Objective
The leading cause of epilepsy‐related premature mortality is sudden unexpected death in epilepsy (SUDEP). The cause of SUDEP remains unknown. To search for genetic risk factors in SUDEP ...cases, we performed an exome‐based analysis of rare variants.
Methods
Demographic and clinical information of 61 SUDEP cases were collected. Exome sequencing and rare variant collapsing analysis with 2,936 control exomes were performed to test for genes enriched with damaging variants. Additionally, cardiac arrhythmia, respiratory control, and epilepsy genes were screened for variants with frequency of <0.1% and predicted to be pathogenic with multiple in silico tools.
Results
The 61 SUDEP cases were categorized as definite SUDEP (n = 54), probable SUDEP (n = 5), and definite SUDEP plus (n = 2). We identified de novo mutations, previously reported pathogenic mutations, or candidate pathogenic variants in 28 of 61 (46%) cases. Four SUDEP cases (7%) had mutations in common genes responsible for the cardiac arrhythmia disease, long QT syndrome (LQTS). Nine cases (15%) had candidate pathogenic variants in dominant cardiac arrhythmia genes. Fifteen cases (25%) had mutations or candidate pathogenic variants in dominant epilepsy genes. No gene reached genome‐wide significance with rare variant collapsing analysis; however, DEPDC5 (p = 0.00015) and KCNH2 (p = 0.0037) were among the top 30 genes, genome‐wide.
Interpretation
A sizeable proportion of SUDEP cases have clinically relevant mutations in cardiac arrhythmia and epilepsy genes. In cases with an LQTS gene mutation, SUDEP may occur as a result of a predictable and preventable cause. Understanding the genetic basis of SUDEP may inform cascade testing of at‐risk family members. Ann Neurol 2016;79:522–534
We performed genomic mapping of a family with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and intellectual and psychiatric problems, identifying a disease-associated region on ...chromosome 9q34.3. Whole-exome sequencing identified a mutation in KCNT1, encoding a sodium-gated potassium channel subunit. KCNT1 mutations were identified in two additional families and a sporadic case with severe ADNFLE and psychiatric features. These findings implicate the sodium-gated potassium channel complex in ADNFLE and, more broadly, in the pathogenesis of focal epilepsies.
Objective
Mutations in KCNT1 have been implicated in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and epilepsy of infancy with migrating focal seizures (EIMFS). More recently, a whole ...exome sequencing study of epileptic encephalopathies identified an additional de novo mutation in 1 proband with EIMFS. We aim to investigate the electrophysiological and pharmacological characteristics of hKCNT1 mutations and examine developmental expression levels.
Methods
Here we use a Xenopus laevis oocyte‐based automated 2‐electrode voltage clamp assay. The effects of quinidine (100 and 300μM) are also tested. Using quantitative reverse transcriptase polymerase chain reaction, the relative levels of mouse brain mKcnt1 mRNA expression are determined.
Results
We demonstrate that KCNT1 mutations implicated in epilepsy cause a marked increase in function. Importantly, there is a significant group difference in gain of function between mutations associated with ADNFLE and EIMFS. Finally, exposure to quinidine significantly reduces this gain of function for all mutations studied.
Interpretation
These results establish direction for a targeted therapy and potentially exemplify a translational paradigm for in vitro studies informing novel therapies in a neuropsychiatric disease. Ann Neurol 2014;75:581–590
Objective
Benign familial infantile seizures (BFIS), paroxysmal kinesigenic dyskinesia (PKD), and their combination—known as infantile convulsions and paroxysmal choreoathetosis (ICCA)—are related ...autosomal dominant diseases. PRRT2 (proline‐rich transmembrane protein 2 gene) has been identified as the major gene in all 3 conditions, found to be mutated in 80 to 90% of familial and 30 to 35% of sporadic cases.
Methods
We searched for the genetic defect in PRRT2‐negative, unrelated families with BFIS or ICCA using whole exome or targeted gene panel sequencing, and performed a detailed cliniconeurophysiological workup.
