Drug resistant epilepsy driven by RHEB mutations – Current evidence and a novel report of a paedatric case

• We describe a novel pediatric case with a large FCDIIb caused by a somatic RHEB p.Tyr35Leu mutation. • In a comprehensive integrated case and literature review we delineate genotype–phenotype patterns in RHEB-related mTORopathies. • RHEB (both somatic and germline) variants are rare but represent potentially druggable targets, emphasizing the relevance of comprehensive clinical knowledge of these genes for precision epilepsy care. Malformations of cortical development (MCD), including focal cortical dysplasia type II (FCDII) and hemimegalencephaly (HME), are major causes of drug-resistant focal epilepsy (DRFE). Recent genetic discoveries implicate dysregulation of the mechanistic target of rapamycin (mTOR) signaling pathway as a key driver of abnormal cortical organization and epileptogenesis. Among these, somatic variants in RHEB are exceedingly rare but pathogenic, with the recurrent RHEB p.Tyr35Leu variant known to hyperactivate mTORC1 signaling. We report a paediatric case with an extensive transmantle FCDIIb associated with a somatic RHEB p.Tyr35Leu mutation identified through targeted deep sequencing of resected brain tissue. Clinical, radiological and histopathological data were correlated with genetic findings. Additionally, we conducted a comprehensive literature review to contextualize RHEB -related neurological disorders within the mTORopathy spectrum and to assess genotype–phenotype correlations. The identified mosaic RHEB variant showed a variant allele frequency (VAF) of 5%, correlating with early-onset, pharmacoresistant epilepsy and extensive cortical dysplasia. Literature synthesis revealed that higher VAF values are associated with greater lesion burden and more severe neurological outcomes. Importantly, somatic RHEB variants typically manifest as focal, surgically treatable epilepsies, whereas germline variants produce broader neurodevelopmental and neuropsychiatric phenotypes. This report expands the clinical and molecular spectrum of RHEB -related mTORopathies and emphasizes the diagnostic importance of deep sequencing of brain tissue, as low-level mosaic variants often escape detection in peripheral blood samples. Given that RHEB mutations represent potentially druggable mTOR pathway targets, these findings have significant implications for individualized therapeutic strategies and precision epilepsy care.