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See detailIntestinal-Cell Kinase and Juvenile Myoclonic Epilepsy.
Lerche, Holger; Berkovic, Sam F.; Lowenstein, Daniel H. et al

in New England Journal of Medicine (2019), 380(16), 24

With regard to the article by Bailey et al. (March 15, 2018, issue) on the potential role of variants in the gene encoding intestinal cell kinase (ICK) in genetic generalized epilepsies, including ... [more ▼]

With regard to the article by Bailey et al. (March 15, 2018, issue) on the potential role of variants in the gene encoding intestinal cell kinase (ICK) in genetic generalized epilepsies, including juvenile myoclonic epilepsy: We attempted replication by rechecking for enrichment of ICK variants in two previously published analyses of mainly familial cases of genetic generalized epilepsy, which included a total of 1149 cases of genetic generalized epilepsy and 5911 ethnically matched controls. We analyzed the burden of single-gene rare variants with the use of whole exome sequencing data, applying population stratification and both sample and variant quality control. We found no evidence of an enrichment of ICK variants in genetic generalized epilepsies or juvenile myoclonic epilepsy. Specifically, we did not detect a nonsynonymous variant in 357 persons with juvenile myoclonic epilepsy at a minor allele frequency at or below 0.1%. Although we cannot exclude the possibility that ICK variants may be population-specific risk factors for juvenile myoclonic epilepsy, the lack of validation in our cohorts does not support a true disease association but rather suggests that the authors’ results may be due to chance, possibly owing to methodologic issues (see the Supplementary Appendix, available with the full text of this letter at NEJM.org). [less ▲]

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See detailClinical spectrum of STX1B-related epileptic disorders
Wolking, Stefan; May, Patrick UL; Mei, Davide et al

in Neurology (2019), 92

Objective: The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B, encoding the presynaptic protein syntaxin-1B, and to establish genotype-phenotype correlations by ... [more ▼]

Objective: The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B, encoding the presynaptic protein syntaxin-1B, and to establish genotype-phenotype correlations by identifying further disease-related variants. Methods: We used next generation sequencing in the framework of research projects and diagnostic testing. Clinical data and EEGs were reviewed, including already published cases. To estimate the pathogenicity of the variants, we used established and newly developed in silico prediction tools. Results: We describe fifteen new variants in STX1B which are distributed across the whole gene. We discerned four different phenotypic groups across the newly identified and previously published patients (49 in 23 families): 1) Six sporadic patients or families (31 affected individuals) with febrile and afebrile seizures with a benign course, generally good drug response, normal development and without permanent neurological deficits; 2) two patients of genetic generalized epilepsy without febrile seizures and cognitive deficits; 3) thirteen patients or families with intractable seizures, developmental regression after seizure onset and additional neuropsychiatric symptoms; 4) two patients with focal epilepsy. Nonsense mutations were found more often in benign syndromes, whereas missense variants in the SNARE motif of syntaxin-1B were associated with more severe phenotypes. Conclusion: These data expand the genetic and phenotypic spectrum of STX1B-related epilepsies to a diverse range of epilepsies that span the ILAE classification. Variants in STX1B are protean, and able to contribute to many different epilepsy phenotypes, similar to SCN1A, the most important gene associated with fever-associated epilepsies. [less ▲]

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See detailSpectrum of GABAA receptor variants in epilepsy
Maljevic, Snezana; Møller, Rikke S.; Reid, Christopher A. et al

in Current Opinion in Neurology (2019)

Purpose of review: Recent publications point to an increasingly important role of variants in genes encoding GABAA receptor subunits associated with both common and rare forms of epilepsies. The aim of ... [more ▼]

Purpose of review: Recent publications point to an increasingly important role of variants in genes encoding GABAA receptor subunits associated with both common and rare forms of epilepsies. The aim of this review is to give an overview of the current clinical phenotypes, genetic findings and pathophysiological mechanisms related to GABAA receptor variants. Recent findings: Early work showed that inherited variants in GABRG2 and GABRA1 cause relatively mild forms of monogenic epilepsies in large families. More recent studies have revealed that de novo variants in several GABAA receptor genes cause severe developmental and epileptic encephalopathies, inherited variants cause remarkably variable phenotypes within the same pedigrees ranging from asymptomatic carriers to developmental and epileptic encephalopathies, and variants in all GABAA receptor genes are enriched in common forms of epilepsy, namely rolandic epilepsy and genetic generalized epilepsy. Analyses from cellular expression systems and mouse models suggest that all variants cause a loss of GABAA receptor function resulting in GABAergic disinhibition. Summary: Genetic studies have revealed a crucial role of the GABAergic system in the underlying pathogenesis of various forms of common and rare epilepsies. Our understanding of functional consequences of GABAA receptor variants provide an opportunity to develop precision-based therapeutic strategies that are hopefully free from the side-effect burden seen with currently available GABAergic drugs. [less ▲]

