NARS2 is a gene that encodes for an aminoacyl-tRNA synthetase, enzymes that play a crucial role in protein biosynthesis. While the protein is encoded by the nuclear genome, it is imported to the mitochondrion where it is thought to catalyze the ligation of asparagine to tRNA molecules. Mutation in this gene have been previously associated with COXPD24. We report novel variants in the NARS2 gene presenting as early infantile epileptic encephalopathy and associated cardiac hypertrophy and skeletal muscle COX deficiency on the ETC.

Case description

A 3-month-old girl with acute onset focal seizures, epilepsia partialis continua and myoclonic seizures. Opthalmoplegia on exam. She developed rapidly progressive hypertrophic cardiomyopathy and cardiac failure. Due to progressive cardiac decline and intractable epilepsy, care was redirected. Exome testing revealed a compound heterozygous mutation in NARS2 gene. Subsequent autopsy confirmed left ventricular hypertrophy with massively increased numbers of pathologic appearing mitochondria. Skeletal muscle biopsy showed with abnormal COX staining and analysis of respiratory chain function revealed significantly decreased complex IV activity. Biopsies showed an Alper’s type histology with punched out neuropil vacuolation in a Leigh’s disease type distribution (Pallidum, thalamus, midbrain tectum and pontine tegmentum), mitochondrial accumulation in heart muscle and COX deficiency on skeletal muscle ETC.

Here we present a case report of novel variants in the NARS2 gene. While the specific variants have not previously been reported as pathogenic, in the given clinical presentation we believe the pathology findings strongly suggest pathogenicity.