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

Abstract

In recent years, an increasing number of mitochondrial disorders have been associated with mutations in mitochondrial aminoacyl‐tRNA synthetases (mt‐aaRSs), which are key enzymes of mitochondrial protein synthesis. Bi‐allelic functional variants in VARS2, encoding the mitochondrial valyl tRNA‐synthetase, were first reported in a patient with psychomotor delay and epilepsia partialis continua associated with an oxidative phosphorylation (OXPHOS) Complex I defect, before being described in a patient with a neonatal form of encephalocardiomyopathy. Here we provide a detailed genetic, clinical, and biochemical description of 13 patients, from nine unrelated families, harboring VARS2 mutations. 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 comprised a combined Complex I and Complex IV OXPHOS defect in muscle, with patient fibroblasts displaying normal OXPHOS activity. Homology modeling supported the pathogenicity of VARS2 missense variants. The detailed description of this cohort further delineates our understanding of the clinical presentation associated with pathogenic VARS2 variants and we recommend that this gene should be considered in early‐onset mitochondrial encephalomyopathies or encephalocardiomyopathies.

A novel VARS2 gene variant in a patient with epileptic encephalopathy

“…Clinical, biochemical and molecular findings in previously reported patients with VARS2 mutation. Taylor et al 5Baertling et al 8Bruni et al 10Bruni et al 10Bruni et al (10) Bruni et al (10) Variant Ala: alanine; CSF: cerebrospinal fluid; DD: developmental delay; HCM: hypertrophic cardiomyopathy; Lac: lactate; MIC: microcephaly; N/P: information not provided by the author.…”

“…Bruni et al (10) elaborated clinical, biochemical, and molecular features in 13 patients from 9 families diagnosed by WES. Two previously reported cases by Taylor et al (5) and by Pronicka et al (9) were also included.…”

“…Two previously reported cases by Taylor et al (5) and by Pronicka et al (9) were also included. Bruni et al (10) presented a new homozygous (c.1258G>A; p.Ala420Thr) variant and four new compound heterozygous variants, along with already known pathogenic variants ( Table 1). The study found the mutant VARS2 allele c.1100C>T; p.Thr367Ile the most common-in six patients in homozygous and in five patients in heterozygous states.…”

The combination of whole‐exome sequencing and clinical analysis allows better diagnosis of rare syndromic retinal dystrophies

“…Bruni et al. ; described nine unrelated families with VARS2 ‐associated mitochondrial diseases including encephalomyopathy and cardiomyopathy, hypotonia, psychomotor delay, seizures, feeding difficulty, abnormal brain MRI and elevated lactate. One patient showed prominent eyes with shallow orbits; one was found to have poor eye contact; and one demonstrated restricted range of eye movements in all directions with some sparing of downgaze and bilateral ptosis (Bruni et al.…”

“…One patient showed prominent eyes with shallow orbits; one was found to have poor eye contact; and one demonstrated restricted range of eye movements in all directions with some sparing of downgaze and bilateral ptosis (Bruni et al. ).…”