Evaluating the utility of growth differentiation factor 15 and fibroblast growth factor 21 as blood biomarkers for Rett syndrome

Rett syndrome (RTT, OMIM #312750) is a severe genetic, neurodevelopmental disorder, primarily affecting females, that occurs due to pathogenic variants in MECP2. Clinical features include loss of acquired developmental milestones, such as purposeful hand movements and communicative abilities and the onset of stereotypic hand movements. Mitochondrial dysfunction/impairment, and inflammation have been reported in individuals with RTT. Despite numerous clinical trials and medications thought to be disease-modifying, treatment often remains purely symptomatic. A significant impediment in determining treatment efficacy has been the lack of clinical biomarkers that correlate with disease state. Mitokines, such as fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15), have been established as biomarkers of cellular stress and mitochondrial dysfunction that may be of clinical utility for patients with RTT. We aimed to determine the suitability of these mitokines as biomarkers for RTT where we analysed their expression levels in blood samples from individuals with RTT as well as fromthe Mecp2^T158A mouse model . Our data showed higher FGF21 and GDF15 levels in female Mecp2-deficient mice compared to their wild type littermates. Median FGF21 and GDF15 levels also trended higher in the affected human cohort compared to controls; however, these elevations did not reach statistical significance and appear to be correlated with sodium valproate therapy.