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See detailRare gene deletions in genetic generalized and Rolandic epilepsies
Jabbari, Kamel; Bobbili, Dheeraj Reddy UL; Lal, Dennis et al

in PLoS ONE (2018)

Genetic Generalized Epilepsy (GGE) and benign epilepsy with centro-temporal spikes or Rolandic Epilepsy (RE) are common forms of genetic epilepsies. Rare copy number variants have been recognized as ... [more ▼]

Genetic Generalized Epilepsy (GGE) and benign epilepsy with centro-temporal spikes or Rolandic Epilepsy (RE) are common forms of genetic epilepsies. Rare copy number variants have been recognized as important risk factors in brain disorders. We performed a systematic survey of rare deletions affecting protein-coding genes derived from exome data of patients with common forms of genetic epilepsies. We analysed exomes from 390 European patients (196 GGE and 194 RE) and 572 population controls to identify low-frequency genic deletions. We found that 75 (32 GGE and 43 RE) patients out of 390, i.e. ~19%, carried rare genic deletions. In particular, large deletions (>400 kb) represent a higher burden in both GGE and RE syndromes as compared to controls. The detected low-frequency deletions (1) share genes with brain-expressed exons that are under negative selection, (2) overlap with known autism and epilepsy-associated candidate genes, (3) are enriched for CNV intolerant genes recorded by the Exome Aggregation Consortium (ExAC) and (4) coincide with likely disruptive de novo mutations from the NPdenovo database. Employing several knowledge databases, we discuss the most prominent epilepsy candidate genes and their protein-protein networks for GGE and RE. [less ▲]

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See detailRare coding variants in genes encoding GABAA receptors in genetic generalised epilepsies: an exome-based case-control study
May, Patrick UL; Girard, Simon; Harrer, Merle et al

in Lancet Neurology (2018), 17(8), 699-708

Background Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We ... [more ▼]

Background Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy. Methods For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABAA receptors and was compared to the respective GABAA receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes. Findings Statistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABAA receptors in cases (odds ratio [OR] 2·40 [95% CI 1·41–4·10]; pNonsyn=0·0014, adjusted pNonsyn=0·019). Enrichment for these genes was validated in a whole-exome sequencing cohort of 357 sporadic and familial genetic generalised epilepsy cases and 1485 independent controls (OR 1·46 [95% CI 1·05–2·03]; pNonsyn=0·0081, adjusted pNonsyn=0·016). Comparison of genes encoding GABAA receptors in the independent replication cohort of 583 familial and sporadic genetic generalised epilepsy index cases, based on candidate-gene panel sequencing, with a third independent control cohort of 635 controls confirmed the overall enrichment of rare missense variants for 15 GABAA receptor genes in cases compared with controls (OR 1·46 [95% CI 1·02–2·08]; pNonsyn=0·013, adjusted pNonsyn=0·027). Functional studies for two selected genes (GABRB2 and GABRA5) showed significant loss-of-function effects with reduced current amplitudes in four of seven tested variants compared with wild-type receptors. Interpretation Functionally relevant variants in genes encoding GABAA receptor subunits constitute a significant risk factor for genetic generalised epilepsy. Examination of the role of specific gene groups and pathways can disentangle the complex genetic architecture of genetic generalised epilepsy. [less ▲]

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See detailExome-wide analysis of mutational burden in patients with typical and atypical Rolandic Epilepsy
Bobbili, Dheeraj Reddy UL; Lal, Dennis; May, Patrick UL et al

in European Journal of Human Genetics (2018)

Rolandic Epilepsy (RE) is the most common focal epilepsy in childhood. To date no hypothesis-free exome-wide mutational screen has been conducted for RE and Atypical RE (ARE). Here we report on whole ... [more ▼]

