Publications by authors named "Holger Lerche"

212 Publications

Genetics of Paroxysmal Dyskinesia: Novel Variants Corroborate the Role of in Paroxysmal Dyskinesia and Highlight the Diverse Phenotypic Spectrum of - and -Related Disorders.

Front Neurol 2021 8;12:701351. Epub 2021 Jul 8.

Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.

Paroxysmal dyskinesias (PxD) are rare movement disorders with characteristic episodes of involuntary mixed hyperkinetic movements. Scientific efforts and technical advances in molecular genetics have led to the discovery of a variety of genes associated with PxD; however, clinical and genetic information of rarely affected genes or infrequent variants is often limited. In our case series, we present two individuals with PxD including one with classical paroxysmal kinesigenic dyskinesia, who carry new likely pathogenic variants in (p.Gly396Val and p.Gly396Arg). The gene has only recently been discovered to be causative for familial paroxysmal kinesigenic dyskinesia. We also provide genetic evidence for pathogenicity of two newly identified disease-causing variants in (p.Met96Thr and p.Leu231Pro) leading to paroxysmal exercise-induced dyskinesia. Since clinical information of carriers of variants in known disease-causing genes is often scarce, we encourage to share clinical data of individuals with rare or novel (likely) pathogenic variants to improve disease understanding.
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http://dx.doi.org/10.3389/fneur.2021.701351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297685PMC
July 2021

Optically pumped magnetometers reveal fasciculations non-invasively.

Clin Neurophysiol 2021 Jul 1. Epub 2021 Jul 1.

Children's Hospital of Eastern Switzerland, Sankt Gallen, Switzerland.

Objective: This proof-of-principle-study evaluated the extent to which spontaneous activity (SA) of the muscle can be detected via non-invasive magnetomyography (MMG) with optically pumped magnetometers (OPM).

Methods: Five patients, who together exhibited all forms of SA (fibrillations, positive sharp waves, fasciculations, myotonic discharges, complex-repetitive discharges) with conventional needle electromyography (EMG), were studied by OPM-MMG and simultaneous surface EMG (sEMG) while at rest, during light muscle activation, and when a muscle stretch reflex was elicited. Three healthy subjects were measured as controls. SA was considered apparent in the OPM-MMG if a signal could be visually detected that corresponded in shape and frequency to the SA in the respective needle EMG.

Results: SA in the context of fasciculations could be detected in 2 of 5 patients by simultaneous OPM-MMG/sEMG. Other forms of SA could not be detected at rest, during light muscle activation, or after provocation of a muscle stretch reflex.

Conclusions: Results show that fasciculations could be detected non-invasively via a new method (OPM).

Significance: We show that other forms of SA are not detectable with current OPM and propose necessary technical solutions to overcome this circumstance. Our results motivate to pursue OPM-MMG as a new clinical neurophysiological diagnostic.
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http://dx.doi.org/10.1016/j.clinph.2021.06.009DOI Listing
July 2021

KCND2 variants associated with global developmental delay differentially impair Kv4.2 channel gating.

Hum Mol Genet 2021 Jul 10. Epub 2021 Jul 10.

Institute for Cellular and Integrative Physiology, Center for Experimental Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany.

Here, we report on six unrelated individuals, all presenting with early-onset global developmental delay, associated with impaired motor, speech and cognitive development, partly with developmental epileptic encephalopathy and physical dysmorphisms. All individuals carry heterozygous missense variants of KCND2, which encodes the voltage-gated potassium (Kv) channel α-subunit Kv4.2. The amino acid substitutions associated with the variants, p.(Glu323Lys) (E323K), p.(Pro403Ala) (P403A), p.(Val404Leu) (V404L) and p.(Val404Met) (V404M), affect sites known to be critical for channel gating. To unravel their likely pathogenicity, recombinant mutant channels were studied in the absence and presence of auxiliary β-subunits under two-electrode voltage-clamp in Xenopus oocytes. All channel mutants exhibited slowed and incomplete macroscopic inactivation, and the P403A variant in addition slowed activation. Co-expression of KChIP2 or DPP6 augmented the functional expression of both wild-type and mutant channels, however, the auxiliary β-subunit-mediated gating modifications differed from wild-type and among mutants. To simulate the putative setting in the affected individuals, heteromeric Kv4.2 channels (wild-type + mutant) were studied as ternary complexes (containing both KChIP2 and DPP6). In the heteromeric ternary configuration, the E323K variant exhibited only marginal functional alterations compared to homomeric wild-type ternary, compatible with mild loss-of-function. By contrast, the P403A, V404L and V404M variants displayed strong gating impairment in the heteromeric ternary configuration, compatible with loss or gain-of-function. Our results support the etiological involvement of Kv4.2 channel gating impairment in early-onset monogenic global developmental delay. In addition, they suggest that gain-of-function mechanisms associated with a substitution of V404 increase epileptic seizure susceptibility.
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http://dx.doi.org/10.1093/hmg/ddab192DOI Listing
July 2021

Role of Common Genetic Variants for Drug-Resistance to Specific Anti-Seizure Medications.

Front Pharmacol 2021 9;12:688386. Epub 2021 Jun 9.

Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.

Resistance to anti-seizure medications (ASMs) presents a significant hurdle in the treatment of people with epilepsy. Genetic markers for resistance to individual ASMs could support clinicians to make better-informed choices for their patients. In this study, we aimed to elucidate whether the response to individual ASMs was associated with common genetic variation. A cohort of 3,649 individuals of European descent with epilepsy was deeply phenotyped and underwent single nucleotide polymorphism (SNP)-genotyping. We conducted genome-wide association analyses (GWASs) on responders to specific ASMs or groups of functionally related ASMs, using non-responders as controls. We performed a polygenic risk score (PRS) analyses based on risk variants for epilepsy and neuropsychiatric disorders and ASM resistance itself to delineate the polygenic burden of ASM-specific drug resistance. We identified several potential regions of interest but did not detect genome-wide significant loci for ASM-specific response. We did not find polygenic risk for epilepsy, neuropsychiatric disorders, and drug-resistance associated with drug response to specific ASMs or mechanistically related groups of ASMs. This study could not ascertain the predictive value of common genetic variants for ASM responder status. The identified suggestive loci will need replication in future studies of a larger scale.
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http://dx.doi.org/10.3389/fphar.2021.688386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220970PMC
June 2021

An identical-by-descent novel splice-donor variant in PRUNE1 causes a neurodevelopmental syndrome with prominent dystonia in two consanguineous Sudanese families.

