title: A role for metabolism in Rett syndrome pathogenesis: New clinical findings and potential treatment targets.
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.
authors.affiliation: Department of Molecular and Human Genetics; Baylor College of Medicine; Houston, TX USA.
authors.forename: Monica J
authors.initials: MJ
authors.lastname: Justice
authors.affiliation: Department of Molecular and Human Genetics; Baylor College of Medicine; Houston, TX USA.
authors.forename: Christie M
authors.initials: CM
authors.lastname: Buchovecky
authors.affiliation: Department of Molecular and Human Genetics; Baylor College of Medicine; Houston, TX USA.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Kyle
authors.affiliation: Tri-state Rett Syndrome Clinic; Montefiore Medical Center; Albert Einstein College of Medicine; Yeshiva University; Bronx, NY USA.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Djukic
keywords: HDAC3; Mecp2; autism; cholesterol; fatty liver; lipids; metabolism; mutation; statins; triglycerides