579 - Unveiling ultra-rare genetic epilepsy in the Neonatal Neurological ICU: electroclinical phenotypes and treatment

Publication Number: 3560.579

Federica Basile, Department of Pediatrics, Division of Neonatology, Cliniques universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium, Tribiano (MILAN), Lombardia, Italy; Evelina Carapancea, Catholic University of Louvain, Wolluwe Saint Lambert, Brussels Hoofdstedelijk Gewest, Belgium; Chiara Pizzuto, Cliniques Universitaires Saint Luc, Brussels, Brussels Hoofdstedelijk Gewest, Belgium; Rosa Pugliano, Division of Pediatric Neurology, Department of Pediatrics, Saint-Luc University Hospital, Catholic University of Louvain, Brussels, Belgium, Bologna, Emilia-Romagna, Italy; Damien Lederer, IPG, Centre for Human Genetics, Charleroi, Hainaut, Belgium; Monica Reis Da Silva, Clinique Universitaire Saint-Luc Bruxelles, Bruxelles, Brussels Hoofdstedelijk Gewest, Belgium; yves sznajer, Center for Human Genetic, Brussels, Brussels Hoofdstedelijk Gewest, Belgium; Maria Roberta R. Cilio, Saint-Luc University Hospital, Catholic University of Louvain, Bruxelles, Brussels Hoofdstedelijk Gewest, Belgium

Background: Neonatal genetic epilepsies are increasingly recognized. Early diagnosis has a significant impact on treatment and prognosis. However, most infants with ultra-rare disorders remain undiagnosed and possibly inappropriately treated.

Objective: To define the electroclinical presentation and treatment response in neonates with ultra-rare epilepsies.

Design/Methods: Neonates who underwent EEG monitoring in a single level IV Neuro-NICU between 2019-2025 were screened for seizures. Clinical and neuroimaging data were extracted from the EMR, and actual video-EEG reviewed for interictal and ictal findings.

Results: Of 308 neonates, 95 (31%) had seizures; 73 (77%) were acute provoked and 22 (23%) neonatal epilepsies, including 2 due to inborn errors of metabolism, 3 to brain malformations, and 17 MRI-negative genetic epilepsies. Among these, 5/17 (29%) had rare KCNQ2/3- or STXBP1-epilepsies, and 12/17 (71%) ultra-rare epilepsies associated with HPDL, CPS1, STAMBP, PHF6, ALDH18A1, KCNT1, FGF12, SCN3A, BRAT1, and 2q34dup (SCN1A, SCN2A, SCN3A). Infants with HPDL and CPS1 variants presented with ictal apnea; STAMBP syndrome with epileptic spasms; BRAT1 encephalopathy with multifocal myoclonus; 2q34dup and ALDH18A1 syndromes with focal clonic seizures. Infants with FGF12, SCN3A and PHF6 variants presented with asymmetric tonic seizures; in SCN3A accompanied by facial flushing, and in PHF6, followed profound apnea and desaturation. Epilepsy of Infancy with Migrating Focal Seizures (EIMFS, KCNT1 gene) was associated with multiple seizure types: focal tonic or focal clonic, and ictal apnea. Infants with BRAT1 and KCNT1 encephalopathy were highly refractory, neonates with STAMBP- and HPDL-related epilepsies responded to vigabatrin, CPS1 and STXBP1 disorders responded to levetiracetam, PHF6-, FGF12-, ALDH18A1, and SCN3A-related epilepsies responded to sodium channel blockers. The infant with 2q34dup responded to valproate. Infants with BRAT1 and CPS1 encephalopathies and one patient with EIMFS underwent redirection of care. The remaining nine were discharged on monotherapy with complete or almost complete seizure control.

Conclusion(s): The diagnosis of ultra-rare, MRI-negative, genetic epilepsies is challenging. Most neonates receive multiple ASMs before achieving seizure control, and some are highly refractory. As for rare neonatal epilepsies years ago, nailing the electroclinical phenotype of ultra-rare neonatal epilepsy may shorten the diagnosis pathway, allowing to identify targeted treatments, including ASMs rarely used in the NICU such as vigabatrin. Videos will be presented.

ULTRARARE NEONATAL EPILEPSIES IN OUR COHORT
Ultrarare - variants.pdf