Publications by authors named "Sarah von Spiczak"

53 Publications

Bi-allelic variants in OGDHL cause a neurodevelopmental spectrum disease featuring epilepsy, hearing loss, visual impairment, and ataxia.

Am J Hum Genet 2021 Nov 17. Epub 2021 Nov 17.

Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran 1316943551, Iran.

The 2-oxoglutarate dehydrogenase-like (OGDHL) protein is a rate-limiting enzyme in the Krebs cycle that plays a pivotal role in mitochondrial metabolism. OGDHL expression is restricted mainly to the brain in humans. Here, we report nine individuals from eight unrelated families carrying bi-allelic variants in OGDHL with a range of neurological and neurodevelopmental phenotypes including epilepsy, hearing loss, visual impairment, gait ataxia, microcephaly, and hypoplastic corpus callosum. The variants include three homozygous missense variants (p.Pro852Ala, p.Arg244Trp, and p.Arg299Gly), three compound heterozygous single-nucleotide variants (p.Arg673Gln/p.Val488Val, p.Phe734Ser/p.Ala327Val, and p.Trp220Cys/p.Asp491Val), one homozygous frameshift variant (p.Cys553Leufs16), and one homozygous stop-gain variant (p.Arg440Ter). To support the pathogenicity of the variants, we developed a novel CRISPR-Cas9-mediated tissue-specific knockout with cDNA rescue system for dOgdh, the Drosophila ortholog of human OGDHL. Pan-neuronal knockout of dOgdh led to developmental lethality as well as defects in Krebs cycle metabolism, which was fully rescued by expression of wild-type dOgdh. Studies using the Drosophila system indicate that p.Arg673Gln, p.Phe734Ser, and p.Arg299Gly are severe loss-of-function alleles, leading to developmental lethality, whereas p.Pro852Ala, p.Ala327Val, p.Trp220Cys, p.Asp491Val, and p.Arg244Trp are hypomorphic alleles, causing behavioral defects. Transcript analysis from fibroblasts obtained from the individual carrying the synonymous variant (c.1464T>C [p.Val488Val]) in family 2 showed that the synonymous variant affects splicing of exon 11 in OGDHL. Human neuronal cells with OGDHL knockout exhibited defects in mitochondrial respiration, indicating the essential role of OGDHL in mitochondrial metabolism in humans. Together, our data establish that the bi-allelic variants in OGDHL are pathogenic, leading to a Mendelian neurodevelopmental disease in humans.
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http://dx.doi.org/10.1016/j.ajhg.2021.11.003DOI Listing
November 2021

Zonisamide-responsive myoclonus in SEMA6B-associated progressive myoclonic epilepsy.

Ann Clin Transl Neurol 2021 07 6;8(7):1524-1527. Epub 2021 Jun 6.

Institute of Systems Motor Science, University Lübeck, Lübeck, Germany.

We present a female patient in her early twenties with global development delay, progressive ataxia, epilepsy, and myoclonus caused by a stop mutation in the SEMA6B gene. Truncating DNA variants located in the last exon of SEMA6B have recently been identified as a cause of autosomal dominant progressive myoclonus epilepsy. In many cases, myoclonus in the context of progressive myoclonic epilepsy is refractory to medical treatment. In the present case, treatment with zonisamide caused clinical improvement, particularly of positive and negative truncal myoclonus, considerably improving patient's gait and thus mobility.
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http://dx.doi.org/10.1002/acn3.51403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283161PMC
July 2021

Semantic Similarity Analysis Reveals Robust Gene-Disease Relationships in Developmental and Epileptic Encephalopathies.

Am J Hum Genet 2020 10 26;107(4):683-697. Epub 2020 Aug 26.

Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA 19146, USA; Department of Neurology, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

More than 100 genetic etiologies have been identified in developmental and epileptic encephalopathies (DEEs), but correlating genetic findings with clinical features at scale has remained a hurdle because of a lack of frameworks for analyzing heterogenous clinical data. Here, we analyzed 31,742 Human Phenotype Ontology (HPO) terms in 846 individuals with existing whole-exome trio data and assessed associated clinical features and phenotypic relatedness by using HPO-based semantic similarity analysis for individuals with de novo variants in the same gene. Gene-specific phenotypic signatures included associations of SCN1A with "complex febrile seizures" (HP: 0011172; p = 2.1 × 10) and "focal clonic seizures" (HP: 0002266; p = 8.9 × 10), STXBP1 with "absent speech" (HP: 0001344; p = 1.3 × 10), and SLC6A1 with "EEG with generalized slow activity" (HP: 0010845; p = 0.018). Of 41 genes with de novo variants in two or more individuals, 11 genes showed significant phenotypic similarity, including SCN1A (n = 16, p < 0.0001), STXBP1 (n = 14, p = 0.0021), and KCNB1 (n = 6, p = 0.011). Including genetic and phenotypic data of control subjects increased phenotypic similarity for all genetic etiologies, whereas the probability of observing de novo variants decreased, emphasizing the conceptual differences between semantic similarity analysis and approaches based on the expected number of de novo events. We demonstrate that HPO-based phenotype analysis captures unique profiles for distinct genetic etiologies, reflecting the breadth of the phenotypic spectrum in genetic epilepsies. Semantic similarity can be used to generate statistical evidence for disease causation analogous to the traditional approach of primarily defining disease entities through similar clinical features.
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http://dx.doi.org/10.1016/j.ajhg.2020.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536581PMC
October 2020

