Ion Mobility QTOF-MS Untargeted Lipidomics of Human Serum Reveals a Metabolic Fingerprint for GNE Myopathy

GNE myopathy, also known as hereditary inclusion body myopathy (HIBM), is a rare genetic muscle disorder marked by a gradual onset of muscle weakness in young adults. GNE myopathy (GNEM) is caused by bi-allelic variants in the UDP- -acetylglucosamine 2-epimerase (UDP-GlcNAc 2-epimerase)/ -acetylmann...

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Published in:Molecules (Basel, Switzerland) Switzerland), 2024-11, Vol.29 (21), p.5211
Main Authors: Manis, Cristina, Casula, Mattia, Roos, Andreas, Hentschel, Andreas, Vorgerd, Matthias, Pogoryelova, Oksana, Derksen, Alexa, Spendiff, Sally, Lochmüller, Hanns, Caboni, Pierluigi
Format: Article
Language:English
Subjects:
Acids
Adult
Biomarkers
Biomarkers - blood
carnitines
Ceramides
Enzymes
Female
GNE myopathy
GNEM biomarkers
HIBM
Humans
Information management
Instrument industry
Kinases
Lipidomics - methods
Lipids
Lipids - blood
lysophosphocholines
Male
Mass Spectrometry - methods
Metabolism
Metabolites
Middle Aged
Multienzyme Complexes - blood
Multienzyme Complexes - genetics
Multienzyme Complexes - metabolism
Myositis, Inclusion Body - congenital
Nonaka myopathy
Patients
Plant lipids
Software
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Summary:GNE myopathy, also known as hereditary inclusion body myopathy (HIBM), is a rare genetic muscle disorder marked by a gradual onset of muscle weakness in young adults. GNE myopathy (GNEM) is caused by bi-allelic variants in the UDP- -acetylglucosamine 2-epimerase (UDP-GlcNAc 2-epimerase)/ -acetylmannosamine kinase (ManNAc kinase) gene ( ), clinically resulting in the loss of ambulation within 10-20 years from the onset of the initial symptoms. The disease's mechanism is poorly understood and non-invasive biomarkers are lacking, hindering effective therapy development. Based on the available evidence, we employed a lipidomic approach to study the serum lipid profile of GNE patients. The multivariate statistical analysis revealed a downregulation of carnitines, as well as of lysophosphatidylcholines, in sera samples derived from GNEM patients. Furthermore, we identified lower levels of sphingomyelins and, concomitantly, high levels of ceramides in serum samples from GNEM patients when compared to control samples derived from healthy donors. Moreover, the GNEM serum samples showed the upregulation of Krebs cycle intermediates, in addition to a decrease in oxaloacetic acid. The correlated data gathered in this study can offer a promising diagnostic panel of complex lipids and polar metabolites that can be used in clinic for GNEM in terms of a metabolic fingerprint measurable in a minimally invasive manner.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules29215211