Thesis defense Tessa Peters (Donders series 588)

16 March 2023

Promotors: prof. dr. ir. M.M. Verbeek, prof. dr. R.A. Wevers, prof. dr. M.A.A.P. Willemsen
Copromotor: Dr. K.L.M. Coene (ETZ TweeSteden)

Neurometabolic disorders: metabolic screening and biomarker discovery

Neurometabolic disorders are a group of diseases in which brain metabolism is disturbed due to a genetic defect. The aim of this thesis was to improve the diagnostic yield and increase the knowledge of the underlying pathophysiological mechanisms of neurometabolic disorders by application of innovative metabolic screening strategies, with a focus on application of next-generation metabolic screening (NGMS) to cerebrospinal fluid (CSF) analysis. The work in this thesis shows that NGMS is a useful screening tool for a broad range of diseases and biomarkers and can identify new biomarkers that may be implemented in diagnostics at a later timepoint. This includes decreased levels of N-acetylated amino acids in CSF as a metabolic fingerprint for Huppke-Brendel syndrome. Moreover, comparing CSF of groups of patients with the same neurometabolic diagnosis to the CSF of controls by NGMS shows great potential for biomarker discovery. Examples are the newly identified biomarkers xylose-α1-3-glucose and xylose-α1-3-xylose-α1-3-glucose for GLUT1 deficiency syndrome and 4,5-dihydroxyheptanoic acid for SSADH deficiency. Overall, NGMS yielded many features that are significantly different between patients and controls and are of interest for further research. These features will eventually greatly improve the diagnosis as well as the pathophysiological understanding of neurometabolic disorders.