TY - JOUR
T1 - Remarkable Phenytoin Sensitivity in 4 Children with SCN8A-related Epilepsy
T2 - A Molecular Neuropharmacological Approach
AU - Boerma, Ragna S.
AU - Braun, Kees P.
AU - van de Broek, Maarten P. H.
AU - van Berkestijn, Frederique M. C.
AU - Swinkels, Marielle E.
AU - Hagebeuk, Eveline O.
AU - Lindhout, Dick
AU - van Kempen, Marjan
AU - Boon, Maartje
AU - Nicolai, Joost
AU - de Kovel, Carolien G.
AU - Brilstra, Eva H.
AU - Koeleman, Bobby P. C.
PY - 2016/1
Y1 - 2016/1
N2 - Mutations in SCN8A are associated with epilepsy and intellectual disability. SCN8A encodes for sodium channel Nav1.6, which is located in the brain. Gain-of-function missense mutations in SCN8A are thought to lead to increased firing of excitatory neurons containing Nav1.6, and therefore to lead to increased seizure susceptibility. We hypothesized that sodium channel blockers could have a beneficial effect in patients with SCN8A-related epilepsy by blocking the over-active Nav1.6 and thereby counteracting the effect of the mutation. Herein, we describe 4 patients with a missense SCN8A mutation and epilepsy who all show a remarkably good response on high doses of phenytoin and loss of seizure control when phenytoin medication was reduced, while side effects were relatively mild. In 2 patients, repeated withdrawal of phenytoin led to the reoccurrence of seizures. Based on the findings in these patients and the underlying molecular mechanism we consider treatment with (high-dose) phenytoin as a possible treatment option in patients with difficult-to-control seizures due to an SCN8A mutation.
AB - Mutations in SCN8A are associated with epilepsy and intellectual disability. SCN8A encodes for sodium channel Nav1.6, which is located in the brain. Gain-of-function missense mutations in SCN8A are thought to lead to increased firing of excitatory neurons containing Nav1.6, and therefore to lead to increased seizure susceptibility. We hypothesized that sodium channel blockers could have a beneficial effect in patients with SCN8A-related epilepsy by blocking the over-active Nav1.6 and thereby counteracting the effect of the mutation. Herein, we describe 4 patients with a missense SCN8A mutation and epilepsy who all show a remarkably good response on high doses of phenytoin and loss of seizure control when phenytoin medication was reduced, while side effects were relatively mild. In 2 patients, repeated withdrawal of phenytoin led to the reoccurrence of seizures. Based on the findings in these patients and the underlying molecular mechanism we consider treatment with (high-dose) phenytoin as a possible treatment option in patients with difficult-to-control seizures due to an SCN8A mutation.
KW - SCN8A
KW - phenytoin
KW - epileptic encephalopathy
KW - sodium channel blockers
KW - ENCEPHALOPATHY
KW - MUTATION
KW - PATIENT
U2 - 10.1007/s13311-015-0372-8
DO - 10.1007/s13311-015-0372-8
M3 - Article
SN - 1933-7213
VL - 13
SP - 192
EP - 197
JO - Neurotherapeutics
JF - Neurotherapeutics
IS - 1
ER -