Childhood-onset focal epilepsy and acute para-infectious encephalopathy in a patient with biallelic QARS1 variants.

introductionBiallelic variants in QARS1, a house-keeping gene involved in protein synthesis, cause a rare encephalopathy classically characterized by severe developmental delay, drug-resistant neonatal-onset epilepsy, microcephaly, and brain atrophy. We aim to raise awareness on mild QARS1-related phenotypes describing a 6-year-old patient. CASE DESCRIPTION: Epilepsy onset occurred at 3.5 years with a sleep-related focal autonomic seizure, accompanied by interictal occipital spikes at EEG. In the following months, daytime focal impaired awareness seizures appeared. Due to developmental delay and short stature, trio-based whole-exome sequencing was performed, unraveling two compound heterozygous QARS1 variants: the likely pathogenic c.1304A>G (p.Y435C) and the c.799C>T (p.R267W), extremely rare and predicted deleterious by in silico analysis. At 5 years, the patient had a para-infectious encephalopathy with acute psychomotor slowing, delta-theta activity at EEG, new-onset bilateral subcortical white matter T2-hyperintensities with diffusion restriction at brain MRI, and optimal response to intravenous methylprednisolone administration. At 12-month follow-up, the patient had been seizure-free for a year with levetiracetam monotherapy. DISCUSSION: Mild QARS1-related encephalopathies may present with a childhood-onset focal epilepsy accompanied by developmental delay and short stature as red flags of monogenic etiology. The episode of steroid-responsive acute para-infectious encephalopathy, previously reported in another patient harboring the p.Y435C variant, suggests that milder cases might be more susceptible to encephalopathy caused by intercurrent illnesses (e.g., infection). As recommended for other aminoacyl-tRNA synthetase-related diseases, it is important to provide this cohort with an early genetic diagnosis in order to encourage precision medicine and personalized treatment.