Neurological, metabolic and inflammatory phenotypes in a mouse model of ECHS1 deficiency

ECHS1 deficiency (ECHS1D) is a rare and devastating neurometabolic disease that currently has no defined treatments. This disorder results from missense loss-of-function mutations in the <i>ECHS1</i> gene that results in severe developmental delays, encephalopathy, hypotonia and early death. ECHS1 enzymatic activity is necessary for the beta-oxidation of fatty acids and the oxidation of branched-chain amino acids within the inner mitochondrial matrix. The pathogenesis of disease remains poorly understood. To expand our knowledge on disease mechanisms, we generated a novel mouse model of ECHS1D that possesses a disease-associated variant knocked-in (KI) the <i>Echs1</i> allele and a knock-out (KO) of the other <i>Echs1</i> allele. Neurological and metabolic abnormalities were assessed under basal conditions, and acute inflammation was tested as a potential disease driver. Mice containing KI/KI or KI/KO alleles were viable with normal development and survival, and the combined KI and KO alleles resulted in more than a 95% reduction of Echs1 protein levels. ECHS1D mice had significantly increased epileptiform EEG activity and were sensitive to seizure induction, which resulted in the death of 60% of ECHS1D mice. Power spectral analysis revealed ECHS1D mice had increased slow-wave EEG power that was associated with sleep dysfunction. Under basal conditions, energy status and mitochondrial function within the brain was unaffected, while aromatic amino acid content was increased. Markers of neuroinflammation were increased in ECHS1D mice in an age-dependent manner and acute inflammatory challenge resulted in failure to thrive and early lethality in ECHS1D mice. In conclusion, we developed a novel model of ECHS1D that can be used to study disease mechanisms and for therapeutic development.