De novo gain-of-function and loss-of-function mutations ofSCN8Ain patients with intellectual disabilities and epilepsy

Abstract

BackgroundMutations of SCN8A encoding the neuronal voltage-gated sodium channel NaV1.6 are associated with early-infantile epileptic encephalopathy type 13 (EIEE13) and intellectual disability. Using clinical exome sequencing, we have detected three novel de novo SCN8A mutations in patients with intellectual disabilities, and variable clinical features including seizures in two patients. To determine the causality of these SCN8A mutations in the disease of those three patients, we aimed to study the (dys)function of the mutant sodium channels.MethodsThe functional consequences of the three SCN8A mutations were assessed using electrophysiological analyses in transfected cells. Genotype–phenotype correlations of these and other cases were related to the functional analyses.ResultsThe first mutant displayed a 10 mV hyperpolarising shift in voltage dependence of activation (gain of function), the second did not form functional channels (loss of function), while the third mutation was functionally indistinguishable from the wildtype channel.ConclusionsComparison of the clinical features of these patients with those in the literature suggests that gain-of-function mutations are associated with severe EIEE, while heterozygous loss-of-function mutations cause intellectual disability with or without seizures. These data demonstrate that functional analysis of missense mutations detected by clinical exome sequencing, both inherited and de novo, is valuable for clinical interpretation in the age of massive parallel sequencing.

Pathogenic mechanism of recurrent mutations of SCN8A in epileptic encephalopathy

“…Along with the original mutation, p.Asn1768Asp, this work indicates that impaired inactivation of Na v 1.6 is the predominant pathogenic mechanism in EIEE13. A contrasting mechanism, premature channel activation, was observed for two mutations located in transmembrane segments of domain II, pThr767Ile and p.Asn984Lys 6, 9. The other two functionally characterized SCN8A mutations caused reduction in peak current density (p.Gly1451Ser)6 and decreased protein stability (p.Arg223Gly)7; the role of these effects in neuronal hyperexcitability is unclear.…”

“…Clinical features include seizure onset before 18 months of age, intellectual disability, and developmental delay 1, 2, 3, 4, 5. Movement disorders are common and 50% of affected individuals are nonambulatory 1, 3, 6, 7, 8, 9, 10, 11, 12. SUDEP (sudden unexpected death in epilepsy) is reported in 10% of cases 1, 2, 4, 5…”

A Gain-of-Function Mutation in Nav1.6 in a Case of Trigeminal Neuralgia

“…Although gain-of-function mutations of Na V 1.6 have been shown to cause infantile epileptic encephalopathy (17)(18)(19), there has been no genetic evidence thus far for a role for this channel in human pain disorders. We report here a novel Na V 1.6 mutation in an individual with TN.…”

Precision Medicine: SCN8A Encephalopathy Treated with Sodium Channel Blockers

“…The majority of the functionally tested SCN8A mutations result in gain-of-function (GOF), causing the Na v 1.6 channel to be hyperactive, leading to increased neuronal firing [1,[4][5][6]. Thus, it appears that neuronal hyperexcitability caused by GOF mutations is the predominant mechanism underlying epilepsy in SCN8A encephalopathy.…”

“…Seizures in patients with SCN8A mutations are often refractory to conventional antiepileptic treatment. However, in approximately half of patients, good responses to anticonvulsants that directly modulate sodium channel activity (sodium channel blockers) have been described, either as a reduction in seizures or even seizure-free periods [2][3][4][7][8][9]. In particular, carbamazepine and the derivative oxcarbazepine have proven useful in many patients.…”