Efficacy of sodium channel blockers in SCN2A early infantile epileptic encephalopathy.

Recent clinical evidence supports a targeted therapeutic approach for genetic epileptic encephalopathies based on the molecular dysfunction. A 2-day-old male infant presented with epileptic encephalopathy characterized by burst-suppression EEG background and tonic-clonic migrating partial seizures. The condition was refractory to phenobarbital, pyridoxine, pyridoxal phosphate and levetiracetam, but a dramatic response to an intravenous loading dose of phenytoin was documented by video-EEG monitoring. Over weeks phenytoin was successfully switched to carbamazepine to prevent seizure relapses associated with difficulty in maintaining proper blood levels of phenytoin. Genetic analysis identified a novel de novo heterozygous mutation (c.[4633A>G]p.[Met1545Val]) in SCN2A. At two years and three months of age the patient is still seizure-free on carbamazepine, although a developmental delay is evident. Sodium channel blockers represent the first-line treatment for confirmed or suspected SCN2A-related epileptic encephalopathies. In severe cases with compatible electro-clinical features we propose a treatment algorithm based on a test trial with high dose intravenous phenytoin followed in case of a positive response by carbamazepine, more suitable for long-term maintenance treatment. Because of their rarity, collaborative studies are needed to delineate shared therapeutic protocols for EIEE based on the electro-clinical features and the presumed underlying genetic substrate.

Dilena R ，Striano P ，Gennaro E ，Bassi L ，Olivotto S ，Tadini L ，Mosca F ，Barbieri S ，Zara F ，Fumagalli M ... -  《-》

Neonatal SCN2A encephalopathy: A peculiar recognizable electroclinical sequence.

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. 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. 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. 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. 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.

Melikishvili G ，Dulac O ，Gataullina S 《-》

The phenotype and treatment of SCN2A-related developmental and epileptic encephalopathy.

Kim HJ ，Yang D ，Kim SH ，Kim B ，Kim HD ，Lee JS ，Choi JR ，Lee ST ，Kang HC ... -  《-》

Ketogenic diet as a successful early treatment modality for SCN2A mutation.

SCN2A mutations have been described in a very broad spectrum of clinical phenotypes including benign (familial) neonatal/infantile seizures and early infantile epileptic encephalopathies (EIEE) as Ohtahara syndrome (OS), Dravet syndrome (DS), epilepsy of infancy with migrating focal seizures and West syndrome (WS). Treatment modalities for epilepsy caused by SCN2A mutations mainly consist of sodium channel blockers but ketogenic diet (KD) is also considered as an option of treatment for intractible seizures caused by SCN2A mutations. Because of the wide nature of the heterogeneity of mutations related to SCN2A gene, the clinical phenotypes vary in severity and treatment response to KD has been reported to be controversial. We present a patient diagnosed with OS associated with a novel SCN2A mutation (c.408G > A, p.Met136lle; OMIM®: 182390) who had a complete resolution of seizures and EEG abnormalities with KD commenced at 39 days of age. As far as we are aware our case is the youngest patient with SCN2A mutation treated with KD with complete resolution of epilepsy at an early age and has been seizure free of antiepileptic medications for a long duration.

Turkdogan D ，Thomas G ，Demirel B 《-》

Lacosamide for SCN2A-related intractable neonatal and infantile seizures.

Flor-Hirsch H ，Heyman E ，Livneh A ，Reish O ，Watemberg N ，Litmanovits I ，Ben Sason Lilli A ，Lev D ，Lerman Sagie T ，Bassan H ... -  《-》