Mitochondrial Fatty Acid Oxidation Disorders Associated with Short-Chain Enoyl-CoA Hydratase (ECHS1) Deficiency

Abstract

Mitochondrial fatty acid β-oxidation (FAO) is the primary pathway for fatty acid metabolism in humans, performing a key role in liver, heart and skeletal muscle energy homeostasis. FAO is particularly important during times of fasting when glucose supply is limited, providing energy for many organs and tissues, including the heart, liver and brain. Deficiencies in FAO can cause life-threatening metabolic disorders in early childhood that present with liver dysfunction, hypoglycemia, dilated hypertrophic cardiomyopathy and Reye-like Syndrome. Alternatively, FAO defects can also cause ‘milder’ adult-onset disease with exercise-induced myopathy and rhabdomyolysis. Short-chain enoyl-CoA hydratase (ECHS1) is a key FAO enzyme involved in the metabolism of fatty acyl-CoA esters. ECHS1 deficiency (ECHS1D) also causes human disease; however, the clinical manifestation is unlike most other FAO disorders. ECHS1D patients commonly present with Leigh syndrome, a lethal form of subacute necrotizing encephalomyelopathy traditionally associated with defects in oxidative phosphorylation (OXPHOS). In this article, we review the clinical, biochemical and genetic features of the ESHS1D patients described to date, and discuss the significance of the secondary OXPHOS defects associated with ECHS1D and their contribution to overall disease pathogenesis.

ACADSB regulates ferroptosis and affects the migration, invasion, and proliferation of colorectal cancer cells

“…Wang et al, 2020). At the same time, ECHS1 is the key enzyme of mitochondrial fatty acid oxidation process (Sharpe & McKenzie, 2018). At present, the role of ECHS1 in CRC has not been reported.…”

“…formed a control axis. ECHS1 is a member of the hydratase/ isomerase superfamily and plays a role in the second step of mitochondrial fatty acid β oxidation pathway (Sharpe & McKenzie, 2018). It can catalyze the hydration of the intermediate of 2-trans enol COA (COA) to l-3-hydroxyacyl COA (Sharpe & McKenzie, 2018).…”

Clinical, biochemical and metabolic characterization of patients with short-chain enoyl-CoA hydratase(ECHS1) deficiency: two case reports and the review of the literature

“…For patients with mild forms of deficiency, only N-acetyl-S-(2-carboxypropyl) cysteine level is increased in the urine, suggesting that the metabolites of methacrylyl-CoA are important diagnostic markers of the mild and severe forms of ECHS1 deficiency. N-acetyl-S-(2-carboxypropyl)cysteine and its derivatives are formed from methacrylyl-CoA, so methacrylyl-CoA is also an important diagnostic marker for mild SCEHdeficiency [6,12,20,21]. Peter et al found that the content of 2,3-dihydroxy-2-methylbutyrate in urine of two SCEHdeficiency patients increased in the study of ECHS1mutations in LS suggesting that the metabolite may be a common biochemical change in SCEHdeficiency [1].…”

Mitochondrial diseases: expanding the diagnosis in the era of genetic testing

“…If in excess, the random binding of sulfhydryl groups is toxic to cells. Recessive ECHS1 variants induce leukoencephalopathy, changes in the basal ganglia consistent with Leigh syndrome, hypotonia, global developmental delay, cardiomyopathy, and early death [352,353] . 3-Hydroxyisobutyryl-CoA hydrolase (HIBCH) is the enzyme step, just upstream of ECHS1 activity in valine metabolism.…”