Rolandic Epilepsy (RE) is the most common focal epilepsy in childhood. To date no hypothesis-free exome-wide mutational screen has been conducted for RE and Atypical RE (ARE). Here we report on whole-exome sequencing of 194 unrelated patients with RE/ARE and 567 ethnically matched population controls. We identified an exome-wide significantly enriched burden for deleterious and loss-of-function variants only for the established RE/ARE gene GRIN2A. The statistical significance of the enrichment disappeared after removing ARE patients. For several disease-related gene-sets, an odds ratio > 1 was detected for loss-of-function variants. [less ▲]

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See detailGenetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients.
McCormack, Mark; Gui, Hongsheng; Ingason, Andres et al

in Neurology (2017)

OBJECTIVE: To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs. METHODS ... [more ▼]

OBJECTIVE: To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs. METHODS: We conducted a case-control genome-wide association study of autosomal genotypes, including Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent. Results from each cohort were meta-analyzed. RESULTS: We report an association between a rare variant in the complement factor H-related 4 (CFHR4) gene and phenytoin-induced MPE in Europeans (p = 4.5 x 10(-11); odds ratio [95% confidence interval] 7 [3.2-16]). This variant is in complete linkage disequilibrium with a missense variant (N1050Y) in the complement factor H (CFH) gene. In addition, our results reinforce the association between HLA-A*31:01 and carbamazepine hypersensitivity. We did not identify significant genetic associations with MPE among Han Chinese patients. CONCLUSIONS: The identification of genetic predictors of MPE in CFHR4 and CFH, members of the complement factor H-related protein family, suggest a new link between regulation of the complement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients. [less ▲]

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See detailRare GABRA3 variants are associated with epileptic seizures, encephalopathy and dysmorphic features
Niturad, Elena Christina; Lev, Dorit; Kalscheuer, Vera M et al

in Brain : A Journal of Neurology (2017), 140(11), 2879-2894

Genetic epilepsies are caused by mutations in a range of different genes, many of them encoding ion channels, receptors or transporters. While the number of detected variants and genes increased ... [more ▼]

Genetic epilepsies are caused by mutations in a range of different genes, many of them encoding ion channels, receptors or transporters. While the number of detected variants and genes increased dramatically in the recent years, pleiotropic effects have also been recognized, revealing that clinical syndromes with various degrees of severity arise from a single gene, a single mutation, or from different mutations showing similar functional defects. Accordingly, several genes coding for GABAA receptor subunits have been linked to a spectrum of benign to severe epileptic disorders and it was shown that a loss of function presents the major correlated pathomechanism. Here, we identified six variants in GABRA3 encoding the α3-subunit of the GABAA receptor. This gene is located on chromosome Xq28 and has not been previously associated with human disease. Five missense variants and one microduplication were detected in four families and two sporadic cases presenting with a range of epileptic seizure types, a varying degree of intellectual disability and developmental delay, sometimes with dysmorphic features or nystagmus. The variants co-segregated mostly but not completely with the phenotype in the families, indicating in some cases incomplete penetrance, involvement of other genes, or presence of phenocopies. Overall, males were more severely affected and there were three asymptomatic female mutation carriers compared to only one male without a clinical phenotype. X-chromosome inactivation studies could not explain the phenotypic variability in females. Three detected missense variants are localized in the extracellular GABA-binding NH2-terminus, one in the M2-M3 linker and one in the M4 transmembrane segment of the α3-subunit. Functional studies in Xenopus laevis oocytes revealed a variable but significant reduction of GABA-evoked anion currents for all mutants compared to wild-type receptors. The degree of current reduction correlated partially with the phenotype. The microduplication disrupted GABRA3 expression in fibroblasts of the affected patient. In summary, our results reveal that rare loss-of-function variants in GABRA3 increase the risk for a varying combination of epilepsy, intellectual disability/developmental delay and dysmorphic features, presenting in some pedigrees with an X-linked inheritance pattern. [less ▲]

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See detailAlterations in the α2δ ligand, thrombospondin-1, in a rat model of spontaneous absence epilepsy and in patients with idiopathic/genetic generalized epilepsies
Santolini, Ines; Celli, Roberta; Cannella, Milena et al

in Epilepsia (2017)

OBJECTIVES: Thrombospondins, which are known to interact with the α2 δ subunit of voltage-sensitive calcium channels to stimulate the formation of excitatory synapses, have recently been implicated in the ... [more ▼]

