VARS2‐related mitochondrial disease: a glimpse into mitochondrial complexity

Background: Mitochondrial aminoacyl‐tRNA synthetases are key enzymes in mitochondrial protein synthesis. Recently, an increasing number of mitochondrial disorders have been associated with variants in VARS2, encoding the mitochondrial valyl tRNA‐synthetase.
Case Study / Methods: We present the case of a 54-year-old male of nonconsanguineous parents referred to the adult metabolic clinic due to previous history of psychomotor delay detected in infancy and uncontrolled epilepsy. He had low set ears, deviated nasal septum, widened nasal dorsum and nipples apart and not inverted. Facies not very expressive. Little eye contact and little fluent speech. Head CT showed bilateral and symmetrical calcifications in the region of the dentate nuclei and basal nuclei bilaterally, including thalamus, semioval centers region, and bilateral frontal subcortical region, that correlated in MRI to extensive areas of altered signal in the white matter. Karyotype and X-fragile syndrome studies were normal. Extensive metabolic work-up including lactate and pyruvate levels, aminoacids, organic acid profile, acylcarnitines and study of creatine metabolism were negative. Muscle biopsy showed moderate changes of predominantly nonspecific myopathic profile with fibers in necrosis and regeneration. Study of the mitochondrial respiratory chain showed elevated citrate synthetase activity suggesting mitochondrial proliferation with no relevant changes in enzymatic activity. Clinical exome revealed two heterozygous variants in VARS2 gene (NM_001167734.2): c.1100C>T (p.(Thr367Ile)) classified as pathogenic, and c.1258G>A (p.(Ala420Thr)), likely pathogenic. Family studies to confirm compound heterozygosity are ongoing.
Discussion/Conclusion: VARS2‐related mitochondrial disease is emerging as an important category of mitochondrial disorders. It is still a poorly understood entity and clinical heterogeneity is the rule. Phenotypic characterization is crucial for a better understanding of this disease.