Lipid metabolic stress in development defines which genetically-susceptible DYT- TOR1A mice develop disease

There has been enormous progress defining the genetic landscape of disease. However, genotypes rarely fully predict neurological phenotypes, and we rarely understand why. +/Δgag that causes dystonia with ~30% penetrance is a classic case. Here we show, in inbred mice, that +/Δgag affects embryonic brain lipid metabolism with sex-skewed reduced penetrance. Penetrance is affected by environmental context, including maternal diet. The lipid metabolic defect resolves during post-natal development. Nevertheless, we discover dystonia-like symptoms in ~30% of juvenile female mice, and prevent these symptoms by genetically suppressing abnormal lipid metabolism. We conclude that embryos poorly buffer metabolic stress , resulting in a period of abnormal metabolism that hardwires the brain for dystonia in later life. The data show unexpected and profound impacts of sex, and thus highlight the importance of examining male and female animal models of disease.