A variant of KCC2 from patients with febrile seizures impairs neuronal Cl- extrusion and dendritic spine formation

Genetic variation in SLC12A5 which encodes KCC2, the neuron‐specific cation‐chloride cotransporter that is essential for hyperpolarizing GABAergic signaling and formation of cortical dendritic spines, has not been reported in human disease. Screening of SLC12A5 revealed a co‐segregating variant (KCC2‐R952H) in an Australian family with febrile seizures. We show that KCC2‐R952H reduces neuronal Cl− extrusion and has a compromised ability to induce dendritic spines in vivo and in vitro. Biochemical analyses indicate a reduced surface expression of KCC2‐R952H which likely contributes to the functional deficits. Our data suggest that KCC2‐R952H is a bona fide susceptibility variant for febrile seizures.Peer reviewe

A variant of KCC2 from patients with febrile seizures impairs neuronal Cl- extrusion and dendritic spine formation

Genetic variation in SLC12A5 which encodes KCC2, the neuron‐specific cation‐chloride cotransporter that is essential for hyperpolarizing GABAergic signaling and formation of cortical dendritic spines, has not been reported in human disease. Screening of SLC12A5 revealed a co‐segregating variant (KCC2‐R952H) in an Australian family with febrile seizures. We show that KCC2‐R952H reduces neuronal Cl− extrusion and has a compromised ability to induce dendritic spines in vivo and in vitro. Biochemical analyses indicate a reduced surface expression of KCC2‐R952H which likely contributes to the functional deficits. Our data suggest that KCC2‐R952H is a bona fide susceptibility variant for febrile seizures.Peer reviewe

Effects of vaccination on onset and outcome of Dravet syndrome: a retrospective study

BackgroundPertussis 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.MethodsWe 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.FindingsDates 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.InterpretationVaccination 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.Anne M McIntosh, Jacinta McMahon, Leanne M Dibbens, Xenia Iona, John C Mulley, Ingrid E Scheffer, Samuel F Berkovi

Role of the sodium channel SCN9A in genetic epilepsy with febrile seizures plus and Dravet syndrome

Mutations of the SCN1A subunit of the sodium channel is a cause of genetic epilepsy with febrile seizures plus (GEFS+) in multiplex families and accounts for 70–80% of Dravet syndrome (DS). DS cases without SCN1A mutation inherited have predicted SCN9A susceptibility variants, which may contribute to complex inheritance for these unexplained cases of DS. Compared with controls, DS cases were significantly enriched for rare SCN9A genetic variants. None of the multiplex febrile seizure or GEFS+ families could be explained by highly penetrant SCN9A mutations.

De-novo mutations of the sodium channel gene SCN1A in alleged vaccine encephalopathy: a retrospective study

Copyright © 2006 Elsevier Ltd All rights reserved.BackgroundVaccination, particularly for pertussis, has been implicated as a direct cause of an encephalopathy with refractory seizures and intellectual impairment. We postulated that cases of so-called vaccine encephalopathy could have mutations in the neuronal sodium channel alpha1 subunit gene (SCN1A) because of a clinical resemblance to severe myoclonic epilepsy of infancy (SMEI) for which such mutations have been identified.MethodsWe retrospectively studied 14 patients with alleged vaccine encephalopathy in whom the first seizure occurred within 72 h of vaccination. We reviewed the relation to vaccination from source records and assessed the specific epilepsy phenotype. Mutations in SCN1A were identified by PCR amplification and denaturing high performance liquid chromatography analysis, with subsequent sequencing. Parental DNA was examined to ascertain the origin of the mutation.FindingsSCN1A mutations were identified in 11 of 14 patients with alleged vaccine encephalopathy; a diagnosis of a specific epilepsy syndrome was made in all 14 cases. Five mutations predicted truncation of the protein and six were missense in conserved regions of the molecule. In all nine cases where parental DNA was available the mutations arose de novo. Clinical-molecular correlation showed mutations in eight of eight cases with phenotypes of SMEI, in three of four cases with borderline SMEI, but not in two cases with Lennox-Gastaut syndrome.InterpretationCases of alleged vaccine encephalopathy could in fact be a genetically determined epileptic encephalopathy that arose de novo. These findings have important clinical implications for diagnosis and management of encephalopathy and, if confirmed in other cohorts, major societal implications for the general acceptance of vaccination.Samuel F Berkovic, Louise Harkin, Jacinta M McMahon, James T Pelekanos, Sameer M Zuberi, Elaine C Wirrell, Deepak S Gill, Xenia Iona, John C Mulley and Ingrid E Schefferhttp://www.elsevier.com/wps/find/journaldescription.cws_home/622235/description#descriptio