SVD Square-root Iterated Extended Kalman Filter for Modeling of Epileptic Seizure Count Time Series with External Inputs.

Annu Int Conf IEEE Eng Med Biol Soc 2019 Jul;2019:616-619

In this paper a nonlinear filtering algorithm for count time series is developed that takes the non-negativity of the data into account and preserves positive definiteness of the covariance matrices of the model. For this purpose, a recently proposed variant of Kalman Filtering based on Singular Value Decomposition is incorporated into Iterative Extended Kalman Filtering, in order to estimate the states of a nonlinear state space model. The resulting algorithm is applied to the evaluation and design of therapies for patients suffering from Myoclonic Astatic Epilepsy, employing time series of daily seizure rate. The analysis provides a decision whether for a specific patient a particular anti-epileptic drug is increasing or reducing the seizure rate. Through a simulation study the proposed algorithm is validated. Additionally, for clinical data results obtained by the proposed algorithm are compared with the results from a Cox-Stuart trend test as well as with the visual assessment of experienced pediatric epileptologists.
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http://dx.doi.org/10.1109/EMBC.2019.8857159DOI Listing
July 2019

RARS1-related hypomyelinating leukodystrophy: Expanding the spectrum.

Ann Clin Transl Neurol 2020 01 8;7(1):83-93. Epub 2019 Dec 8.

Metabolic Unit, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam Gastroenterology & Metabolism, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.

Objective: Biallelic variants in RARS1, encoding the cytoplasmic tRNA synthetase for arginine (ArgRS), cause a hypomyelinating leukodystrophy. This study aimed to investigate clinical, neuroradiological and genetic features of patients with RARS1-related disease, and to identify possible genotype-phenotype relationships.

Methods: We performed a multinational cross-sectional survey among 20 patients with biallelic RARS1 variants identified by next-generation sequencing techniques. Clinical data, brain MRI findings and genetic results were analyzed. Additionally, ArgRS activity was measured in fibroblasts of four patients, and translation of long and short ArgRS isoforms was quantified by western blot.

Results: Clinical presentation ranged from severe (onset in the first 3 months, usually with refractory epilepsy and early brain atrophy), to intermediate (onset in the first year with nystagmus and spasticity), and mild (onset around or after 12 months with minimal cognitive impairment and preserved independent walking). The most frequent RARS1 variant, c.5A>G, led to mild or intermediate phenotypes, whereas truncating variants and variants affecting amino acids close to the ArgRS active centre led to severe phenotypes. ArgRS activity was significantly reduced in three patients with intermediate and severe phenotypes; in a fourth patient with intermediate to severe presentation, we measured normal ArgRS activity, but found translation mainly of the short instead of the long ArgRS isoform.

Interpretation: Variants in RARS1 impair ArgRS activity and do not only lead to a classic hypomyelination presentation with nystagmus and spasticity, but to a wide spectrum, ranging from severe, early-onset epileptic encephalopathy with brain atrophy to mild disease with relatively preserved myelination.
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http://dx.doi.org/10.1002/acn3.50960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952319PMC
January 2020

Can commercially available wearable EEG devices be used for diagnostic purposes? An explorative pilot study.

Epilepsy Behav 2020 02 20;103(Pt A):106507. Epub 2019 Oct 20.