Results
In 3 families with a total of 16 affected members, we identified the same, cosegregating heterozygous missense mutation (c.4447G>A; p.E1483K) in SCN8A, encoding a voltage‐gated sodium channel. A founder effect was excluded by linkage analysis. All individuals except 1 had normal cognitive and motor milestones, neuroimaging, and interictal neurological status. Fifteen affected members presented with afebrile focal or generalized tonic–clonic seizures during the first to second year of life; 5 of them experienced single unprovoked seizures later on. One patient had seizures only at school age. All patients stayed otherwise seizure‐free, most without medication. Interictal electroencephalogram (EEG) was normal in all cases but 2. Five of 16 patients developed additional brief paroxysmal episodes in puberty, either dystonic/dyskinetic or “shivering” attacks, triggered by stretching, motor initiation, or emotional stimuli. In 1 case, we recorded typical PKD spells by video‐EEG‐polygraphy, documenting a cortical involvement.
Interpretation
Our study establishes SCN8A as a novel gene in which a recurrent mutation causes BFIS/ICCA, expanding the clinical–genetic spectrum of combined epileptic and dyskinetic syndromes. ANN NEUROL 2016;79:428–436
Objective
Focal epilepsies are the most common form observed and have not generally been considered to be genetic in origin. Recently, we identified mutations in DEPDC5 as a cause of familial focal ...epilepsy. In this study, we investigated whether mutations in the mammalian target of rapamycin (mTOR) regulators, NPRL2 and NPRL3, also contribute to cases of focal epilepsy.
Methods
We used targeted capture and next‐generation sequencing to analyze 404 unrelated probands with focal epilepsy. We performed exome sequencing on two families with multiple members affected with focal epilepsy and linkage analysis on one of these.
Results
In our cohort of 404 unrelated focal epilepsy patients, we identified five mutations in NPRL2 and five in NPRL3. Exome sequencing analysis of two families with focal epilepsy identified NPRL2 and NPRL3 as the top candidate‐causative genes. Some patients had focal epilepsy associated with brain malformations. We also identified 18 new mutations in DEPDC5.
Interpretation
We have identified NPRL2 and NPRL3 as two new focal epilepsy genes that also play a role in the mTOR‐signaling pathway. Our findings show that mutations in GATOR1 complex genes are the most significant cause of familial focal epilepsy identified to date, including cases with brain malformations. It is possible that deregulation of cellular growth control plays a more important role in epilepsy than is currently recognized. ANN NEUROL 2016;79:120–131
Benign familial infantile epilepsy (BFIE) is a self-limited seizure disorder that occurs in infancy and has autosomal-dominant inheritance. We have identified heterozygous mutations in PRRT2, which ...encodes proline-rich transmembrane protein 2, in 14 of 17 families (82%) affected by BFIE, indicating that PRRT2 mutations are the most frequent cause of this disorder. We also report PRRT2 mutations in five of six (83%) families affected by infantile convulsions and choreoathetosis (ICCA) syndrome, a familial syndrome in which infantile seizures and an adolescent-onset movement disorder, paroxysmal kinesigenic choreoathetosis (PKC), co-occur. These findings show that mutations in PRRT2 cause both epilepsy and a movement disorder. Furthermore, PRRT2 mutations elicit pleiotropy in terms of both age of expression (infancy versus later childhood) and anatomical substrate (cortex versus basal ganglia).
