Ion Mobility QTOF-MS Untargeted Lipidomics of Human Serum Reveals a Metabolic Fingerprint for GNE Myopathy
Cristina Manis,
Mattia Casula,
Andreas Roos,
Andreas Hentschel,
Matthias Vorgerd,
Oksana Pogoryelova,
Alexa Derksen,
Sally Spendiff,
Hanns Lochmüller,
Pierluigi Caboni
Affiliations
Cristina Manis
Department of Life and Environmental Sciences, Cittadella Universitaria di Monserrato, Blocco A, Room 13, 09042 Monserrato, Italy
Mattia Casula
Department of Life and Environmental Sciences, Cittadella Universitaria di Monserrato, Blocco A, Room 13, 09042 Monserrato, Italy
Andreas Roos
Department of Pediatric Neurology, Centre for Neuromuscular Disorders, Centre for Translational Neuro- and Behavioral Sciences, University Duisburg-Essen, 45147 Essen, Germany
Andreas Hentschel
Leibniz-Institut für Analytische Wissenschaften, 44139 Dortmund, Germany
Matthias Vorgerd
Department of Neurology, BG-University Hospital Bergmannsheil gGmbH, Ruhr-University Bochum, 44789 Bochum, Germany
Oksana Pogoryelova
Directorate of Neurosciences, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals, NHS Foundation Trust, Newcastle upon Tyne NE7 7DN, UK
Alexa Derksen
Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada
Sally Spendiff
Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada
Hanns Lochmüller
Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada
Pierluigi Caboni
Department of Life and Environmental Sciences, Cittadella Universitaria di Monserrato, Blocco A, Room 13, 09042 Monserrato, Italy
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-N-acetylglucosamine 2-epimerase (UDP-GlcNAc 2-epimerase)/N-acetylmannosamine kinase (ManNAc kinase) gene (GNE), 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.
