Mutations in ECHS1 Gene Found to be Linked to a New Mitochondrial Disease

A recent study led by a large international research team recently characterized a new mitochondrial disease associated with specific gene mutations. The study is entitled “Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement” and was published in the journal Annals of Clinical and Translational Neurology.

Mitochondria are considered the powerhouses of cells, as they are responsible for converting glucose and fatty acids into adenosine triphosphate (ATP), the energy that virtually drives all the cells’ metabolic functions. Genetic mutations in the mitochondrial DNA can interfere with energy production in cells, which can severely affect the central nervous system causing progressive degeneration of motor functions. One disease linked to mitochondrial dysfunction is Leigh disease, a rare, severe, inherited neurometabolic disorder that affects the central nervous system, causing a progressive loss of mental and motor abilities that lead to an early death, often due to respiratory failure.

The short-chain enoyl-CoA hydratase (ECHS1) gene encodes a multifunctional mitochondrial matrix protein involved in the oxidation of fatty acids and essential amino acids like valine. Mutations in the mitochondrial ECHS1 have been suggested to potentially be associated with medical disorders.

In the study, by analyzing an international cohort of patients with suspected mitochondrial disorders, the research team found ten unrelated patients who tested positive for ECHS1 mutations. Patients were found to experience disease onset in the first year of life, although a heterogeneous phenotype was observed varying from neonatal death to survival into adulthood. The main clinical features reported were encephalopathy (10/10, brain dysfunction), deafness (9/9), epileptic seizures (6/9), optic atrophy (6/10) and cardiomyopathy (4/10, impaired heart muscle). Cardiomyopathy was only found in patients with a severe course and early death. Brain magnetic resonance imaging (MRI) showed that patients had white matter changes that resembled a Leigh-like pattern and disorders related to the mitochondrial energy metabolism.

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The team assessed the functional impact of these ECHS1 mutations using patient-derived fibroblast cell lines and found further evidence of the pathogenicity caused by these mutations. Reduced ECHS1 protein levels were found in these patient cell lines, as well as a functional defect in mitochondrial beta-oxidation of fatty acids and impaired valine oxidation.

The research team concluded that ECHS1 mutations are responsible for a new clinical mitochondrial disease that has a broad phenotypic spectrum and is characterized by an early onset, very severe (Leigh-like) mitochondrial encephalopathy with deafness, optic atrophy, epilepsy and cardiomyopathy. The researchers suggest that the defect in beta-oxidation and valine metabolism are important factors that contribute to disease development, and that both could be susceptible to metabolic treatment strategies.