Peri-ictal respiratory dysfunction: Expanding the association between mTOR pathway disorders and ictal central apnea

Among the etiologies of focal epilepsy, mutations of the GATOR1 complex genes-comprising NPRL3, NPRL2, and DEPDC5-are known to result in overactivation of mTORC1. A recent study highlighted an association between ictal and postictal central apnea (ICA) and pathogenic variants of DEPDC5. Here, we analyzed data from 134 patients across two independent cohorts diagnosed with focal epilepsy who underwent video-electroencephalographic long-term monitoring (VLTM) with cardiorespiratory polygraphy. Genetic testing results done for clinical-diagnostic purposes were reviewed in patients with epilepsy of unknown etiology and patients with magnetic resonance imaging (MRI)-defined/suspected focal cortical dysplasia (FCD). In 46 patients, we recorded at least one seizure associated with ICA. Genetic testing was performed in 21 of 22 MRI-negative patients with ICA, revealing variants in mTOR pathway genes in 10 cases (48%), including DEPDC5 (n = 6), NPRL3 (n = 3), and MTOR (n = 1). Regarding MRI-positive patients with ICA (n = 24), an acquired lesional etiology was found in 11. Of 13 patients with MRI-defined FCD, genetic testing was carried out in seven, all of whom had negative results. Moreover, no pathogenic variants were detected in the 14-MRI negative patients without ICA. Our findings confirm that variants in mTOR pathway genes (not only in DEPDC5) are present in patients with ICA and underline the potential risk of sudden unexpected death in epilepsy. These results also highlight the importance of performing respiratory polygraphy during VLTM to document ictal apnea.