Technical University of Munich, Department of Informatics, Boltzmannstraße 3, 85748 Garching, Germany. Electronic address:

Electroencephalography (EEG) is a core element in the diagnosis of epilepsy syndromes and can help to monitor antiseizure treatment. Mobile EEG (mEEG) devices are increasingly available on the consumer market and may offer easier access to EEG recordings especially in rural or resource-poor areas. The usefulness of consumer-grade devices for clinical purposes is still underinvestigated. Here, we compared EEG traces of a commercially available mEEG device (Emotiv EPOC) to a simultaneously recorded clinical video EEG (vEEG). Twenty-two adult patients (11 female, mean age 40.2 years) undergoing noninvasive vEEG monitoring for clinical purposes were prospectively enrolled. The EEG recordings were evaluated by 10 independent raters with unmodifiable view settings. The individual evaluations were compared with respect to the presence of abnormal EEG findings (regional slowing, epileptiform potentials, seizure pattern). Video EEG yielded a sensitivity of 56% and specificity of 88% for abnormal EEG findings, whereas mEEG reached 39% and 85%, respectively. Interrater reliability coefficients were better in vEEG as compared to mEEG (ϰ = 0.50 vs. 0.30), corresponding to a moderate and fair agreement. Intrarater reliability between mEEG and vEEG evaluations of simultaneous recordings of a given participant was moderate (ϰ = 0.48). Given the limitations of our exploratory pilot study, our results suggest that vEEG is superior to mEEG, but that mEEG can be helpful for diagnostic purposes. We present the first quantitative comparison of simultaneously acquired clinical and mobile consumer-grade EEG for a clinical use-case.
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http://dx.doi.org/10.1016/j.yebeh.2019.106507DOI Listing
February 2020

Genetic heterogeneity in infantile spasms.

Epilepsy Res 2019 10 29;156:106181. Epub 2019 Jul 29.

Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA. Electronic address:

Infantile spasms (IS) is a developmental and epileptic encephalopathy with heterogeneous etiologies including many genetic causes. Genetic studies have identified pathogenic variants in over 30 genes as causes of IS. Many of these genetic causes are extremely rare, with only one reported incidence in an individual with IS. To better understand the genetic landscape of IS, we used targeted sequencing to screen 42 candidate IS genes and 53 established developmental and epileptic encephalopathy genes in 92 individual with IS. We identified a genetic diagnosis for 7.6% of our cohort, including pathogenic variants in KCNB1 (n = 2), GNAO1 (n = 1), STXBP1 (n = 1), SLC35A2 (n = 1), TBL1XR1 (n = 1), and KIF1A (n = 1). Our data emphasize the genetic heterogeneity of IS and will inform the diagnosis and management of individuals with this devastating disorder.
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http://dx.doi.org/10.1016/j.eplepsyres.2019.106181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814289PMC
October 2019

Seizure management and prescription patterns of anticonvulsants in Dravet syndrome: A multicenter cohort study from Germany and review of literature.

Epilepsy Behav 2019 09 10;98(Pt A):88-95. Epub 2019 Jul 10.

Epilepsy Center Frankfurt Rhine-Main and Department of Neurology, Goethe-University Frankfurt, Frankfurt am Main, Germany; LOEWE Center for Personalized Translational Epilepsy Research (CePTER), Goethe-University Frankfurt, Frankfurt am Main, Germany; Epilepsy Center Hessen and Department of Neurology, Philipps-University Marburg, Marburg (Lahn), Germany. Electronic address:

Objective: The aim of this study was to describe the treatment pattern of patients with Dravet syndrome (DS) in Germany with routine antiepileptic drugs (AEDs) and emergency medication, and to review the literature of real-world evidence on medicine utilization of patients with DS in Europe.

Methods: Patient use of routine AEDs and emergency medications over 3-6 months was analyzed from a 2018 multicenter survey of 93 caregivers of patients with DS throughout Germany. Results were contextualized in a review of real-world evidence on medicine utilization of patients with DS in Europe.

Results: The variety of medications and the most frequent combinations routinely used by patients with DS (AEDs and others) are described. Patients use a large number of pharmaceutical treatments to manage seizures. The five most commonly used AEDs were sodium valproate (66% of the patients; mean daily dose: 660 mg; 24.5 mg per kg bodyweight), bromide (44%; 1462 mg; 51.2 mg per kg), clobazam (41%; 10.4 mg; 0.32 mg per kg), stiripentol (35%; 797 mg; 27.6 mg per kg), and topiramate (24%; 107 mg; 3.5 mg per kg). Ninety percent had reported using emergency medications in the last 3 months;, with the most common medications being Buccolam (40%, an oromucosal form of midazolam) and diazepam (20%, mostly rectal application). No discernable relationships between current medication and age or seizure frequency were observed.

Significance: This is the first comprehensive report of routine AEDs and emergency medication use in a large sample of patients with DS in Germany over a period of 3-6 months and shows that despite the most common AED combinations being in line with clinical guidelines/best practice, there is no discernable impact of best treatment on seizure frequency. We find a higher use of bromide in Germany compared with other real-world evidence in Europe.
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http://dx.doi.org/10.1016/j.yebeh.2019.06.021DOI Listing
September 2019

A multicenter, matched case-control analysis comparing burden-of-illness in Dravet syndrome to refractory epilepsy and seizure remission in patients and caregivers in Germany.