OBJECTIVES: Thrombospondins, which are known to interact with the α2 δ subunit of voltage-sensitive calcium channels to stimulate the formation of excitatory synapses, have recently been implicated in the process of epileptogenesis. No studies have been so far performed on thrombospondins in models of absence epilepsy. We examined whether expression of the gene encoding for thrombospondin-1 was altered in the brain of WAG/Rij rats, which model absence epilepsy in humans. In addition, we examined the frequency of genetic variants of THBS1 in a large cohort of children affected by idiopathic/genetic generalized epilepsies (IGE/GGEs). METHODS: We measured the transcripts of thrombospondin-1 and α2 δ subunit, and protein levels of α2 δ, Rab3A, and the vesicular glutamate transporter, VGLUT1, in the somatosensory cortex and ventrobasal thalamus of presymptomatic and symptomatic WAG/Rij rats and in two control strains by real-time polymerase chain reaction (PCR) and immunoblotting. We examined the genetic variants of THBS1 and CACNA2D1 in two independent cohorts of patients affected by IGE/GGE recruited through the Genetic Commission of the Italian League Against Epilepsy (LICE) and the EuroEPINOMICS-CoGIE Consortium. RESULTS: Thrombospondin-1 messenger RNA (mRNA) levels were largely reduced in the ventrobasal thalamus of both presymptomatic and symptomatic WAG/Rij rats, whereas levels in the somatosensory cortex were unchanged. VGLUT1 protein levels were also reduced in the ventrobasal thalamus of WAG/Rij rats. Genetic variants of THBS1 were significantly more frequent in patients affected by IGE/GGE than in nonepileptic controls, whereas the frequency of CACNA2D1 was unchanged. SIGNIFICANCE: These findings suggest that thrombospondin-1 may have a role in the pathogenesis of IGE/GGEs. [less ▲]

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See detailComparative effectiveness of antiepileptic drugs in patients with mesial temporal lobe epilepsy with hippocampal sclerosis
Androsova, Ganna UL; Krause, Roland UL; Borghei, Mojgansadat et al

in Epilepsia (2017)

Objective: Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is a common epilepsy syndrome that is often poorly controlled by antiepileptic drug (AED) treatment. Comparative AED ... [more ▼]

Objective: Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is a common epilepsy syndrome that is often poorly controlled by antiepileptic drug (AED) treatment. Comparative AED effectiveness studies in this condition are lacking. Wereport retention, efficacy, and tolerability in a cohort of patients with MTLE-HS. Methods: Clinical data were collected from a European database of patients with epilepsy. We estimated retention, 12-month seizure freedom, and adverse drug reaction (ADR) rates for the 10 most commonly used AEDs in patients with MTLE-HS. Results: Seven hundred sixty-seven patients with a total of 3,249 AED trials were included. The highest 12-month retention rates were observed with carbamazepine (85.9%), valproate (85%), and clobazam (79%). Twelve-month seizure freedom rates varied from 1.2% for gabapentin and vigabatrin to 11% for carbamazepine. Response rates were highest for AEDs that were prescribed as initial treatment and lowest for AEDs that were used in a third or higher instance. ADRs were reported in 47.6% of patients, with the highest rates observed with oxcarbazepine (35.7%), topiramate (30.9%), and pregabalin (27.4%), and the lowest rates with clobazam (6.5%), gabapentin (8.9%), and lamotrigine (16.6%). The most commonly reported ADRs were lethargy and drowsiness, dizziness, vertigo and ataxia, and blurred vision and diplopia. Significance: Our results did not demonstrate any clear advantage of newer versus older AEDs. Our results provide useful insights into AED retention, efficacy, and ADR rates in patients with MTLE-HS. [less ▲]

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See detailApplication of rare variant transmission disequilibrium tests to epileptic encephalopathy trio sequence data
Allen, Andrew S.; Berkovic, Samuel F.; Bridgers, Joshua et al

in European Journal of Human Genetics (2017)

The classic epileptic encephalopathies, including infantile spasms (IS) and Lennox–Gastaut syndrome (LGS), are severe seizure disorders that usually arise sporadically. De novo variants in genes mainly ... [more ▼]