Ann Hum Genet 2021 Jun 10. Epub 2021 Jun 10.

Institut du Cerveau, INSERM U1127, CNRS UMR7225, Sorbonne Université, Paris, France.

PRUNE1 is linked to a wide range of neurodevelopmental and neurodegenerative phenotypes. Multiple pathogenic missense and stop-gain PRUNE1 variants were identified in its DHH and DHHA2 phosphodiesterase domains. Conversely, a single splice alteration was previously reported. We investigated five patients from two unrelated consanguineous Sudanese families with an inherited severe neurodevelopmental disorder using whole-exome sequencing coupled with homozygosity mapping, segregation, and haplotype analysis. We identified a founder haplotype transmitting a homozygous canonical splice-donor variant (NM_021222.3:c.132+2T > C) in intron 2 of PRUNE1 segregated with the phenotype in all the patients. This splice variant possibly results in an in-frame deletion in the DHH domain or premature truncation of the protein. The phenotypes of the affected individuals showed phenotypic similarities characterized by remarkable pyramidal dysfunction and prominent extrapyramidal features (severe dystonia and bradykinesia). In conclusion, we identified a novel founder variant in PRUNE1 and corroborated abnormal splicing events as a disease mechanism in PRUNE1-related disorders. Given the phenotypes' consistency coupled with the founder effect, canonical and cryptic PRUNE1 splice-site variants should be carefully evaluated in patients presenting with prominent dystonia and pyramidal dysfunction.
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http://dx.doi.org/10.1111/ahg.12437DOI Listing
June 2021

Heritability of Magnetoencephalography Phenotypes Among Patients With Genetic Generalized Epilepsy and Their Siblings.

Neurology 2021 07 27;97(2):e166-e177. Epub 2021 May 27.

From the Clinic of Clinical Neurophysiology (C.S., R.K., N.K.F.), University Medical Center Göttingen; Department of Neurology and Epileptology, Hertie Institute of Clinical Brain Research (C.S., A.E., Y.L.H., R.K., J.M., H.L., N.K.F., C.B.), and MEG Center (C.B.), University of Tübingen, Germany; Department of Neurology (A.E.), University Hospital Zurich; Institute of Psychology (R.K.), University of Bern, Switzerland; and CIMeC (C.B.), Center for Mind/Brain Sciences, University of Trento, Italy.

Objective: To assess whether neuronal signals in patients with genetic generalized epilepsy (GGE) are heritable, we examined magnetoencephalography resting-state recordings in patients and their healthy siblings.

Methods: In a prospective, cross-sectional design, we investigated source-reconstructed power and functional connectivity in patients, siblings, and controls. We analyzed 5 minutes of cleaned and awake data without epileptiform discharges in 6 frequency bands (1-40 Hz). We further calculated intraclass correlations to estimate heritability for the imaging patterns within families.

Results: Compared with controls (n = 45), patients with GGE (n = 25) showed widespread increased functional connectivity (θ to γ frequency bands) and power (δ to γ frequency bands) across the spectrum. Siblings (n = 18) fell between the levels of patients and controls. Heritability of the imaging metrics was observed in regions where patients strongly differed from controls, mainly in β frequencies, but also for δ and θ power. Network connectivity in GGE was heritable in frontal, central, and inferior parietal brain areas and power in central, temporo-parietal, and subcortical structures. Presence of generalized spike-wave activity during recordings and medication were associated with the network patterns, whereas other clinical factors such as age at onset, disease duration, or seizure control were not.

Conclusion: Metrics of brain oscillations are well suited to characterize GGE and likely relate to genetic factors rather than the active disease or treatment. High power and connectivity levels co-segregated in patients with GGE and healthy siblings, predominantly in the β band, representing an endophenotype of GGE.
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http://dx.doi.org/10.1212/WNL.0000000000012144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279565PMC
July 2021

Assessing the role of rare genetic variants in drug-resistant, non-lesional focal epilepsy.

Ann Clin Transl Neurol 2021 Jul 21;8(7):1376-1387. Epub 2021 May 21.

Université de Montréal, Montreal, Canada.

Objective: Resistance to antiseizure medications (ASMs) is one of the major concerns in the treatment of epilepsy. Despite the increasing number of ASMs available, the proportion of individuals with drug-resistant epilepsy remains unchanged. In this study, we aimed to investigate the role of rare genetic variants in ASM resistance.

Methods: We performed exome sequencing of 1,128 individuals with non-familial non-acquired focal epilepsy (NAFE) (762 non-responders, 366 responders) and were provided with 1,734 healthy controls. We undertook replication in a cohort of 350 individuals with NAFE (165 non-responders, 185 responders). We performed gene-based and gene-set-based kernel association tests to investigate potential enrichment of rare variants in relation to drug response status and to risk for NAFE.

Results: We found no gene or gene set that reached genome-wide significance. Yet, we identified several prospective candidate genes - among them DEPDC5, which showed a potential association with resistance to ASMs. We found some evidence for an enrichment of truncating variants in dominant familial NAFE genes in our cohort of non-familial NAFE and in association with drug-resistant NAFE.

Interpretation: Our study identifies potential candidate genes for ASM resistance. Our results corroborate the role of rare variants for non-familial NAFE and imply their involvement in drug-resistant epilepsy. Future large-scale genetic research studies are needed to substantiate these findings.
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http://dx.doi.org/10.1002/acn3.51374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283173PMC
July 2021

Frame-based and robot-assisted insular stereo-electroencephalography via an anterior or posterior oblique approach.