Epilepsia 2019 08 27;60(8):1697-1710. Epub 2019 Jun 27.

Epilepsy Center Frankfurt Rhine-Main and Department of Neurology, Goethe-University Frankfurt, Frankfurt am Main, Germany.

Objective: To compare direct and indirect costs and quality of life (QoL) of pediatric and adult patients with Dravet syndrome (DS), with drug-resistant epilepsy (DRE) and in seizure remission (SR), and their caregivers, in Germany.

Methods: Questionnaire responses from 93 DS patients and their caregivers were matched by age and gender with responses from 93 DRE and 93 SR patients collected in independent studies, and were compared across main components of QoL, direct costs (patient visits, medication use, care level, medical equipment, and ancillary treatments), and indirect costs (quitting job, reduced working hours, missed days).

Results: Mean total direct costs were highest for DS patients (€4864 [median €3564] vs €3049 [median €1506] for DRE [excluding outliers], P = 0.01; and €1007 [median €311], P < 0.001 for SR). Total lost productivity over 3 months was highest among caregivers of pediatric DS (€4757, median €2841), compared with those of DRE (€1541, P < 0.001; median €0) and SR patients (€891, P < 0.001; median €0). The proportions of caregivers in employment were similar across groups (62% DS, 63% DRE, and 63% SR) but DS caregivers were more likely to experience changes to their working situation, such as quitting their job (40% DS vs 16% DRE and 9% SR, P < 0.001 in both comparisons). KINDL scores were significantly lower for DS patients (62 vs 74 and 72, P < 0.001 in both comparisons), and lower than for the average German population (77). Pediatric caregiver EQ-5D scores across all cohorts were comparable with population norms, but more DS caregivers experienced moderate to severe depressive symptoms (24% vs 11% and 5%). Mean Beck Depression Inventory (BDI-II) score was significantly higher in DS caregivers than either of the other groups (P < 0.001).

Significance: This first comparative study of Dravet syndrome to difficult-to-treat epilepsy and to epilepsy patients in seizure remission emphasizes the excess burden of DS in components of QoL and direct costs. The caregivers of DS patients have a greater impairment of their working lives (indirect costs) and increased depression symptoms.
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http://dx.doi.org/10.1111/epi.16099DOI Listing
August 2019

The spectrum of intermediate SCN8A-related epilepsy.

Epilepsia 2019 05 10;60(5):830-844. Epub 2019 Apr 10.

Neuroscience Department, Children's Hospital Anna Meyer, University of Florence, Florence, Italy.

Objective: Pathogenic variants in SCN8A have been associated with a wide spectrum of epilepsy phenotypes, ranging from benign familial infantile seizures (BFIS) to epileptic encephalopathies with variable severity. Furthermore, a few patients with intellectual disability (ID) or movement disorders without epilepsy have been reported. The vast majority of the published SCN8A patients suffer from severe developmental and epileptic encephalopathy (DEE). In this study, we aimed to provide further insight on the spectrum of milder SCN8A-related epilepsies.

Methods: A cohort of 1095 patients were screened using a next generation sequencing panel. Further patients were ascertained from a network of epilepsy genetics clinics. Patients with severe DEE and BFIS were excluded from the study.

Results: We found 36 probands who presented with an SCN8A-related epilepsy and normal intellect (33%) or mild (61%) to moderate ID (6%). All patients presented with epilepsy between age 1.5 months and 7 years (mean = 13.6 months), and 58% of these became seizure-free, two-thirds on monotherapy. Neurological disturbances included ataxia (28%) and hypotonia (19%) as the most prominent features. Interictal electroencephalogram was normal in 41%. Several recurrent variants were observed, including Ile763Val, Val891Met, Gly1475Arg, Gly1483Lys, Phe1588Leu, Arg1617Gln, Ala1650Val/Thr, Arg1872Gln, and Asn1877Ser.

Significance: With this study, we explore the electroclinical features of an intermediate SCN8A-related epilepsy with mild cognitive impairment, which is for the majority a treatable epilepsy.
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http://dx.doi.org/10.1111/epi.14705DOI Listing
May 2019

Burden-of-illness and cost-driving factors in Dravet syndrome patients and carers: A prospective, multicenter study from Germany.

Eur J Paediatr Neurol 2019 May 28;23(3):392-403. Epub 2019 Feb 28.