The classic epileptic encephalopathies, including infantile spasms (IS) and Lennox–Gastaut syndrome (LGS), are severe seizure disorders that usually arise sporadically. De novo variants in genes mainly encoding ion channel and synaptic proteins have been found to account for over 15% of patients with IS or LGS. The contribution of autosomal recessive genetic variation, however, is less well understood. We implemented a rare variant transmission disequilibrium test (TDT) to search for autosomal recessive epileptic encephalopathy genes in a cohort of 320 outbred patient–parent trios that were generally prescreened for rare metabolic disorders. In the current sample, our rare variant transmission disequilibrium test did not identify individual genes with significantly distorted transmission over expectation after correcting for the multiple tests. While the rare variant transmission disequilibrium test did not find evidence of a role for individual autosomal recessive genes, our current sample is insufficiently powered to assess the overall role of autosomal recessive genotypes in an outbred epileptic encephalopathy population. [less ▲]

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See detailDe Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies.
Appenzeller, Silke; Balling, Rudi UL; Barisic, Nina et al

in American Journal of Human Genetics (2017), 100(1), 179-

In the list of consortium members for the Epilepsy Phenome/Genome Project, member Dina Amrom’s name was misspelled as Amron. The authors regret the error.

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See detailEvaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes
Lal, Dennis; Reinthaler, Eva; Dejanovic et al

in PLoS ONE (2016)

Objective The SCN1A gene, coding for the voltage-gated Na+ channel alpha subunit NaV1.1, is the clinically most relevant epilepsy gene. With the advent of high-throughput next-generation sequencing ... [more ▼]

Objective The SCN1A gene, coding for the voltage-gated Na+ channel alpha subunit NaV1.1, is the clinically most relevant epilepsy gene. With the advent of high-throughput next-generation sequencing, clinical laboratories are generating an ever-increasing catalogue of SCN1A variants. Variants are more likely to be classified as pathogenic if they have already been identified previously in a patient with epilepsy. Here, we critically re-evaluate the pathogenicity of this class of variants in a cohort of patients with common epilepsy syndromes and subsequently ask whether a significant fraction of benign variants have been misclassified as pathogenic. Methods We screened a discovery cohort of 448 patients with a broad range of common genetic epilepsies and 734 controls for previously reported SCN1A mutations that were assumed to be disease causing. We re-evaluated the evidence for pathogenicity of the identified variants using in silico predictions, segregation, original reports, available functional data and assessment of allele frequencies in healthy individuals as well as in a follow up cohort of 777 patients. Results and Interpretation We identified 8 known missense mutations, previously reported as pathogenic, in a total of 17 unrelated epilepsy patients (17/448; 3.80%). Our re-evaluation indicates that 7 out of these 8 variants (p.R27T; p.R28C; p.R542Q; p.R604H; p.T1250M; p.E1308D; p.R1928G; NP_001159435.1) are not pathogenic. Only the p.T1174S mutation may be considered as a genetic risk factor for epilepsy of small effect size based on the enrichment in patients (P = 6.60 x 10−4; OR = 0.32, fishers exact test), previous functional studies but incomplete penetrance. Thus, incorporation of previous studies in genetic counseling of SCN1A sequencing results is challenging and may produce incorrect conclusions. [less ▲]

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See detailRecessive mutations in SLC13A5 result in a loss of citrate transport and cause neonatal epilepsy, developmental delay and teeth hypoplasia
Hardies, Katia; de Kovel, Carolien G.F.; Weckhuysen, Sarah et al

in Brain : A Journal of Neurology (2015)

The epileptic encephalopathies are a clinically and aetiologically heterogeneous subgroup of epilepsy syndromes. Most epileptic encephalopathies have a genetic cause and patients are often found to carry ... [more ▼]

The epileptic encephalopathies are a clinically and aetiologically heterogeneous subgroup of epilepsy syndromes. Most epileptic encephalopathies have a genetic cause and patients are often found to carry a heterozygous de novo mutation in one of the genes associated with the disease entity. Occasionally recessive mutations are identified: a recent publication described a distinct neonatal epileptic encephalopathy (MIM 615905) caused by autosomal recessive mutations in the SLC13A5 gene. Here, we report eight additional patients belonging to four different families with autosomal recessive mutations in SLC13A5. SLC13A5 encodes a high affinity sodium-dependent citrate transporter, which is expressed in the brain. Neurons are considered incapable of de novo synthesis of tricarboxylic acid cycle intermediates; therefore they rely on the uptake of intermediates, such as citrate, to maintain their energy status and neurotransmitter production. The effect of all seven identified mutations (two premature stops and five amino acid substitutions) was studied in vitro, using immunocytochemistry, selective western blot and mass spectrometry. We hereby demonstrate that cells expressing mutant sodium-dependent citrate transporter have a complete loss of citrate uptake due to various cellular loss-of-function mechanisms. In addition, we provide independent proof of the involvement of autosomal recessive SLC13A5 mutations in the development of neonatal epileptic encephalopathies, and highlight teeth hypoplasia as a possible indicator for SLC13A5 screening. All three patients who tried the ketogenic diet responded well to this treatment, and future studies will allow us to ascertain whether this is a recurrent feature in this severe disorder. [less ▲]