J Neurosurg 2021 Apr 30:1-10. Epub 2021 Apr 30.

1Department of Neurosurgery.

Objective: There is an increasing interest in stereo-electroencephalography (SEEG) for invasive evaluation of insular epilepsy. The implantation of insular SEEG electrodes, however, is still challenging due to the anatomical location and complex functional segmentation in both an anteroposterior and ventrodorsal (i.e., superoinferior) direction. While the orthogonal approach (OA) is the shortest trajectory to the insula, it might insufficiently cover these networks. In contrast, the anterior approach (AOA) or posterior oblique approach (POA) has the potential for full insular coverage, with fewer electrodes bearing a risk of being more inaccurate due to the longer trajectory. Here, the authors evaluated the implantation accuracy and the detection of epilepsy-related SEEG activity with AOA and POA insular trajectories.

Methods: This retrospective study evaluated the accuracy of 220 SEEG electrodes in 27 patients. Twelve patients underwent a stereotactic frame-based procedure (frame group), and 15 patients underwent a frameless robot-assisted surgery (robot group). In total, 55 insular electrodes were implanted using the AOA or POA considering the insular anteroposterior and ventrodorsal functional organization. The entry point error (EPE) and target point error (TPE) were related to the implantation technique (frame vs robot), the length of the trajectory, and the location of the target (insular vs noninsular). Finally, the spatial distribution of epilepsy-related SEEG activity within the insula is described.

Results: There were no significant differences in EPE (mean 0.9 ± 0.6 for the nonsinsular electrodes and 1.1 ± 0.7 mm for the insular electrodes) and TPE (1.5 ± 0.8 and 1.6 ± 0.9 mm, respectively), although the length of trajectories differed significantly (34.1 ± 10.9 and 70.1 ± 9.0 mm, repsectively). There was a significantly larger EPE in the frame group than in the robot group (1.5 ± 0.6 vs 0.7 ± 0.5 mm). However, there was no group difference in the TPE (1.5 ± 0.8 vs 1.6 ± 0.8 mm). Epilepsy-related SEEG activity was detected in 42% (23/55) of the insular electrodes. Spatial distribution of this activity showed a clustering in both anteroposterior and ventrodorsal directions. In purely insular onset cases, subsequent insular lesionectomy resulted in a good seizure outcome.

Conclusions: The implantation of insular electrodes via the AOA or POA is safe and efficient for SEEG implantation covering both anteroposterior and ventrodorsal functional organization with few electrodes. In this series, there was no decrease in accuracy due to the longer trajectory of insular SEEG electrodes in comparison with noninsular SEEG electrodes. The results of frame-based and robot-assisted implantations were comparable.
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http://dx.doi.org/10.3171/2020.10.JNS201843DOI Listing
April 2021

Real-life survey of pitfalls and successes of precision medicine in genetic epilepsies.

J Neurol Neurosurg Psychiatry 2021 Apr 26. Epub 2021 Apr 26.

Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, and Chalfont Centre for Epilepsy, Gerrard Cross, UK

Objective: The term 'precision medicine' describes a rational treatment strategy tailored to one person that reverses or modifies the disease pathophysiology. In epilepsy, single case and small cohort reports document nascent precision medicine strategies in specific genetic epilepsies. The aim of this multicentre observational study was to investigate the deeper complexity of precision medicine in epilepsy.

Methods: A systematic survey of patients with epilepsy with a molecular genetic diagnosis was conducted in six tertiary epilepsy centres including children and adults. A standardised questionnaire was used for data collection, including genetic findings and impact on clinical and therapeutic management.

Results: We included 293 patients with genetic epilepsies, 137 children and 156 adults, 162 females and 131 males. Treatment changes were undertaken because of the genetic findings in 94 patients (32%), including rational precision medicine treatment and/or a treatment change prompted by the genetic diagnosis, but not directly related to known pathophysiological mechanisms. There was a rational precision medicine treatment for 56 patients (19%), and this was tried in 33/56 (59%) and was successful (ie, >50% seizure reduction) in 10/33 (30%) patients. In 73/293 (25%) patients there was a treatment change prompted by the genetic diagnosis, but not directly related to known pathophysiological mechanisms, and this was successful in 24/73 (33%).

Significance: Our survey of clinical practice in specialised epilepsy centres shows high variability of clinical outcomes following the identification of a genetic cause for an epilepsy. Meaningful change in the treatment paradigm after genetic testing is not yet possible for many people with epilepsy. This systematic survey provides an overview of the current application of precision medicine in the epilepsies, and suggests the adoption of a more considered approach.
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http://dx.doi.org/10.1136/jnnp-2020-325932DOI Listing
April 2021

Characterization of the GABRB2-Associated Neurodevelopmental Disorders.

Ann Neurol 2021 03 24;89(3):573-586. Epub 2020 Dec 24.

Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA.

Objective: We aimed to characterize the phenotypic spectrum and functional consequences associated with variants in the gene GABRB2, coding for the γ-aminobutyric acid type A (GABA ) receptor subunit β2.

Methods: We recruited and systematically evaluated 25 individuals with variants in GABRB2, 17 of whom are newly described and 8 previously reported with additional clinical data. Functional analysis was performed using a Xenopus laevis oocyte model system.

Results: Our cohort of 25 individuals from 22 families with variants in GABRB2 demonstrated a range of epilepsy phenotypes from genetic generalized epilepsy to developmental and epileptic encephalopathy. Fifty-eight percent of individuals had pharmacoresistant epilepsy; response to medications targeting the GABAergic pathway was inconsistent. Developmental disability (present in 84%) ranged from mild intellectual disability to severe global disability; movement disorders (present in 44%) included choreoathetosis, dystonia, and ataxia. Disease-associated variants cluster in the extracellular N-terminus and transmembrane domains 1-3, with more severe phenotypes seen in association with variants in transmembrane domains 1 and 2 and the allosteric binding site between transmembrane domains 2 and 3. Functional analysis of 4 variants in transmembrane domains 1 or 2 (p.Ile246Thr, p.Pro252Leu, p.Ile288Ser, p.Val282Ala) revealed strongly reduced amplitudes of GABA-evoked anionic currents.