Epilepsy Center Frankfurt Rhine-Main and Department of Neurology, Goethe-University, Frankfurt am Main, Germany; LOEWE Center for Personalized Translational Epilepsy Research (CePTER), Goethe-University, Frankfurt am Main, Germany; Department of Neuropediatrics, Goethe-University Frankfurt, Frankfurt am Main, Germany.

Introduction: Dravet syndrome (DS) is a rare developmental and epileptic encephalopathy. This study estimated cost, cost-driving factors and quality of life (QoL) in patients with Dravet syndrome and their caregivers in a prospective, multicenter study in Germany.

Methods: A validated 3-12-month retrospective questionnaire and a prospective 3-month diary assessing clinical characteristics, QoL, and direct, indirect and out-of-pocket (OOP) costs were administered to caregivers of patients with DS throughout Germany.

Results: Caregivers of 93 patients (mean age 10.1 years, ±7.1, range 15 months-33.7 years) submitted questionnaires and 77 prospective diaries. The majority of patients (95%) experienced at least one seizure during the previous 12 months and 77% a status epilepticus (SE) at least once in their lives. Over 70% of patients had behavioural problems and delayed speech development and over 80% attention deficit symptoms and disturbance of motor skills and movement coordination. Patient QoL was lower than in the general population and 45% of caregivers had some form of depressive symptoms. Direct health care costs per three months were a mean of €6,043 ± €5,825 (median €4054, CI €4935-€7350) per patient. Inpatient costs formed the single most important cost category (28%, €1,702 ± €4,315), followed by care grade benefits (19%, €1,130 ± €805), anti-epileptic drug (AED) costs (15%, €892 ± €1,017) and ancillary treatments (9%, €559 ± €503). Total indirect costs were €4,399 ±€ 4,989 (median €0, CI €3466-€5551) in mothers and €391 ± €1,352 (median €0, CI €195-€841) in fathers. In univariate analysis seizure frequency, experience of SE, nursing care level and severe additional symptoms were found to be associated with total direct healthcare costs. Severe additional symptoms was the single independently significant explanatory factor in a multivariate analysis.

Conclusions: This study over a period up to 15 months revealed substantial direct and indirect healthcare costs of DS in Germany and highlights the relatively low patient and caregiver QoL compared with the general population.
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http://dx.doi.org/10.1016/j.ejpn.2019.02.014DOI Listing
May 2019

Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish.

Nat Commun 2019 02 12;10(1):708. Epub 2019 Feb 12.

Pediatric Department B' Emek Medical Center, Afula, 1834111, Israel.

Aminoacyl tRNA synthetases (ARSs) link specific amino acids with their cognate transfer RNAs in a critical early step of protein translation. Mutations in ARSs have emerged as a cause of recessive, often complex neurological disease traits. Here we report an allelic series consisting of seven novel and two previously reported biallelic variants in valyl-tRNA synthetase (VARS) in ten patients with a developmental encephalopathy with microcephaly, often associated with early-onset epilepsy. In silico, in vitro, and yeast complementation assays demonstrate that the underlying pathomechanism of these mutations is most likely a loss of protein function. Zebrafish modeling accurately recapitulated some of the key neurological disease traits. These results provide both genetic and biological insights into neurodevelopmental disease and pave the way for further in-depth research on ARS related recessive disorders and precision therapies.
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http://dx.doi.org/10.1038/s41467-018-07953-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372652PMC
February 2019

Genotypes and phenotypes of patients with Lafora disease living in Germany.

Neurol Res Pract 2019 12;1. Epub 2019 Nov 12.

Center for Genomics and Transcriptomics (CeGaT) GmbH and Practice for Human Genetics, Tübingen, Germany.

Background: Lafora progressive myoclonus epilepsy (Lafora disease) is a rare, usually childhood-onset, fatal neurodegenerative disease caused by biallelic mutations in (Laforin) or (, Malin). The epidemiology of Lafora disease in Germany is largely unknown. The objective of this retrospective case series is to characterize the genotypes and phenotypes of patients with Lafora disease living in Germany.

Methods: The patients described in this case series initially had the suspected clinical diagnosis of Lafora disease, or unclassified progressive myoclonus epilepsy. Molecular genetic diagnostics including next generation sequencing-based diagnostic panel analysis or whole exome sequencing was performed.

Results: The parents of four out of the 11 patients are nonconsanguineous and of German origin while the other patients had consanguineous parents. Various variants were found in (six patients) and in (five patients). Eight variants have not been reported in the literature so far. The patients bearing novel variants had typical disease onset during adolescence and show classical disease courses.