Mutations in DEPDC5 cause Familial Focal Epilepsy with Variable Foci and are a common cause of familial non-lesional focal epilepsy

OBJECTIVE: To identify the genetic cause of autosomal dominant Familial Focal Epilepsy with Variable Foci (FFEVF), to investigate the prevalence of mutations in the FFEVF causative gene in familial cases of non-lesional focal epilepsy, to study the expression in the brain and the subcellular localization of the encoded protein. BACKGROUND: FFEVF is characterized by seizures arising from different cortical regions in different affected family members. Brain imaging is normal. Seizure onset varies from infancy to adult life. Affected individuals occasionally have neuropsychiatric co-morbidities. Linkage studies mapped FFEVF to chromosome 22q12, but the causative gene had so far eluded identification. DESIGN/METHODS: We applied exome sequencing to two FFEVF families previously linked to chromosome 22q12, identifying DEPDC5 as the most likely candidate gene. We sequenced DEPDC5 in six additional 22q12-linked families and scanned DEPDC5 for sequence variation in 82 unrelated probands from families with at least two individuals with non-lesional focal epilepsy. We used qRT-PCR, immunofluorescence and western blot analysis to study DEPDC5 expression and subcellular localization. RESULTS: Heterozygous mutations in DEPDC5 were identified in 7/8 FFEVF families linked to chromosome 22q12 and in 10/82 (12.2%) probands from the small families with focal epilepsy. Each DEPDC5 mutation segregated with the FFEVF phenotype in the respective family and was absent in both dbSNP135 and an in-house exome sequencing database of 710 chromosomes. Most mutations caused premature termination codons suggesting haploinsufficiency as pathogenic mechanism. DEPDC5 encodes a1604 amino acid protein of unknown function, probably implicated in modulation of intracellular signaling.Mouse Depdc5 transcripts were detected at low levels in all brain regions and throughout brain development. Immunofluorescence analyses in mouse and human brain showed specific expression in neurons and perinuclear localization. CONCLUSIONS: Our findings establish DEPDC5 mutations as the most common known cause of familial focal epilepsy and identify a novel pathogenic pathway for epilepsy

PRRT2 mutations cause benign familial infantile epilepsy and infantile convulsions with choreoathetosis syndrome

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)

The spectrum of SCNIA-related infantile epileptic encephalopathies

The relationship between severe myoclonic epilepsy of infancy (SMEI or Dravet syndrome) and the related syndrome SMEI-borderland (SMEB) with mutations in the sodium channel alpha 1 subunit gene SCN1A is well established. To explore the phenotypic variability associated with SCN1A mutations, 188 patients with a range of epileptic encephalopathies were examined for SCN1A sequence variations by denaturing high performance liquid chromatography and sequencing. All patients had seizure onset within the first 2 years of life. A higher proportion of mutations were identified in patients with SMEI (52/66; 79%) compared to patients with SMEB (25/36; 69%). By studying a broader spectrum of infantile epileptic encephalopathies, we identified mutations in other syndromes including cryptogenic generalized epilepsy (24%) and cryptogenic focal epilepsy (22%). Within the latter group, a distinctive subgroup designated as severe infantile multifocal epilepsy had SCN1A mutations in three of five cases. This phenotype is characterized by early onset multifocal seizures and later cognitive decline. Knowledge of an expanded spectrum of epileptic encephalopathies associated with SCN1A mutations allows earlier diagnostic confirmation for children with these devastating disorders.Louise A. Harkin, Jacinta M. McMahon, Xenia Iona, Leanne Dibbens, James T. Pelekanos, Sameer M. Zuberi, Lynette G. Sadleir, Eva Andermann, Deepak Gill, Kevin Farrell, Mary Connolly, Thorsten Stanley, Michael Harbord, Frederick Andermann, Jing Wang, Sat Dev Batish, Jeffrey G. Jones, William K. Seltzer, Alison Gardner, The Infantile Epileptic Encephalopathy Referral Consortium, Grant Sutherland, Samuel F. Berkovic, John C. Mulley, and Ingrid E. Scheffe