Interpretation: GABRB2-related epilepsy ranges broadly in severity from genetic generalized epilepsy to developmental and epileptic encephalopathies. Developmental disability and movement disorder are key features. The phenotypic spectrum is comparable to other GABA receptor-encoding genes. Phenotypic severity varies by protein domain. Experimental evidence supports loss of GABAergic inhibition as the mechanism underlying GABRB2-associated neurodevelopmental disorders. ANN NEUROL 2021;89:573-586.
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http://dx.doi.org/10.1002/ana.25985DOI Listing
March 2021

Neuro-Sweet syndrome - a rare differential diagnosis in aseptic meningoencephalitis.

Neurol Res Pract 2019 21;1:36. Epub 2019 Nov 21.

Department of Epileptology, University Hospital for Neurology, Eberhard Karls University, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany.

Acute febrile neutrophilic dermatosis (Sweet's syndrome) is a dermatological entity, which may be associated with malignancies, drugs, and infections and which is characterized by high fever, elevated neutrophils, and tender erythematous skin lesions. Involvement of the nervous system - Neuro-Sweet syndrome (NSS) - is rare, manifesting most commonly with an encephalitic syndrome in addition to fever and dermal lesions. Here, we report an unusual case of NSS in a Caucasian male patient in the setting of B-cell-lymphocytosis, with encephalitis preceding dermal lesions. Symptoms resolved completely in response to corticoids. NSS is a rare, but important differential diagnosis in the work-up of febrile aseptic meningoencephalitis unresponsive to anti-infectious treatment. Due to its rarity and clinical variability, diagnosis of NSS might be challenging. Knowledge of this entity may facilitate proper diagnosis and differentiation from conditions with similar clinical presentation, especially Neuro-Behçet's disease. It may further lead to early detection of a potentially underlying malignancy and help in initiating adequate therapy.
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http://dx.doi.org/10.1186/s42466-019-0041-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650048PMC
November 2019

Tetraparesis and sensorimotor axonal polyneuropathy due to co-occurrence of Pompe disease and hereditary ATTR amyloidosis.

Neurol Sci 2021 Apr 13;42(4):1523-1525. Epub 2020 Nov 13.

Department of Neurology and Hertie Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.

Introduction/aims: Hereditary transthyretin amyloidosis with polyneuropathy (hATTRPN) is an autosomal dominant multi-organ disorder manifesting in the third to fifth decade with the key clinical features of distal and painful sensory loss of the lower limbs and autonomic dysregulation. Motor neuropathy and cardiomyopathy evolve in the course of the disease. Pompe disease is an autosomal recessive disease leading to decreased levels of lysosomal enzyme acid α-glucosidase and proximal muscle weakness. We report the clinical features and diagnostic workup in the rare case of a patient with ATTR amyloidosis and late-onset Pompe disease, both genetically confirmed.

Methods: We performed a detailed clinical assessment, exome sequencing, and biochemical measurements.

Results: The patient presented with a distal, painful hypaesthesia of both legs, a cardiomyopathy, and a muscle weakness in the form of a girdle-type pattern of the arms and legs at the beginning and a spreading to distal muscle groups in the course of disease.

Discussion: This study highlights the importance of searching for co-occurrence of rare monogenetic neuromuscular diseases, especially in cases in which all clinical features can be readily explained by a single gene defect.
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http://dx.doi.org/10.1007/s10072-020-04896-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955998PMC
April 2021

Drug-resistant epilepsy - time to target mechanisms.

Authors:
Holger Lerche

Nat Rev Neurol 2020 Nov;16(11):595-596

Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.

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http://dx.doi.org/10.1038/s41582-020-00419-yDOI Listing
November 2020

Brivaracetam substituting other antiepileptic treatments: Results of a retrospective study in German epilepsy centers.

Epilepsia Open 2020 Sep 22;5(3):451-460. Epub 2020 Jul 22.

Epilepsy Center Kleinwachau Radeberg Germany.

Objective: To evaluate the success of initiation of adjunctive brivaracetam in patients who required a change in antiepileptic drug (AED) regimen and substituted at least one AED with brivaracetam.

Methods: In this retrospective noninterventional study conducted in specialized epilepsy centers across Germany, patients initiated adjunctive brivaracetam between February 15, 2016, and August 31, 2016, as part of an intended change in AED regimen. The primary effectiveness variable was the proportion of patients who continued on brivaracetam after 3 months, and withdrew at least one AED either before or within 6 months after brivaracetam initiation.

Results: Five hundred and six patients had at least one brivaracetam dose and were included in the safety set (SS). Four hundred and seventy patients started to reduce the dose of one AED before/after brivaracetam initiation, had at least one concomitant AED at brivaracetam initiation, and were included in the full analysis set (FAS) for effectiveness analyses. At baseline, patients had a median of seven lifetime AEDs and a median of 3.8 seizures/28 days. In the SS, 85.2% of patients withdrew one AED before/after initiation of brivaracetam, most commonly levetiracetam (49.4%). 46.2% of patients substituted another AED with brivaracetam within 24 hours (fast withdrawal). The proportions of patients (FAS) who continued on brivaracetam after 3 and 6 months and withdrew one AED were 75.5% and 46.6%, respectively. After 6 months, 32.1% of patients were 50% responders; 13.0% were seizure-free. In the SS, 34.6% of patients reported treatment-emergent adverse events (TEAEs); 21.9% had TEAEs that were assessed by the treating physician as drug-related. Incidences of behavioral AEs before (3-month baseline) and after brivaracetam initiation in patients who withdrew levetiracetam were 19.2% and 8.0%, respectively (5.0% and 7.7% in patients who withdrew other AEDs).