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See detailDe novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy
Syrbe, Steffen; Hedrich, Ulrike B.S.; Riesch, Erik et al

in Nature Genetics (2015), 47(4), 393-9

Epileptic encephalopathies are a phenotypically and genetically heterogeneous group of severe epilepsies accompanied by intellectual disability and other neurodevelopmental features1–6. Using next ... [more ▼]

Epileptic encephalopathies are a phenotypically and genetically heterogeneous group of severe epilepsies accompanied by intellectual disability and other neurodevelopmental features1–6. Using next-generation sequencing, we identified four different de novo mutations in KCNA2, encoding the potassium channel KV1.2, in six patients with epileptic encephalopathy (one mutation recurred three times independently). Four individuals presented with febrile and multiple afebrile, often focal seizure types, multifocal epileptiform discharges strongly activated by sleep, mild to moderate intellectual disability, delayed speech development and sometimes ataxia. Functional studies of the two mutations associated with this phenotype showed almost complete loss of function with a dominant-negative effect. Two further individuals presented with a different and more severe epileptic encephalopathy phenotype. They carried mutations inducing a drastic gain-of-function effect leading to permanently open channels. These results establish KCNA2 as a new gene involved in human neurodevelopmental disorders through two different mechanisms, predicting either hyperexcitability or electrical silencing of KV1.2-expressing neurons. [less ▲]

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See detailCHD2 myoclonic encephalopathy is frequently associated with self-induced seizures
Thomas, Rhys H.; Zhang, Lin Mei; Carvill, Gemma L. et al

in Neurology (2015), 84(9), 951-958

Objective: To delineate the phenotype of early childhood epileptic encephalopathy due to de novo mutations of CHD2, which encodes the chromodomain helicase DNA binding protein 2. Methods: We analyzed the ... [more ▼]

Objective: To delineate the phenotype of early childhood epileptic encephalopathy due to de novo mutations of CHD2, which encodes the chromodomain helicase DNA binding protein 2. Methods: We analyzed the medical history, MRI, and video-EEG recordings of 9 individuals with de novo CHD2 mutations and one with a de novo 15q26 deletion encompassing CHD2. Results: Seizures began at a mean of 26 months (12–42) with myoclonic seizures in all 10 cases. Seven exhibited exquisite clinical photosensitivity; 6 self-induced with the television. Absence seizures occurred in 9 patients including typical (4), atypical (2), and absence seizures with eyelid myoclonias (4). Generalized tonic-clonic seizures occurred in 9 of 10 cases with a mean onset of 5.8 years. Convulsive and nonconvulsive status epilepticus were later features (6/10, mean onset 9 years). Tonic (40%) and atonic (30%) seizures also occurred. In 3 cases, an unusual seizure type, the atonic-myoclonic-absence was captured on video. A phenotypic spectrum was identified with 7 cases having moderate to severe intellectual disability and refractory seizures including tonic attacks. Their mean age at onset was 23 months. Three cases had a later age at onset (34 months) with relative preservation of intellect and an initial response to antiepileptic medication. Conclusion: The phenotypic spectrum of CHD2 encephalopathy has distinctive features of myoclonic epilepsy, marked clinical photosensitivity, atonic-myoclonic-absence, and intellectual disability ranging from mild to severe. Recognition of this genetic entity will permit earlier diagnosis and enable the development of targeted therapies. [less ▲]

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See detailInvestigation of GRIN2A in common epilepsy phenotypes.
Lal, Dennis; Steinbrucker, Sandra; Schubert, Julian et al

in Epilepsy research (2015), 115

Recently, mutations and deletions in the GRIN2A gene have been identified to predispose to benign and severe idiopathic focal epilepsies (IFE), revealing a higher incidence of GRIN2A alterations among the ... [more ▼]

