RARS2 mutations cause early onset epileptic encephalopathy without ponto-cerebellar hypoplasia.

Objective Early onset epileptic encephalopathies (EOEEs) are a group of devastating diseases, manifesting in the first year of life with frequent seizures and/or prominent interictal epileptiform discharges on the electroencephalogram (EEG), developmental delay/regression and usually a poor prognosis. There are numerous causes for EOEEs making the diagnostic workup time consuming and costly. We describe the diagnostic workup in two siblings with EOEE, profound global developmental delay (GDD) and post natal microcephaly. Neuro-imaging disclosed non-specific progressive cerebral atrophy. Methods Whole-exome sequencing analysis. Results Two causative mutations in the gene encoding for mitochondrial arginyl-transfer RNA synthetase, RARS2, were found. This gene is presently related to ponto-cerebellar hypoplasia (PCH) type 6. Reviewing our cases and 16 others published, a common phenotype emerges of EOEE with onset in the immediate post natal or early infantile period (range 1 day-4 months). Many children had more than one seizure type; the most frequent types were myoclonic (50%) followed by clonic (31.5%). The seizures were described as multifocal/alternating sides in 37.5%. Initial EEG demonstrated slowing of the background in 62.5% and epileptiform discharges in 50%. EEG was reported as initially normal in 19%, but almost all the following recordings showed deterioration. Few patients demonstrated initial response to an anti-epileptic drug but eventually all but one had intractable epilepsy. All patients displayed profound GDD – none attained any significant milestones. Most patients had normal occipito-frontal circumference at birth, but almost all developed progressive microcephaly, up to –6 standard deviations. The most common radiological finding was progressive cerebral (100%) and cerebellar (93%) atrophy and NOT progressive PCH (present in 67%). The condition proved to be fatal in 50%. Conclusion We suggest that RARS2 gene mutations can cause a metabolic neurodegenerative disease manifesting primarily as EOEE with post natal microcephaly, without the distinctive radiological feature of PCH.