Summary Background Pertussis vaccination has been alleged to cause an encephalopathy that involves seizures and subsequent intellectual disability. In a previous retrospective study, 11 of 14 ...patients with so-called vaccine encephalopathy had Dravet syndrome that was associated with de-novo mutations of the sodium channel gene SCN1A . In this study, we aimed to establish whether the apparent association of Dravet syndrome with vaccination was caused by recall bias and, if not, whether vaccination affected the onset or outcome of the disorder. Methods We retrospectively studied patients with Dravet syndrome who had mutations in SCN1A , whose first seizure was a convulsion, and for whom validated source data were available. We analysed medical and vaccination records to investigate whether there was an association between vaccination and onset of seizures in these patients. Patients were separated into two groups according to whether seizure onset occurred shortly after vaccination (vaccination-proximate group) or not (vaccination-distant group). We compared clinical features, intellectual outcome, and type of SCN1A mutation between the groups. Findings Dates of vaccination and seizure onset were available from source records for 40 patients. We identified a peak in the number of patients who had seizure onset within 2 days after vaccination. Thus, patients who had seizure onset on the day of or the day after vaccination (n=12) were included in the vaccination-proximate group and those who had seizure onset 2 days or more after vaccination (n=25) or before vaccination (n=3) were included in the vaccination-distant group. Mean age at seizure onset was 18·4 weeks (SD 5·9) in the vaccination-proximate group and 26·2 weeks (8·1) in the vaccination-distant group (difference 7·8 weeks, 95% CI 2·6–13·1; p=0·004). There were no differences in intellectual outcome, subsequent seizure type, or mutation type between the two groups (all p values >0·3). Furthermore, in a post-hoc analysis, intellectual outcome did not differ between patients who received vaccinations after seizure onset and those who did not. Interpretation Vaccination might trigger earlier onset of Dravet syndrome in children who, because of an SCN1A mutation, are destined to develop the disease. However, vaccination should not be withheld from children with SCN1A mutations because we found no evidence that vaccinations before or after disease onset affect outcome. Funding Australian National Health and Medical Research Council.
Mutations in the sodium-gated potassium channel subunit gene KCNT1 have recently emerged as a cause of several different epileptic disorders. This review describes the mutational and phenotypic ...spectrum associated with the gene and discusses the comorbidities found in patients, which include intellectual disability and psychiatric features. The gene may also be linked with cardiac disorders. KCNT1 missense mutations have been found in 39% of patients with the epileptic encephalopathy malignant migrating focal seizures of infancy (MMFSI), making it the most significant MMFSI disease-causing gene identified to date. Mutations in KCNT1 have also been described in eight unrelated cases of sporadic and familial autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE). These patients have a high frequency of associated intellectual disability and psychiatric features. Two mutations in KCNT1 have been associated with both ADNFLE and MMFSI, suggesting that the genotype-phenotype relationship for KCNT1 mutations is not straightforward. Mutations have also been described in several patients with infantile epileptic encephalopathies other than MMFSI. Notably, all mutations in KCNT1 described to date are missense mutations, and electrophysiological studies have shown that they result in increased potassium current. Together, these genetic and electrophysiological studies raise the possibility of delivering precision medicine by treating patients with KCNT1 mutations using drugs that alter the action of potassium channels to specifically target the biological effects of their disease-causing mutation. Such trials are now in progress. Better understanding of the mechanisms underlying KCNT1-related disease will produce further improvements in treatment of the associated severe seizure disorders.
Mutations in the KCNT1 potassium channel cause severe forms of epilepsy which are poorly controlled with current treatments. In vitro studies have shown that KCNT1-epilepsy mutations are gain of ...function, significantly increasing K
current amplitudes. To investigate if Drosophila can be used to model human KCNT1 epilepsy, we generated Drosophila melanogaster lines carrying human KCNT1 with the patient mutation G288S, R398Q or R928C. Expression of each mutant channel in GABAergic neurons gave a seizure phenotype which responded either positively or negatively to 5 frontline epilepsy drugs most commonly administered to patients with KCNT1-epilepsy, often with little or no improvement of seizures. Cannabidiol showed the greatest reduction of the seizure phenotype while some drugs increased the seizure phenotype. Our study shows that Drosophila has the potential to model human KCNT1- epilepsy and can be used as a tool to assess new treatments for KCNT1- epilepsy.
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