Valine Restriction Extends Survival in a <i>Drosophila</i> Model of Short‐Chain Enoyl‐<scp>CoA</scp> Hydratase 1 (<scp>ECHS1</scp>) Deficiency

Short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) is a rare genetic disorder caused by biallelic pathogenic variants in the ECHS1 gene. 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 the 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 a Drosophila model of ECHS1D. Flies carrying mutations in Echs1 (CG6543) were characterised for their physical and metabolic phenotypes, and dietary intervention to improve fly model health was explored. The Echs1 null larvae recapitulated human ECHS1D phenotypes including poor motor behaviour and early mortality and could be rescued by the expression of a human ECHS1 transgene. 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 that Echs1 loss causes widespread metabolic dysregulation beyond valine metabolism. The similarities between Drosophila and 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.