Biallelic pathogenic variants of PARS2 cause developmental and epileptic encephalopathy with spike‐and‐wave activation in sleep

Abstract

BackgroundBiallelic pathogenic variants in the mitochondrial prolyl‐tRNA synthetase 2 gene (PARS2, OMIM * 612036) have been associated with Developmental and Epileptic Encephalopathy‐75 (DEE‐75, MIM #618437). This condition is typically characterized by early‐onset refractory infantile spasms with hypsarrhythmia, intellectual disability, microcephaly, cerebral atrophy with hypomyelination, lactic acidemia, and cardiomyopathy. Most affected individuals do not survive beyond the age of 10 years.MethodsWe describe a patient with early‐onset DEE, consistently showing an EEG pattern of Spike‐and‐Wave Activation in Sleep (SWAS) since childhood. The patient underwent extensive clinical, metabolic and genetic investigations, including whole exome sequencing (WES).ResultsWES analysis identified compound heterozygous variants in PARS2 that have been already reported as pathogenic. A literature review of PARS2‐associated DEE, focusing mainly on the electroclinical phenotype, did not reveal the association of SWAS with pathogenic variants in PARS2.Notably, unlike previously reported cases with the same genotype, this patient had longer survival without cardiac involvement or lactic acidosis, suggesting potential genetic modifiers contributing to disease variability.ConclusionThese findings widen the genetic heterogeneity of DEE‐SWAS, including PARS2 as a causative gene in this syndromic entity, and highlight the importance of prolonged sleep EEG recording for the recognition of SWAS as a possible electroclinical evolution of PARS2‐related DEE.

tRNA Modifications and Dysregulation: Implications for Brain Diseases

“…This syndrome, referred to as developmental epileptic encephalopathy with sleep-related spikes (DEE-SWAS), establishes a connection between epileptic abnormalities and gradual cognitive deterioration. The identification of PARS2 as the causative gene for DEE-SWAS highlights the genetic diversity underlying this syndrome and underscores the essential role of mitochondrial tRNA synthetases in the etiology of complex neurological conditions [233]. Additionally, mutations in the neuron-and muscle-specific translation factor eEF1A2, specifically G70S, E122K, and D252H, have been implicated in epilepsy.…”