Conclusions: This is the first larger case series of Lafora patients in Germany. Our data enable an approximation of the prevalence of manifest Lafora disease in Germany to 1,69 per 10 million people. Broader application of gene panel or whole-exome diagnostics helps clarifying unclassified progressive myoclonus epilepsy and establish an early diagnosis, which will be even more important as causal therapy approaches have been developed and are soon to be tested in a phase I study.
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http://dx.doi.org/10.1186/s42466-019-0040-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316188PMC
November 2019

In response: Neuronal networks in epileptic encephalopathies with CSWS.

Epilepsia 2017 07;58(7):1297-1298

Department of Medical Psychology and Medical Sociology, Christian-Albrechts-University, Kiel, Germany.

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http://dx.doi.org/10.1111/epi.13788DOI Listing
July 2017

encephalopathy: A new disease of vesicle fission.

Neurology 2017 Jul 30;89(4):385-394. Epub 2017 Jun 30.

Author affiliations are provided at the end of the article.

Objective: To evaluate the phenotypic spectrum caused by mutations in dynamin 1 (), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling.

Methods: We reviewed phenotypic data of 21 patients (7 previously published) with mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function.

Results: We identified 19 patients with de novo mutations in and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function.

Conclusions: The phenotypic spectrum of -related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention.
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http://dx.doi.org/10.1212/WNL.0000000000004152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5574673PMC
July 2017

The role of genetic testing in epilepsy diagnosis and management.

Expert Rev Mol Diagn 2017 08 26;17(8):739-750. Epub 2017 Jun 26.

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

Introduction: Epilepsy is a common neurological disorder characterized by recurrent unprovoked seizures. More than 500 epilepsy-associated genes have been described in the literature. Most of these genes play an important role in neuronal excitability, cortical development or synaptic transmission. A growing number of genetic variations have implications on diagnosis and prognostic or therapeutic advice in terms of a personalized medicine. Area covered: The review presents the different forms of genetic epilepsies with respect to their underlying genetic and functional pathophysiology and aims to give advice for recommended genetic testing. Moreover, it discusses ethical and legal guidelines, costs and technical limitations which should be considered. Expert commentary: Genetic testing is an important component in the diagnosis and treatment of many forms of epilepsy.
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http://dx.doi.org/10.1080/14737159.2017.1335598DOI Listing
August 2017

Gene expression analysis in untreated absence epilepsy demonstrates an inconsistent pattern.

Epilepsy Res 2017 05 28;132:84-90. Epub 2017 Feb 28.

Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Kiel University, Kiel, Germany. Electronic address:

Objective: Childhood and Juvenile Absence Epilepsy account for 30% of all genetic generalized epilepsies with a strong genetic contribution. At the current state the genetic background remains to be resolved. The aim of this study was to identify disease associated transcripts pinpointing potential underlying disease mechanisms in patients with CAE and JAE.

Methods: We performed gene expression analysis from peripheral blood mononuclear cells (PBMCs) in 30 patients with newly-diagnosed absence epilepsy prior to initiating treatment and 30 healthy age - and gender-matched pediatric controls. In a first group (group 1), 10 patients and controls we performed genome-wide transcriptome analysis using the Affymetrix HG U133 2.0+ microarray. 75 differentially expressed genes were followed up by qRT-PCR in two independent groups of 10 patients and controls (group 2 and 3). Furthermore, we analyzed 18 candidate genes by qRT-PCR in groups 2 and 3, which had previously been considered strong candidates for genetic epilepsies.

Results: Genome-wide gene expression analysis in group 1 revealed 601 differentially regulated genes. Independent validation of 75 group 1-derived genes by qRT-PCR in groups 2 and 3 confirmed candidate genes with a consistent, but non-significant pattern of up- or down-regulation across all groups (ATP1B3, CAND1, PRPF6, TRIM8). Previously known genes including GABRA1, GABRB3, GABRG2, and RCN2 showed evidence for up- or down-regulation in individual experiments, but were not reliable across groups either.

Discussion: Gene expression analysis in absence epilepsy from PMBCs displayed a high degree of heterogeneity between different patient groups. Our study provides several potentially interesting candidate genes, while demonstrating the limits of using gene expression analysis from blood in the identification of novel pathogenic mechanisms. In particular, we found that gene expression levels vary in response to altered experimental conditions, representing a substantial challenge for the identification of disease-related gene expression signatures for neurological diseases from whole blood.
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http://dx.doi.org/10.1016/j.eplepsyres.2017.02.008DOI Listing
May 2017

Mutations in GABRB3: From febrile seizures to epileptic encephalopathies.

Neurology 2017 01 4;88(5):483-492. Epub 2017 Jan 4.

