Kantonsspital St.Gallen

Disturbed sphingolipid metabolism with elevated 1-deoxysphingolipids in glycogen storage disease type I - A link to metabolic control

Thorsten Hornemann, Irina Alecu, Niels Hagenbuch, Assem Zhakupova, Alessio Cremonesi, Matthias Gautschi, Hans H Jung, Fabian Meienberg, Stefan Bilz, Emanuel Christ, Matthias R Baumgartner & Michel Hochuli


1-Deoxysphingolipids (1-deoxySLs) are atypical sphingolipids. They are formed during sphingolipid de novo synthesis by the enzyme serine palmitoyltransferase, due to the alternate use of alanine over its canonical substrate serine. Pathologically elevated 1-deoxySL are involved in several neurological and metabolic disorders. The objective of this study was to investigate the role of 1-deoxySL in glycogen storage disease type I (GSDI).

In this prospective, longitudinal observational study (median follow-up 1.8y), the plasma 1-deoxySL profile was analyzed in 15 adult GSDI patients (12 GSDIa, 3 GSDIb), and 31 healthy controls, along with standard parameters for monitoring GSDI.

1-Deoxysphinganine (1-deoxySA) concentrations were elevated in GSDI compared to controls (191 ± 129 vs 35 ± 14 nmol/l, p < 0.0001). Concordant with the mechanism of 1-deoxySL synthesis, plasma alanine was higher (625 ± 182 vs 398 ± 90 μmol/l, p < 0.0001), while serine was lower in GSDI than in controls (88 ± 22 vs 110 ± 18 μmol/l. p < 0.001). Accordingly, serine, alanine and triglycerides were determinants of 1-deoxySA in the longitudinal analysis of GSDIa. 1-deoxySA concentrations correlated with the occurrence of low blood glucose (area under the curve below 4 mmol/l) in continuous glucose monitoring. The 1-deoxySL profile in GSDIb was distinct from GSDIa, with a different ratio of saturated to unsaturated 1-deoxySL.

In addition to the known abnormalities of lipoproteins, GSDI patients also have a disturbed sphingolipid metabolism with elevated plasma 1-deoxySL concentrations. 1-DeoxySA relates to the occurrence of low blood glucose, and may constitute a potential new biomarker for assessing metabolic control. GSDIa and Ib have distinct 1-deoxySL profiles indicating that both GSD subtypes have diverse phenotypes regarding lipid metabolism.
citation Hornemann T, Alecu I, Hagenbuch N, Zhakupova A, Cremonesi A, Gautschi M, Jung H H, Meienberg F, Bilz S, Christ E, Baumgartner M R, Hochuli M. Disturbed sphingolipid metabolism with elevated 1-deoxysphingolipids in glycogen storage disease type I - A link to metabolic control. Mol Genet Metab 2018; 125:73-78.
type journal paper/review (English)
date of publishing 20-07-2018
journal title Mol Genet Metab (125/1-2)
ISSN electronic 1096-7206
pages 73-78
PubMed 30037504
DOI 10.1016/j.ymgme.2018.07.003