Gia Melikishvili1, Olivier Dulac2, Svetlana Gataullina3. 1. Department of Pediatrics, MediClubGeorgia Medical Center, Tbilisi, Georgia. 2. AdPueriVitam, Antony, France. 3. Services d'explorations fonctionnelles, Centre de médecine du sommeil, Hôpital Antoine-Béclère, AP-HP, Clamart, France; Service de pédiatrie, Centre hospitalier intercommunal André Grégoire, Montreuil, France. Electronic address: svetlana.gataullina@aphp.fr.
Abstract
INTRODUCTION: Sodium voltage-gated channel alpha subunit 2 (SCN2A) gene encodes the Nav1.2 subunit of voltage-gated sodium channel in pyramidal neurons. SCN2A gain-of-function mutations are identified more and more often with gene panels and whole exome sequencing. Phenotype ranges from benign neonatal or infantile seizures to severe epileptic encephalopathy. Although large series of patients targeting genetic background point out two main phenotypes with SCN2A encephalopathy, Ohtahara syndrome and malignant migrating partial seizures in infancy (EMPSI), we noticed that in fact, a peculiar clinical and electroencephalogram (EEG) sequence distinct from these syndromes should suggest the diagnosis early. PATIENTS AND METHODS: We report three new cases with de novo SCN2A mutations - 166237617C>A p.(Asp1487Glu), c.407T>G p.(Met136Arg), and c.4633A>G p.(Met1545Val) - diagnosed by direct sequencing or genes panel, their follow-up ranging from 4 to 5 years. RESULTS: For all three patients, seizures started at two days of life and consisted of apnea and cyanosis with partial clonic or tonic, alternating on both sides with, up to 100/day, evolving to generalized tonic-clonic seizures (GTCS) and epileptic spasms by three months. First EEG showed a discontinuous pattern, evolving to multifocal spikes, by 3 (two patients) and 6 months (one). Seizure frequency decreased progressively by the middle or end of the first year of life. Only less frequent GTCS persisted during the second year of life for two patients. Improvement was observed in two patients with sodium channel blocker (phenytoin) used at age of 1 month for one patient and at 2 years for another one. All patients remained with severe psychomotor delay. DISCUSSION: All three infants share a condition different from Ohtahara syndrome in which tonic spasms predominate and suppression-burst pattern is obvious, and from EMPSI, in which partial migrating discharges involve successively the various parts of the brain including occipital regions with oculoclonic seizures, but there is neither discontinuous pattern nor therapeutic response to sodium channel blockers. CONCLUSION: Neonatal SCN2A encephalopathy has a recognizable phenotype starting soon after birth with alternating partial motor seizures evolving to infantile spasms and a discontinuous EEG pattern. Seizures improve spontaneously in the first year of life. This electroclinical sequence should indicate the search of SCN2A mutation and suggest the administration of sodium channel blockers.
INTRODUCTION:Sodium voltage-gated channel alpha subunit 2 (SCN2A) gene encodes the Nav1.2 subunit of voltage-gated sodium channel in pyramidal neurons. SCN2A gain-of-function mutations are identified more and more often with gene panels and whole exome sequencing. Phenotype ranges from benign neonatal or infantile seizures to severe epileptic encephalopathy. Although large series of patients targeting genetic background point out two main phenotypes with SCN2Aencephalopathy, Ohtahara syndrome and malignant migrating partial seizures in infancy (EMPSI), we noticed that in fact, a peculiar clinical and electroencephalogram (EEG) sequence distinct from these syndromes should suggest the diagnosis early. PATIENTS AND METHODS: We report three new cases with de novo SCN2A mutations - 166237617C>A p.(Asp1487Glu), c.407T>G p.(Met136Arg), and c.4633A>G p.(Met1545Val) - diagnosed by direct sequencing or genes panel, their follow-up ranging from 4 to 5 years. RESULTS: For all three patients, seizures started at two days of life and consisted of apnea and cyanosis with partial clonic or tonic, alternating on both sides with, up to 100/day, evolving to generalized tonic-clonic seizures (GTCS) and epileptic spasms by three months. First EEG showed a discontinuous pattern, evolving to multifocal spikes, by 3 (two patients) and 6 months (one). Seizure frequency decreased progressively by the middle or end of the first year of life. Only less frequent GTCS persisted during the second year of life for two patients. Improvement was observed in two patients with sodium channel blocker (phenytoin) used at age of 1 month for one patient and at 2 years for another one. All patients remained with severe psychomotor delay. DISCUSSION: All three infants share a condition different from Ohtahara syndrome in which tonic spasms predominate and suppression-burst pattern is obvious, and from EMPSI, in which partial migrating discharges involve successively the various parts of the brain including occipital regions with oculoclonic seizures, but there is neither discontinuous pattern nor therapeutic response to sodium channel blockers. CONCLUSION: Neonatal SCN2Aencephalopathy has a recognizable phenotype starting soon after birth with alternating partial motor seizures evolving to infantile spasms and a discontinuous EEG pattern. Seizures improve spontaneously in the first year of life. This electroclinical sequence should indicate the search of SCN2A mutation and suggest the administration of sodium channel blockers.