Recently, mutations and deletions in the GRIN2A gene have been identified to predispose to benign and severe idiopathic focal epilepsies (IFE), revealing a higher incidence of GRIN2A alterations among the more severe phenotypes. This study aimed to explore the phenotypic boundaries of GRIN2A mutations by investigating patients with the two most common epilepsy syndromes: (i) idiopathic generalized epilepsy (IGE) and (ii) temporal lobe epilepsy (TLE). Whole exome sequencing data of 238 patients with IGE as well as Sanger sequencing of 84 patients with TLE were evaluated for GRIN2A sequence alterations. Two additional independent cohorts comprising 1469 IGE and 330 TLE patients were screened for structural deletions (>40kb) involving GRIN2A. Apart from a presumably benign, non-segregating variant in a patient with juvenile absence epilepsy, neither mutations nor deletions were detected in either cohort. These findings suggest that mutations in GRIN2A preferentially are involved in genetic variance of pediatric IFE and do not contribute significantly to either adult focal epilepsies as TLE or generalized epilepsies. [less ▲]

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See detailCHD2 variants are a risk factor for photosensitivity in epilepsy
Galizia, Elizabeth C.; Myers, Candace T.; Leu, Costin et al

in Brain (2015)

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See detailMutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes
Schubert, Julian; Siekierska, Aleksandra; Langlois, Melanie UL et al

in Nature Genetics (2014), 46(12), 1327-32

Febrile seizures affect 2–4% of all children1 and have a strong genetic component2. Recurrent mutations in three main genes (SCN1A, SCN1B and GABRG2)3, 4, 5 have been identified that cause febrile ... [more ▼]

Febrile seizures affect 2–4% of all children1 and have a strong genetic component2. Recurrent mutations in three main genes (SCN1A, SCN1B and GABRG2)3, 4, 5 have been identified that cause febrile seizures with or without epilepsy. Here we report the identification of mutations in STX1B, encoding syntaxin-1B6, that are associated with both febrile seizures and epilepsy. Whole-exome sequencing in independent large pedigrees7, 8 identified cosegregating STX1B mutations predicted to cause an early truncation or an in-frame insertion or deletion. Three additional nonsense or missense mutations and a de novo microdeletion encompassing STX1B were then identified in 449 familial or sporadic cases. Video and local field potential analyses of zebrafish larvae with antisense knockdown of stx1b showed seizure-like behavior and epileptiform discharges that were highly sensitive to increased temperature. Wild-type human syntaxin-1B but not a mutated protein rescued the effects of stx1b knockdown in zebrafish. Our results thus implicate STX1B and the presynaptic release machinery in fever-associated epilepsy syndromes. [less ▲]

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See detailDe Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies
Appenzeller, Silke; Balling, Rudi UL; Barisic, Nina et al

in American Journal of Human Genetics (2014), 4

Emerging evidence indicates that epileptic encephalopathies are genetically highly heterogeneous, underscoring the need for large cohorts of well-characterized individuals to further define the genetic ... [more ▼]

Emerging evidence indicates that epileptic encephalopathies are genetically highly heterogeneous, underscoring the need for large cohorts of well-characterized individuals to further define the genetic landscape. Through a collaboration between two consortia (EuroEPINOMICS and Epi4K/EPGP), we analyzed exome-sequencing data of 356 trios with the “classical” epileptic encephalopathies, infantile spasms and Lennox Gastaut syndrome, including 264 trios previously analyzed by the Epi4K/EPGP consortium. In this expanded cohort, we find 429 de novo mutations, including de novo mutations in DNM1 in five individuals and de novo mutations in GABBR2, FASN, and RYR3 in two individuals each. Unlike previous studies, this cohort is sufficiently large to show a significant excess of de novo mutations in epileptic encephalopathy probands compared to the general population using a likelihood analysis (p = 8.2 × 10−4), supporting a prominent role for de novo mutations in epileptic encephalopathies. We bring statistical evidence that mutations in DNM1 cause epileptic encephalopathy, find suggestive evidence for a role of three additional genes, and show that at least 12% of analyzed individuals have an identifiable causal de novo mutation. Strikingly, 75% of mutations in these probands are predicted to disrupt a protein involved in regulating synaptic transmission, and there is a significant enrichment of de novo mutations in genes in this pathway in the entire cohort as well. These findings emphasize an important role for synaptic dysregulation in epileptic encephalopathies, above and beyond that caused by ion channel dysfunction. [less ▲]

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