Recessive variants in RARS2, a nuclear gene encoding a
mitochondrial protein, were initially reported in
pontocerebellar hypoplasia. Subsequently, a recessive RARS2 early-infantile (<12 weeks) developmental and epileptic
encephalopathy was described with hypoglycaemia and
lactic acidosis. Here, we describe two unrelated patients with a novel RARS2 phenotype and reanalyse the published RARS2
epilepsy phenotypes and variants. Our novel cases had infantile-onset myoclonic developmental and epileptic
encephalopathy, presenting with a progressive
movement disorder from 9 months on a background of normal development. Development plateaued and regressed thereafter, with mild to profound impairment. Multiple
drug-resistant generalized and
focal seizures occurred with episodes of
non-convulsive status epilepticus. Seizure types included absence, atonic, myoclonic, and
focal seizures. Electroencephalograms showed diffuse slowing, multifocal, and generalised spike-wave activity, activated by sleep. Both patients had compound heterozygous RARS2 variants with likely impact on splicing and transcription. Remarkably, of the now 52 RARS2 variants reported in 54 patients, our reanalysis found that 44 (85%) have been shown to or are predicted to affect splicing or gene expression leading to
protein truncation or nonsense-mediated decay. We expand the RARS2 phenotypic spectrum to include infantile
encephalopathy and suggest this gene is enriched for pathogenic variants that disrupt splicing.