Valine restriction extends survival in aDrosophilamodel of short-chain enoyl-CoA hydratase 1 (ECHS1) deficiency

Abstract

SummaryShort-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) is a rare genetic disorder caused by biallelic pathogenic variants in theECHS1gene. ECHS1D is characterised by severe neurological and physical impairment that often leads to childhood mortality. Therapies such as protein and single nutrient-restricted diets show poor efficacy, whereas development of new treatments is hindered by the low prevalence of the disorder and a lack of model systems for treatment testing. Here we report on the establishment of aDrosophilamodel of ECHS1D. Flies carrying mutations inEchs1(CG6543) were characterised for their physical and metabolic phenotypes, and dietary intervention to improve fly model health was explored. TheEchs1null larvae recapitulated human ECHS1D phenotypes including elevated biomarkers (S-(2-carboxypropyl)cysteamine and 2,3-dihydroxy-2-methylbutyric acid), poor motor behaviour and early mortality, and could be rescued by expression of a humanECHS1transgene. We observed that both restriction of valine in isolation, or all branched-chain amino acids (BCAAs - leucine, isoleucine, and valine) together, extended larval survival, supporting the idea that reducing BCAA pathway catabolic flux is beneficial in this disorder. Further, metabolic profiling revealed substantial changes to carbohydrate metabolism, suggesting thatEchs1loss causes widespread metabolic dysregulation beyond valine metabolism. The similarities betweenDrosophilaand human ECHS1D suggest that the fly model is a valuable animal system in which to explore mechanisms of pathogenesis and novel treatment options for this disorder.