Person: Pérez Palma, Eduardo
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Pérez Palma
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Eduardo
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Eduardo Esteban Pérez Palma
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Publication Molecular dynamics simulations reveal molecular mechanisms for the gain and loss of function effects of four SCN2A variants(2024) Bhattarai, Nisha; Montanucci, Ludovica; Brünger, Tobias; Pérez Palma, Eduardo; Martin, William; Smith, Iris; Eng, Charis; Cheng, Feixiong; Helbig, Ingo; Müller, Rikke; Brunklaus, Andreas; Schorge, Stephanie; Lal, DennisSCN2A gene disorders cover a wide range of medical conditions, from epileptic encephalopathies to neurodevelopmental disorders. The variants of these disorders, studied through electrophysiology, show complex behaviors that go beyond simple classification as either gain or loss of function. In our study, we simulated the biophysical effects of variants (R937C, V208E, S1336Y, and R853Q) to understand their impact. Our findings reveal that all these variants negatively affect the structural stability of the gene, with R937C being the most unstable. Specifically, R937C disrupts important charged interactions affecting sodium ion flow, while S1336Y introduces a new interaction that impacts the channel’s inactivation gate. Conversely, the variants V208E and R853Q, which are located in the voltage-sensing domains, have opposite effects: R853Q increases compactness and interaction, whereas V208E shows a decrease. Our computer-based method offers a scalable way to gain crucial insights into how genetic variants influence channel dysfunction and contribute to neurodevelopmental disorders.Publication Genotype-phenotype associations in 1018 individuals with SCN1A-related epilepsies(2024) Gallagher, Declan; Pérez; Pérez Palma, Eduardo; Bruenger, Tobias; Ghanty, Ismael; Brilstra, Eva; Ceulemans, Berten; Chemaly, Nicole; De Lange, Iris; Depienne, Christel; Guerrini, Renzo; Mei, Davide; Møller, Rikke; Nabbout, Rima; Regan, Brigid; Schneider, Amy; Scheffer, Ingrid; Schoonjans, An; Symonds, Joseph; Weckhuysen, Sarah; Zuber, Sameer; Lal, Dennis; Brunklaus, AndreasObjective: SCN1A variants are associated with epilepsy syndromes ranging from mild genetic epilepsy with febrile seizures plus (GEFS+) to severe Dravet syndrome (DS). Many variants are de novo, making early phenotype prediction difficult, and genotype-phenotype associations remain poorly understood. Methods: We assessed data from a retrospective cohort of 1018 individuals with SCN1A-related epilepsies. We explored relationships between variant characteristics (position, in silico prediction scores: Combined Annotation Dependent Depletion (CADD), Rare Exome Variant Ensemble Learner (REVEL), SCN1A genetic score), seizure characteristics, and epilepsy phenotype. Results: DS had earlier seizure onset than other GEFS+ phenotypes (5.3 vs. 12.0 months, p < .001). In silico variant scores were higher in DS versus GEFS+ (p < .001). Patients with missense variants in functionally important regions (conserved N-terminus, S4-S6) exhibited earlier seizure onset (6.0 vs. 7.0 months, p = .003) and were more likely to have DS (280/340); those with missense variants in nonconserved regions had later onset (10.0 vs. 7.0 months, p = .036) and were more likely to have GEFS+ (15/29, χ2 = 19.16, p < .001). A minority of protein-truncating variants were associated with GEFS+ (10/393) and more likely to be located in the proximal first and last exon coding regions than elsewhere in the gene (9.7% vs. 1.0%, p < .001). Carriers of the same missense variant exhibited less variability in age at seizure onset compared with carriers of different missense variants for both DS (1.9 vs. 2.9 months, p = .001) and GEFS+ (8.0 vs. 11.0 months, p = .043). Status epilepticus as presenting seizure type is a highly specific (95.2%) but nonsensitive (32.7%) feature of DS. Significance: Understanding genotype-phenotype associations in SCN1A-related epilepsies is critical for early diagnosis and management. We demonstrate an earlier disease onset in patients with missense variants in important functional regions, the occurrence of GEFS+ truncating variants, and the value of in silico prediction scores. Status epilepticus as initial seizure type is a highly specific, but not sensitive, early feature of DS