevier; 2011. p. 479–544.CrossRef
9.
go back to reference Melief J, de Wit SJ, van Eden CG, Teunissen C, Hamann J, Uitdehaag BM, Swaab D, Huitinga I. HPA axis activity in multiple sclerosis correlates with disease severity, lesion type and gene expression in normal-appearing white matter. Acta Neuropathol. 2013;126(2):237–49.CrossRefPubMed Melief J, de Wit SJ, van Eden CG, Teunissen C, Hamann J, Uitdehaag BM, Swaab D, Huitinga I. HPA axis activity in multiple sclerosis correlates with disease severity, lesion type and gene expression in normal-appearing white matter. Acta Neuropathol. 2013;126(2):237–49.CrossRefPubMed
10.
go back to reference Kern S, Rohleder N, Eisenhofer G, Lange J, Ziemssen T. Time matters - acute stress response and glucocorticoid sensitivity in early multiple sclerosis. Brain Behav Immun. 2014;41:82–9.CrossRefPubMed Kern S, Rohleder N, Eisenhofer G, Lange J, Ziemssen T. Time matters - acute stress response and glucocorticoid sensitivity in early multiple sclerosis. Brain Behav Immun. 2014;41:82–9.CrossRefPubMed
11.
go back to reference Goldkorn T, Balaban N, Shannon M, Chea V, Matsukuma K, Gilchrist D, et al. H2O2 acts on cellular membranes to generate ceramide signaling and initiate apoptosis in tracheobronchial epithelial cells. J Cell Sci. 1998;111(Pt 21):3209–20.PubMed Goldkorn T, Balaban N, Shannon M, Chea V, Matsukuma K, Gilchrist D, et al. H2O2 acts on cellular membranes to generate ceramide signaling and initiate apoptosis in tracheobronchial epithelial cells. J Cell Sci. 1998;111(Pt 21):3209–20.PubMed
12.
go back to reference Liu B, Andrieu-Abadie N, Levade T, Zhang P, Obeid LM, Hannun YA. Glutathione regulation of neutral sphingomyelinase in tumor necrosis factor-alpha-induced cell death. J Biol Chem. 1998;273(18):11313–20.CrossRefPubMed Liu B, Andrieu-Abadie N, Levade T, Zhang P, Obeid LM, Hannun YA. Glutathione regulation of neutral sphingomyelinase in tumor necrosis factor-alpha-induced cell death. J Biol Chem. 1998;273(18):11313–20.CrossRefPubMed
13.
go back to reference Saida T, Itoyama Y, Kikuchi S, Hao Q, Kurosawa T, Ueda K, Auberson LZ, Tsumiyama I, Nagato K, Kira JI. Long-term efficacy and safety of fingolimod in Japanese patients with relapsing multiple sclerosis: 3-year results of the phase 2 extension study. BMC Neurol. 2017;17(1):17.CrossRefPubMedPubMedCentral Saida T, Itoyama Y, Kikuchi S, Hao Q, Kurosawa T, Ueda K, Auberson LZ, Tsumiyama I, Nagato K, Kira JI. Long-term efficacy and safety of fingolimod in Japanese patients with relapsing multiple sclerosis: 3-year results of the phase 2 extension study. BMC Neurol. 2017;17(1):17.CrossRefPubMedPubMedCentral
Metadata
Title
Acquired modification of sphingosine-1-phosphate lyase activity is not related to adrenal insufficiency
Authors
Gulin Sunter
Ece Oge Enver
Azad Akbarzade
Serap Turan
Pinar Vatansever
Dilek Ince Gunal
Goncagul Haklar
Abdullah Bereket
Kadriye Agan
Tulay Guran
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Neurology / Issue 1/2018
Electronic ISSN: 1471-2377
DOI
https://doi.org/10.1186/s12883-018-1049-9

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