Clinical, biochemical and genetic features associated with VARS2-related mitochondrial disease

In recent years, an increasing number of mitochondrial disorders have been associated with mutations in aminoacyl-tRNA synthetases (mt-aaRSs), which are key enzymes of mitochondrial protein synthesis. VARS2, the gene encoding the mitochondrial valyl tRNA-synthetase, was first associated with disease in a patient harbouring bi-allelic VARS2 mutations who was characterized by psychomotor delay and epilepsia partialis continua associated with an oxidative phosphorylation (OXPHOS) complex I defect. Here we provide a complete genetic, clinical and biochemical description of 10 patients, from 8 unrelated families, harboring mutations in VARS2. All patients except one, who manifested with a less severe disease course, presented at birth exhibiting severe encephalomyopathy and cardiomyopathy. Features included hypotonia, psychomotor delay, seizures, feeding difficulty, abnormal cranial MRI and elevated lactate. The biochemical phenotype was characterized by a combined complex I-IV OXPHOS defect in muscle, with patient fibroblasts typically displaying normal OXPHOS activity. Structural protein modelling supported the pathogenicity of VARS2 missense variants. The detailed description of this patient cohort improves and further delineates our understanding of the clinical presentation associated with VARS2 mutations. This gene should be considered and investigated in early-onset mitochondrial cardioencephalomyopathies.