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Abstract
Rett syndrome (RTT), an X-linked neurological disorder caused by mutations in MECP2, may have a metabolic component. We reported a genetic suppressor screen in a Mecp2-null mouse model to identify pathways for therapeutic improvement of RTT symptoms. Of note, one suppressor mutation implied that cholesterol homeostasis was perturbed in Mecp2 null mice; indeed, cholesterol synthesis was elevated in the brain and body system. Remarkably, the genetic effect of downregulating the cholesterol pathway could be mimicked chemically by statin drugs, improving motor symptoms, and increasing longevity in the mouse. Our work linked cholesterol metabolism to RTT pathology for the first time. Both neurological and systemic effects of perturbed cholesterol homeostasis overlap with many RTT symptoms. Here we show in patients that peripheral cholesterol, triglycerides, and/or LDLs may be elevated early in RTT disease onset, providing a biomarker for patients that could be aided by therapeutic interventions that modulate lipid metabolism.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Acknowledgments
The Rett Syndrome Research Trust (RSRT) was the primary funder of this work with support provided to both M.J.J. and A.D. M.J.J. also received Angel grant #2608 from the International Rett Syndrome Foundation (IRSF). We thank Sanuja De Costa for helping to compile the patient data. The Rett syndrome community is a unique collaboration, in which families critically read the literature and communicate their personal experiences with their daughters to researchers and physicians to move the field forward. We thank you.