Metabolic collapse as a mechanism of developmental regression: convergent evidence from Kleefstra syndrome FDG-PET/CT imaging and Drosophila modelling

Developmental regression represents a severe yet enigmatic complication of several neurodevelopmental disorders. In Kleefstra syndrome (KLEFS1), resulting from EHMT1 haploinsufficiency, regression frequently manifests during adolescence or early adulthood and is often preceded by significant sleep disruption. Research implicating EHMT1/G9a in metabolic regulation and stress responses suggests that impaired metabolic resilience might contribute to this vulnerability.

This study aimed to determine if altered glucose metabolism is a feature of KLEFS1 and if it correlates with clinical variability, including regression. Using [18F]FDG-PET/CT, individuals with KLEFS1 who experienced regression (n=4) displayed a hypometabolic brain profile, while one individual who had not experienced regression exhibited globally elevated metabolic activity.

Similarly, G9a mutant flies displayed increased baseline metabolic rate and neuronal ATP levels, accompanied by sleep fragmentation that mirrored the clinical phenotype. Feeding flies oxidative stress to model KLEFS1 regression exacerbated sleep disruption and was linked to a reduction in metabolic output. Crucially, providing adult flies with high sugar prevented oxidative stress-induced worsening of sleep and maintained metabolic stability under stress.

These findings suggest that regression in KLEFS1 and associated sleep disturbances are linked to metabolic vulnerability and impaired energy homeostasis maintenance under stress.