From the Danish Epilepsy Centre (R.S.M., K.M.J., M.N.), Dianalund; Institute for Regional Health Services (R.S.M., K.M.J., M.N.), University of Southern Denmark, Odense; Department of Neurology and Epileptology (T.V.W., S.V., H.L., S.M.), Hertie Institute for Clinical Brain Research, and Department of Neurosurgery (T.V.W.), University of Tübingen; Department of Neuropediatrics (I.H., M.P., S.v.S., H.M.), University Medical Center Schleswig-Holstein, Kiel, Germany; Division of Neurology (I.H., S.H., H.D.), The Children's Hospital of Philadelphia, PA; Neuroscience Department (C.M., R.G.), Children's Hospital Anna Meyer-University of Florence, Italy; Department of Genetics (E.H.B., M.S., K.L.v.G.), University Medical Center Utrecht, the Netherlands; Department of Neurology and Neurorehabilitation (U.V., I.T., T.T.), Children's Clinic of Tartu University Hospital, Estonia; Department of Pediatric Neurology and Epilepsy Center (I.B.), LMU Munich, Germany; Department of Pediatrics (I.T., T.T.), University of Tartu; Tallinn Children's Hospital (I.T.), Tallinn, Estonia; Clinic for Neuropediatrics and Neurorehabilitation (G.K., C.B., H.H.), Epilepsy Center for Children and Adolescents, Schön Klinik Vogtareuth, Germany; Paracelsus Medical Private University (G.K.), Salzburg, Austria; Neuropeadiatric Department (L.L.F.), Hospices Civils de Lyon; Department of Genetics (G.L., N.C.), Lyon University Hospitals; Claude Bernard Lyon I University (G.L., N.C.); Lyon Neuroscience Research Centre (G.L., N.C.), CNRS UMR5292, INSERM U1028; Epilepsy, Sleep and Pediatric Neurophysiology Department (J.d.B.), Lyon University Hospitals, France; Clinic for Pediatric Neurology (S.B.), Pediatric Department, University Hospital, Herlev, Denmark; Kleinwachau (N.H.), Sächsisches Epilepsiezentrum Radeberg, Dresden; Department of Neuropediatrics/Epilepsy Center (J.J.), University Medical Center Freiburg; Department of General Paediatrics (S.S.), Division of Child Neurology and Inherited Metabolic Diseases, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg; Department of Women and Child Health (S.S.), Hospital for Children and Adolescents, University of Leipzig Hospitals and Clinics, Germany; Department of Pediatrics (C.T.M., H.C.M.), Division of Genetic Medicine, University of Washington, Seattle; Amplexa Genetics (L.H.G.L., H.A.D.), Odense, Denmark; Northern German Epilepsy Center for Children and Adolescents (S.v.S.), Schwentinental-Raisdorf, Germany; Wilhelm Johannsen Centre for Functional Genome Research (Y.M., N.T.), Department of Cellular and Molecular Medicine, University of Copenhagen; Danish Epilepsy Center (G.R.), Filadelfia/University of Copenhagen, Denmark; Department of Diagnostics (J.R.L.), Institute of Human Genetics, University of Leipzig; and Svt. Luka's Institute of Child Neurology and Epilepsy (K.M.), Moscow, Russia. Dr Maljevic is currently at the Florey Institute of Neuroscience and Mental Health, Melbourne, Australia.

Objective: To examine the role of mutations in GABRB3 encoding the β subunit of the GABA receptor in individual patients with epilepsy with regard to causality, the spectrum of genetic variants, their pathophysiology, and associated phenotypes.

Methods: We performed massive parallel sequencing of GABRB3 in 416 patients with a range of epileptic encephalopathies and childhood-onset epilepsies and recruited additional patients with epilepsy with GABRB3 mutations from other research and diagnostic programs.

Results: We identified 22 patients with heterozygous mutations in GABRB3, including 3 probands from multiplex families. The phenotypic spectrum of the mutation carriers ranged from simple febrile seizures, genetic epilepsies with febrile seizures plus, and epilepsy with myoclonic-atonic seizures to West syndrome and other types of severe, early-onset epileptic encephalopathies. Electrophysiologic analysis of 7 mutations in Xenopus laevis oocytes, using coexpression of wild-type or mutant β, together with α and γ subunits and an automated 2-microelectrode voltage-clamp system, revealed reduced GABA-induced current amplitudes or GABA sensitivity for 5 of 7 mutations.

Conclusions: Our results indicate that GABRB3 mutations are associated with a broad phenotypic spectrum of epilepsies and that reduced receptor function causing GABAergic disinhibition represents the relevant disease mechanism.
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http://dx.doi.org/10.1212/WNL.0000000000003565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5278942PMC
January 2017

Pitfalls in genetic testing: the story of missed SCN1A mutations.

