Abstracts

Rationale: De novo mutations in EEF1A2, encoding the eukaryotic translation elongation factor 1 alpha-2 protein, have been reported in four patients with complex phenotypes including epilepsy, but the phenotypic spectrum and functional consequences associated with mutations in this gene remain unclear. We aim to examine the phenotypic spectrum associated with EEF1A2 mutations and to assess the predicted functional and structural consequences of these alterations.Methods: We evaluated exome sequencing and NGS panel data of individuals with neurodevelopmental disorders to identify patients with mutations in EEF1A2. We examined the phenotypic features of newly identified as well as previously reported patients. Finally we investigated the predicted structural consequences of the identified mutations through in silico modeling.Results: In addition to four previously reported patients, we identified five new patients with de novo mutations in EEF1A2 and one patient with a variant of unknown inheritance. Nine out of 10 individuals had epileptic encephalopathy, with onset ranging from one month to eight years (median 4 months). A variety of seizure types were observed including infantile spasms, absence, myoclonic, tonic, atonic, hemiclonic, and generalized tonic-clonic seizures. Seizures were refractory to multiple AEDs in most patients. Movement disorders were observed in 5/10 individuals including choreoathetotic and other hyperkinetic movement disorders (n=3) and ataxia (n=2). Developmental outcomes were poor in all patients; all were non-verbal and many were non-ambulatory. Those who did achieve walking did so late in childhood. Severe truncal hypotonia, often with distal hypertonia, was observed in all individuals. Two patients had respiratory failure secondary to hypotonia, requiring mechanical ventilation. Brain MRI was unremarkable except for mild cerebral atrophy in 4/10 patients. Microcephaly was observed in 4/10 patients. While most patients had a static encephalopathy, one patient had a neurodegenerative course and died at age four years. 4/10 patients carried a recurrent G70S mutation, while all other patients had non-recurrent mutations. Structural modeling showed that all mutations occur within or interact with the switch I or switch II regions of the eEF1A2 protein, which are essential for GTP hydrolysis and dissociation from the ribosome. All mutations are predicted to impact GTP hydrolysis and exert a dominant-negative effect.Conclusions: De novo mutations in EEF1A2 are a cause of epileptic encephalopathy. The recurrent G70S mutation contributes largely to the disease burden of this gene, accounting for 40% in our cohort. Common phenotypic features include infantile onset refractory seizures, severe hypotonia often with distal hypertonia, absent speech, and moderate to severe intellectual disability. Movement disorders and respiratory failure are also seen in a subset of patients. The observed mutations structurally perturb two catalytically essential regions within eEF1A2 with a predicted impact on GTP hydrolysis. We hypothesize that mutant eEF1A2 stalls on the ribosome, thereby inhibiting translation.