Epilepsja oporna na leki w rzadkich zaburzeniach RAS niezwiązanych z NF1: badanie retrospektywne dwóch ośrodków pediatrycznych i przegląd piśmiennictwa

OBJECTIVE: To characterise drug-resistant epilepsy (DRE) in non-NF1 RASopathies through a scoping review and a two-centre paediatric cohort. METHODS: We searched PubMed (MEDLINE), Embase and Scopus from inception to September 2026 for terms covering non-NF1 RASopathies and epilepsy/seizures. Four reviewers independently screened records and extracted data in duplicate; discrepancies were resolved by consensus. Eligible records reported individuals with a non-NF1 RASopathy, seizure onset up to 17 years, and confirmed epilepsy. DRE was defined by ILAE (failure of ≥2 appropriate antiseizure medications [ASMs] at adequate dose). In parallel, we retrospectively identified paediatric patients with genetically confirmed Noonan syndrome (NS) or cardio-facio-cutaneous syndrome (CFC) and DRE from two London centres over a five-year period; clinical, EEG and MRI features, ASMs and outcomes were abstracted. RESULTS: Of 801 records identified across three databases, 435 were screened following deduplication; 48 met inclusion criteria. Across the literature, NS showed lower epilepsy frequency and severity; DRE was uncommon and often associated with structural aetiologies. CFC displayed a severe, polymorphic phenotype with frequent status epilepticus and high DRE rates. Recent evidence also identified subclinical epileptiform activity, including continuous spike-and-wave during sleep, in CFC patients without overt seizures. Our cohort comprised six patients: two NS (variants in BRAF, PTPN11) and four CFC (all MAP2K1). Seizure types included tonic-clonic, focal seizures and infantile spasms; most required multiple ASMs. EEG abnormalities were non-specific. MRI showed heterogeneous findings, including mesial temporal sclerosis, cerebral atrophy, delayed myelination, and hippocampal dysgyria. Neurodevelopmental impairment (including autism spectrum disorder) was common. CONCLUSIONS: In non-NF1 RASopathies, DRE reflects combined genetic and structural contributors; in CFC, clinical-imaging correlations support a spectrum towards developmental and epileptic encephalopathy. Management should consider non-pharmacological options and carefully selected targeted approaches; mechanism-informed choices may be considered where appropriate, acknowledging that the supporting evidence remains observational.