Significance: Brivaracetam was effective and well-tolerated in patients who required a change in AED drug regimen and initiated adjunctive brivaracetam in German clinical practice.
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http://dx.doi.org/10.1002/epi4.12415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469785PMC
September 2020

Predicting functional effects of missense variants in voltage-gated sodium and calcium channels.

Sci Transl Med 2020 08;12(556)

Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.

Malfunctions of voltage-gated sodium and calcium channels (encoded by and family genes, respectively) have been associated with severe neurologic, psychiatric, cardiac, and other diseases. Altered channel activity is frequently grouped into gain or loss of ion channel function (GOF or LOF, respectively) that often corresponds not only to clinical disease manifestations but also to differences in drug response. Experimental studies of channel function are therefore important, but laborious and usually focus only on a few variants at a time. On the basis of known gene-disease mechanisms of 19 different diseases, we inferred LOF ( = 518) and GOF ( = 309) likely pathogenic variants from the disease phenotypes of variant carriers. By training a machine learning model on sequence- and structure-based features, we predicted LOF or GOF effects [area under the receiver operating characteristics curve (ROC) = 0.85] of likely pathogenic missense variants. Our LOF versus GOF prediction corresponded to molecular LOF versus GOF effects for 87 functionally tested variants in and (ROC = 0.73) and was validated in exome-wide data from 21,703 cases and 128,957 controls. We showed respective regional clustering of inferred LOF and GOF nucleotide variants across the alignment of the entire gene family, suggesting shared pathomechanisms in the family genes.
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http://dx.doi.org/10.1126/scitranslmed.aay6848DOI Listing
August 2020

Epilepsy-causing STX1B mutations translate altered protein functions into distinct phenotypes in mouse neurons.

Brain 2020 07;143(7):2119-2138

Laboratory of Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universität Berlin, Germany.

Syntaxin 1B (STX1B) is a core component of the N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex that is critical for the exocytosis of synaptic vesicles in the presynapse. SNARE-mediated vesicle fusion is assisted by Munc18-1, which recruits STX1B in the auto-inhibited conformation, while Munc13 catalyses the fast and efficient pairing of helices during SNARE complex formation. Mutations within the STX1B gene are associated with epilepsy. Here we analysed three STX1B mutations by biochemical and electrophysiological means. These three paradigmatic mutations cause epilepsy syndromes of different severity, from benign fever-associated seizures in childhood to severe epileptic encephalopathies. An insertion/deletion (K45/RMCIE, L46M) mutation (STX1BInDel), causing mild epilepsy and located in the early helical Habc domain, leads to an unfolded protein unable to sustain neurotransmission. STX1BG226R, causing epileptic encephalopathies, strongly compromises the interaction with Munc18-1 and reduces expression of both proteins, the size of the readily releasable pool of vesicles, and Ca2+-triggered neurotransmitter release when expressed in STX1-null neurons. The mutation STX1BV216E, also causing epileptic encephalopathies, only slightly diminishes Munc18-1 and Munc13 interactions, but leads to enhanced fusogenicity and increased vesicular release probability, also in STX1-null neurons. Even though the synaptic output remained unchanged in excitatory hippocampal STX1B+/- neurons exogenously expressing STX1B mutants, the manifestation of clear and distinct molecular disease mechanisms by these mutants suggest that certain forms of epilepsies can be conceptualized by assigning mutations to structurally sensitive regions of the STX1B-Munc18-1 interface, translating into distinct neurophysiological phenotypes.
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http://dx.doi.org/10.1093/brain/awaa151DOI Listing
July 2020

In Vitro Differentiated Human Stem Cell-Derived Neurons Reproduce Synaptic Synchronicity Arising during Neurodevelopment.

Stem Cell Reports 2020 07 18;15(1):22-37. Epub 2020 Jun 18.

Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany; The Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia. Electronic address:

Neurons differentiated from induced pluripotent stem cells (iPSCs) typically show regular spiking and synaptic activity but lack more complex network activity critical for brain development, such as periodic depolarizations including simultaneous involvement of glutamatergic and GABAergic neurotransmission. We generated human iPSC-derived neurons exhibiting spontaneous oscillatory activity after cultivation of up to 6 months, which resembles early oscillations observed in rodent neurons. This behavior was found in neurons generated using a more "native" embryoid body protocol, in contrast to a "fast" protocol based on NGN2 overexpression. A comparison with published data indicates that EB-derived neurons reach the maturity of neurons of the third trimester and NGN2-derived neurons of the second trimester of human gestation. Co-culturing NGN2-derived neurons with astrocytes only led to a partial compensation and did not reliably induce complex network activity. Our data will help selection of the appropriate iPSC differentiation assay to address specific questions related to neurodevelopmental disorders.
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http://dx.doi.org/10.1016/j.stemcr.2020.05.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363884PMC
July 2020

Desynchronization of temporal lobe theta-band activity during effective anterior thalamus deep brain stimulation in epilepsy.

Neuroimage 2020 09 20;218:116967. Epub 2020 May 20.

Division of Functional and Restorative Neurosurgery, Department of Neurosurgery, And Tübingen NeuroCampus, University of Tübingen, 72076, Tübingen, Germany. Electronic address:

Background: Bilateral cyclic high frequency deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) reduces the seizure count in a subset of patients with epilepsy. Detecting stimulation-induced alterations of pathological brain networks may help to unravel the underlying physiological mechanisms related to effective stimulation delivery and optimize target engagement.

Methods: We acquired 64-channel electroencephalography during ten ANT-DBS cycles (145 ​Hz, 90 ​μs, 3-5 ​V) of 1-min ON followed by 5-min OFF stimulation to detect changes in cortical activity related to seizure reduction. The study included 14 subjects (three responders, four non-responders, and seven healthy controls). Mixed-model ANOVA tests were used to compare differences in cortical activity between subgroups both ON and OFF stimulation, while investigating frequency-specific effects for the seizure onset zones.

Results: ANT-DBS had a widespread desynchronization effect on cortical theta and alpha band activity in responders, but not in non-responders. Time domain analysis showed that the stimulation induced reduction in theta-band activity was temporally linked to the stimulation period. Moreover, stimulation induced theta-band desynchronization in the temporal lobe channels correlated significantly with the therapeutic response. Responders to ANT-DBS and healthy-controls had an overall lower level of theta-band activity compared to non-responders.

Conclusion: This study demonstrated that temporal lobe channel theta-band desynchronization may be a predictive physiological hallmark of therapeutic response to ANT-DBS and may be used to improve the functional precision of this intervention by verifying implantation sites, calibrating stimulation contacts, and possibly identifying treatment responders prior to implantation.
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http://dx.doi.org/10.1016/j.neuroimage.2020.116967DOI Listing
September 2020

Pharmacoresponse in genetic generalized epilepsy: a genome-wide association study.

Pharmacogenomics 2020 04 20;21(5):325-335. Epub 2020 Apr 20.

Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany.

Pharmacoresistance is a major burden in epilepsy treatment. We aimed to identify genetic biomarkers in response to specific antiepileptic drugs (AEDs) in genetic generalized epilepsies (GGE). We conducted a genome-wide association study (GWAS) of 3.3 million autosomal SNPs in 893 European subjects with GGE - responsive or nonresponsive to lamotrigine, levetiracetam and valproic acid. Our GWAS of AED response revealed suggestive evidence for association at 29 genomic loci (p <10) but no significant association reflecting its limited power. The suggestive associations highlight candidate genes that are implicated in epileptogenesis and neurodevelopment. This first GWAS of AED response in GGE provides a comprehensive reference of SNP associations for hypothesis-driven candidate gene analyses in upcoming pharmacogenetic studies.
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http://dx.doi.org/10.2217/pgs-2019-0179DOI Listing
April 2020

Bi-allelic GAD1 variants cause a neonatal onset syndromic developmental and epileptic encephalopathy.

Brain 2020 05;143(5):1447-1461

Neurogenetics Group, VIB-Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium.

Developmental and epileptic encephalopathies are a heterogeneous group of early-onset epilepsy syndromes dramatically impairing neurodevelopment. Modern genomic technologies have revealed a number of monogenic origins and opened the door to therapeutic hopes. Here we describe a new syndromic developmental and epileptic encephalopathy caused by bi-allelic loss-of-function variants in GAD1, as presented by 11 patients from six independent consanguineous families. Seizure onset occurred in the first 2 months of life in all patients. All 10 patients, from whom early disease history was available, presented with seizure onset in the first month of life, mainly consisting of epileptic spasms or myoclonic seizures. Early EEG showed suppression-burst or pattern of burst attenuation or hypsarrhythmia if only recorded in the post-neonatal period. Eight patients had joint contractures and/or pes equinovarus. Seven patients presented a cleft palate and two also had an omphalocele, reproducing the phenotype of the knockout Gad1-/- mouse model. Four patients died before 4 years of age. GAD1 encodes the glutamate decarboxylase enzyme GAD67, a critical actor of the γ-aminobutyric acid (GABA) metabolism as it catalyses the decarboxylation of glutamic acid to form GABA. Our findings evoke a novel syndrome related to GAD67 deficiency, characterized by the unique association of developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele.
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http://dx.doi.org/10.1093/brain/awaa085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241960PMC
May 2020

Testing association of rare genetic variants with resistance to three common antiseizure medications.

Epilepsia 2020 04 6;61(4):657-666. Epub 2020 Mar 6.

Department of Applied Sciences, University of Quebec in Chicoutimi, Saguenay, Canada.

Objective: Drug resistance is a major concern in the treatment of individuals with epilepsy. No genetic markers for resistance to individual antiseizure medication (ASM) have yet been identified. We aimed to identify the role of rare genetic variants in drug resistance for three common ASMs: levetiracetam (LEV), lamotrigine (LTG), and valproic acid (VPA).

Methods: A cohort of 1622 individuals of European descent with epilepsy was deeply phenotyped and underwent whole exome sequencing (WES), comprising 575 taking LEV, 826 LTG, and 782 VPA. We performed gene- and gene set-based collapsing analyses comparing responders and nonresponders to the three drugs to determine the burden of different categories of rare genetic variants.

Results: We observed a marginally significant enrichment of rare missense, truncating, and splice region variants in individuals who were resistant to VPA compared to VPA responders for genes involved in VPA pharmacokinetics. We also found a borderline significant enrichment of truncating and splice region variants in the synaptic vesicle glycoprotein (SV2) gene family in nonresponders compared to responders to LEV. We did not see any significant enrichment using a gene-based approach.

Significance: In our pharmacogenetic study, we identified a slightly increased burden of damaging variants in gene groups related to drug kinetics or targeting in individuals presenting with drug resistance to VPA or LEV. Such variants could thus determine a genetic contribution to drug resistance.
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http://dx.doi.org/10.1111/epi.16467DOI Listing
April 2020

Biological concepts in human sodium channel epilepsies and their relevance in clinical practice.

Epilepsia 2020 03 23;61(3):387-399. Epub 2020 Feb 23.

Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.

Objective: Voltage-gated sodium channels (SCNs) share similar amino acid sequence, structure, and function. Genetic variants in the four human brain-expressed SCN genes SCN1A/2A/3A/8A have been associated with heterogeneous epilepsy phenotypes and neurodevelopmental disorders. To better understand the biology of seizure susceptibility in SCN-related epilepsies, our aim was to determine similarities and differences between sodium channel disorders, allowing us to develop a broader perspective on precision treatment than on an individual gene level alone.

Methods: We analyzed genotype-phenotype correlations in large SCN-patient cohorts and applied variant constraint analysis to identify severe sodium channel disease. We examined temporal patterns of human SCN expression and correlated functional data from in vitro studies with clinical phenotypes across different sodium channel disorders.

Results: Comparing 865 epilepsy patients (504 SCN1A, 140 SCN2A, 171 SCN8A, four SCN3A, 46 copy number variation [CNV] cases) and analysis of 114 functional studies allowed us to identify common patterns of presentation. All four epilepsy-associated SCN genes demonstrated significant constraint in both protein truncating and missense variation when compared to other SCN genes. We observed that age at seizure onset is related to SCN gene expression over time. Individuals with gain-of-function SCN2A/3A/8A missense variants or CNV duplications share similar characteristics, most frequently present with early onset epilepsy (<3 months), and demonstrate good response to sodium channel blockers (SCBs). Direct comparison of corresponding SCN variants across different SCN subtypes illustrates that the functional effects of variants in corresponding channel locations are similar; however, their clinical manifestation differs, depending on their role in different types of neurons in which they are expressed.

Significance: Variant function and location within one channel can serve as a surrogate for variant effects across related sodium channels. Taking a broader view on precision treatment suggests that in those patients with a suspected underlying genetic epilepsy presenting with neonatal or early onset seizures (<3 months), SCBs should be considered.
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http://dx.doi.org/10.1111/epi.16438DOI Listing
March 2020

Genetic potassium channel-associated epilepsies: Clinical review of the K family.

Eur J Paediatr Neurol 2020 Jan 14;24:105-116. Epub 2019 Dec 14.

Department of Neurology and Epileptology, Hertie Institute of Clinical Brain Research, University of Tubingen, Germany.

Next-generation sequencing has enhanced discovery of many disease-associated genes in previously unexplained epilepsies, mainly in developmental and epileptic encephalopathies and familial epilepsies. We now classify these disorders according to the underlying molecular pathways, which encompass a diverse array of cellular and sub-cellular compartments/signalling processes including voltage-gated ion-channel defects. With the aim to develop and increase the use of precision medicine therapies, understanding the pathogenic mechanisms and consequences of disease-causing variants has gained major relevance in clinical care. The super-family of voltage-gated potassium channels is the largest and most diverse family among the ion channels, encompassing approximately 80 genes. Key potassium channelopathies include those affecting the K, K and K families, a significant proportion of which have been implicated in neurological disease. As for other ion channel disorders, different pathogenic variants within any individual voltage-gated potassium channel gene tend to affect channel protein function differently, causing heterogeneous clinical phenotypes. The focus of this review is to summarise recent clinical developments regarding the key voltage-gated potassium (K) family-related epilepsies, which now encompasses approximately 12 established disease-associated genes, from the KCNA-, KCNB-, KCNC-, KCND-, KCNV-, KCNQ- and KCNH-subfamilies.
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http://dx.doi.org/10.1016/j.ejpn.2019.12.002DOI Listing
January 2020

Differential excitatory vs inhibitory SCN expression at single cell level regulates brain sodium channel function in neurodevelopmental disorders.

Eur J Paediatr Neurol 2020 Jan 28;24:129-133. Epub 2019 Dec 28.

Cologne Center for Genomics, University of Cologne, University Hospital Cologne, Cologne, Germany; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Cambridge, MA, USA; Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA; Genomic Medicine Institute, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA. Electronic address:

The four voltage-gated sodium channels SCN1/2/3/8A have been associated with heterogeneous types of developmental disorders, each presenting with disease specific temporal and cell type specific gene expression. Using single-cell RNA sequencing transcriptomic data from humans and mice, we observe that SCN1A is predominantly expressed in inhibitory neurons. In contrast, SCN2/3/8A are profoundly expressed in excitatory neurons with SCN2/3A starting prenatally, followed by SCN1/8A neonatally. In contrast to previous observations from low resolution RNA screens, we observe that all four genes are expressed in both excitatory and inhibitory neurons, however, exhibit differential expression strength. These findings provide molecular evidence, at single-cell resolution, to support the hypothesis that the excitatory/inhibitory (E/I) neuronal expression ratios of sodium channels are important regulatory mechanisms underlying brain homeostasis and neurological diseases. Modulating the E/I expression balance within cell types of sodium channels could serve as a potential strategy to develop targeted treatment for Na-associated neuronal developmental disorders.
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http://dx.doi.org/10.1016/j.ejpn.2019.12.019DOI Listing
January 2020

SCN2A channelopathies: Mechanisms and models.

Epilepsia 2019 12;60 Suppl 3:S68-S76

Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.

Variants in the SCN2A gene, encoding the voltage-gated sodium channel Na 1.2, cause a variety of neuropsychiatric syndromes with different severity ranging from self-limiting epilepsies with early onset to developmental and epileptic encephalopathy with early or late onset and intellectual disability (ID), as well as ID or autism without seizures. Functional analysis of channel defects demonstrated a genotype-phenotype correlation and suggested effective treatment options for one group of affected patients carrying gain-of-function variants. Here, we sum up the functional mechanisms underlying different phenotypes of patients with SCN2A channelopathies and present currently available models that can help in understanding SCN2A-related disorders.
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http://dx.doi.org/10.1111/epi.14731DOI Listing
December 2019

Genomic and clinical predictors of lacosamide response in refractory epilepsies.

Epilepsia Open 2019 Dec 25;4(4):563-571. Epub 2019 Sep 25.

School of Pharmacy and Biomolecular Sciences Royal College of Surgeons Dublin Ireland.

Objective: Clinical and genetic predictors of response to antiepileptic drugs (AEDs) are largely unknown. We examined predictors of lacosamide response in a real-world clinical setting.

Methods: We tested the association of clinical predictors with treatment response using regression modeling in a cohort of people with refractory epilepsy. Genetic assessment for lacosamide response was conducted via genome-wide association studies and exome studies, comprising 281 candidate genes.

Results: Most patients (479/483) were treated with LCM in addition to other AEDs. Our results corroborate previous findings that patients with refractory genetic generalized epilepsy (GGE) may respond to treatment with LCM. No clear clinical predictors were identified. We then compared 73 lacosamide responders, defined as those experiencing greater than 75% seizure reduction or seizure freedom, to 495 nonresponders (<25% seizure reduction). No variants reached the genome-wide significance threshold in our case-control analysis.

Significance: No genetic predictor of lacosamide response was identified. Patients with refractory GGE might benefit from treatment with lacosamide.
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http://dx.doi.org/10.1002/epi4.12360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885661PMC
December 2019

Delirium Screening in Aphasic Patients With the Intensive Care Delirium Screening Checklist (ICDSC): A Prospective Cohort Study.

Front Neurol 2019 12;10:1198. Epub 2019 Nov 12.

Department of Neurology and Stroke, Hertie-Institute for Clinical Brain Research, Eberhard-Karls University of Tübingen, Tübingen, Germany.

Ten to thirty percent of stroke patients suffer from post-stroke delirium. This leads to a longer hospital stay and increased mortality. Therefore, early detection and treatment are needed. All established delirium screening tools require some degree of language function. We sought to investigate whether the Intensive Care Delirium Screening Checklist (ICDSC) is suitable for delirium screening in patients with post-stroke aphasia. A prospective cohort study was carried out in adult patients consecutively admitted to the Stroke Unit of University Hospital Tuebingen, between July 2017 and December 2018. The index test, ICDSC, was compared with the DSM-V diagnostic criteria as reference standard. Measures of diagnostic precision and the degree of agreement were obtained. Three hundred and forty six patients were included in the analysis. Aphasia was present in 231 (66.8%) and absent in 115 (33.2%) patients. Delirium was present in 83 out of 231 (36%) patients with aphasia and 32 out of 115 (27.8%) patients without aphasia ( = 0.132). For patients without aphasia, sensitivity and specificity at the established cut-off value of ≥ 4 points were 100% and 78%, respectively. For patients with aphasia, the test demonstrated inferior performance, with a sensitivity and specificity of 98% and 55%, respectively. It was necessary to increase the cut-off value to ≥ 5 points. Through this, sensitivity was 90% (95% CI, 81.9-95.8%) and specificity was 75% (95% CI, 67.2-81.8%). The degree of agreement to the DSM-V criteria was "substantial" (Cohen's κ = 0.61). For the purpose of delirium screening in patients with aphasia, increasing the ICDSC cut-off value to ≥ 5 points enables effective screening. Further studies are necessary to characterize post-stroke delirium.
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http://dx.doi.org/10.3389/fneur.2019.01198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861445PMC
November 2019

Novel treatment approaches and pediatric research networks in status epilepticus.

Epilepsy Behav 2019 12 8;101(Pt B):106564. Epub 2019 Nov 8.

Boston Children's Hospital & Harvard Medical School, Boston, MA 02115, USA. Electronic address:

This paper contains five contributions which were presented as part of the novel therapies section of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures. These illustrate recent advances being made in the management and therapy of status epilepticus. The five contributions concern: genetic variations in Na + channel genes and their importance in status epilepticus; the European Reference Network for rare and complex epilepsies EpiCARE; the North American Pediatric Status Epilepticus Research Group (pSERG); Fenfluramine as a potential therapy for status epilepticus' and the valproate derivatives, valnoctamide and sec-butylpropylacetamide (SPD), as potential therapies for status epilepticus. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".
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http://dx.doi.org/10.1016/j.yebeh.2019.106564DOI Listing
December 2019

Polygenic burden in focal and generalized epilepsies.

Brain 2019 11;142(11):3473-3481

Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.

Rare genetic variants can cause epilepsy, and genetic testing has been widely adopted for severe, paediatric-onset epilepsies. The phenotypic consequences of common genetic risk burden for epilepsies and their potential future clinical applications have not yet been determined. Using polygenic risk scores (PRS) from a European-ancestry genome-wide association study in generalized and focal epilepsy, we quantified common genetic burden in patients with generalized epilepsy (GE-PRS) or focal epilepsy (FE-PRS) from two independent non-Finnish European cohorts (Epi25 Consortium, n = 5705; Cleveland Clinic Epilepsy Center, n = 620; both compared to 20 435 controls). One Finnish-ancestry population isolate (Finnish-ancestry Epi25, n = 449; compared to 1559 controls), two European-ancestry biobanks (UK Biobank, n = 383 656; Vanderbilt biorepository, n = 49 494), and one Japanese-ancestry biobank (BioBank Japan, n = 168 680) were used for additional replications. Across 8386 patients with epilepsy and 622 212 population controls, we found and replicated significantly higher GE-PRS in patients with generalized epilepsy of European-ancestry compared to patients with focal epilepsy (Epi25: P = 1.64×10-15; Cleveland: P = 2.85×10-4; Finnish-ancestry Epi25: P = 1.80×10-4) or population controls (Epi25: P = 2.35×10-70; Cleveland: P = 1.43×10-7; Finnish-ancestry Epi25: P = 3.11×10-4; UK Biobank and Vanderbilt biorepository meta-analysis: P = 7.99×10-4). FE-PRS were significantly higher in patients with focal epilepsy compared to controls in the non-Finnish, non-biobank cohorts (Epi25: P = 5.74×10-19; Cleveland: P = 1.69×10-6). European ancestry-derived PRS did not predict generalized epilepsy or focal epilepsy in Japanese-ancestry individuals. Finally, we observed a significant 4.6-fold and a 4.5-fold enrichment of patients with generalized epilepsy compared to controls in the top 0.5% highest GE-PRS of the two non-Finnish European cohorts (Epi25: P = 2.60×10-15; Cleveland: P = 1.39×10-2). We conclude that common variant risk associated with epilepsy is significantly enriched in multiple cohorts of patients with epilepsy compared to controls-in particular for generalized epilepsy. As sample sizes and PRS accuracy continue to increase with further common variant discovery, PRS could complement established clinical biomarkers and augment genetic testing for patient classification, comorbidity research, and potentially targeted treatment.
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http://dx.doi.org/10.1093/brain/awz292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821205PMC
November 2019
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