Mol Genet Genomic Med 2016 Jul 14;4(4):457-64. Epub 2016 Apr 14.

Department of Neuropediatrics University Medical Center Schleswig-Holstein Kiel Germany.

Background: Sanger sequencing, still the standard technique for genetic testing in most diagnostic laboratories and until recently widely used in research, is gradually being complemented by next-generation sequencing (NGS). No single mutation detection technique is however perfect in identifying all mutations. Therefore, we wondered to what extent inconsistencies between Sanger sequencing and NGS affect the molecular diagnosis of patients. Since mutations in SCN1A, the major gene implicated in epilepsy, are found in the majority of Dravet syndrome (DS) patients, we focused on missed SCN1A mutations.

Methods: We sent out a survey to 16 genetic centers performing SCN1A testing.

Results: We collected data on 28 mutations initially missed using Sanger sequencing. All patients were falsely reported as SCN1A mutation-negative, both due to technical limitations and human errors.

Conclusion: We illustrate the pitfalls of Sanger sequencing and most importantly provide evidence that SCN1A mutations are an even more frequent cause of DS than already anticipated.
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http://dx.doi.org/10.1002/mgg3.217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4947864PMC
July 2016

Neuronal networks in epileptic encephalopathies with CSWS.

Epilepsia 2016 08 15;57(8):1245-55. Epub 2016 Jun 15.

Department of Medical Psychology and Medical Sociology, Christian-Albrechts-University, Kiel, Germany.

Objective: The aim of our study was to investigate the neuronal networks underlying background oscillations of epileptic encephalopathy with continuous spikes and waves during slow sleep (CSWS).

Methods: Sleep electroencephalography (EEG) studies before and after the treatment were investigated in 15 patients with CSWS. To investigate functional and effective connectivity within the network generating the delta activity in the background sleep EEG, the methods of dynamic imaging of coherent sources (DICS) and renormalized partial directed coherence (RPDC) were applied.

Results: Independent of etiology and severity of epilepsy, background EEG pattern in patients with CSWS before treatment is associated with the complex network of coherent sources in medial prefrontal cortex, somatosensory association cortex/posterior cingulate cortex, medial prefrontal cortex, middle temporal gyrus/parahippocampal gyrus/insular cortex, thalamus, and cerebellum. The analysis of information flow within this network revealed that the medial parietal cortex, the precuneus, and the thalamus act as central hubs, driving the information flow to other areas, especially to the temporal and frontal cortex. The described CSWS-specific pattern was no longer observed in patients with normalized sleep EEG. In addition, frequency of spiking showed a strong linear correlations with absolute source power, source coherence strength, and source RPDC strength at both time points: (1) Spike and wave index (SWI) versus absolute source power at EEG1 (r = 0.56; p = 0.008) and at EEG2 (r = 0.45; p = 0.009); (2) SWI versus source coherence strength at EEG1 (r = 0.71; p = 0.005) and at EEG2 (r = 0.52; p = 0.006); and (3) SWI versus source RPDC strength at EEG1 (r = 0.65; p = 0.003) and at EEG2 (r = 0.47; p = 0.009).

Significance: The leading role of the precuneus and thalamus in the hierarchical organization of the network underlying the background EEG points toward the significance of fluctuations of vigilance in the generation of CSWS. This hierarchical network organization appears to be specific for CSWS as it is resolved after successful treatment.
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http://dx.doi.org/10.1111/epi.13428DOI Listing
August 2016

Analysis of epileptic seizure count time series by ensemble state space modelling.

Annu Int Conf IEEE Eng Med Biol Soc 2015 Aug;2015:5601-5

We propose an approach for the analysis of epileptic seizure count time series within a state space framework. Time-dependent dosages of several simultaneously administered anticonvulsants are included as external inputs. The method aims at distinguishing which temporal correlations in the data are due to the medications, and which correspond to an unrelated background signal. Through this method it becomes possible to disentagle the effects of the individual anticonvulsants, i.e., to decide which anticonvulsant in a particular patient decreases or rather increases the number of seizures.
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http://dx.doi.org/10.1109/EMBC.2015.7319662DOI Listing
August 2015

The role of SLC2A1 mutations in myoclonic astatic epilepsy and absence epilepsy, and the estimated frequency of GLUT1 deficiency syndrome.

Epilepsia 2015 Dec 5;56(12):e203-8. Epub 2015 Nov 5.

Danish Epilepsy Center, Dianalund, Denmark.

The first mutations identified in SLC2A1, encoding the glucose transporter type 1 (GLUT1) protein of the blood-brain barrier, were associated with severe epileptic encephalopathy. Recently, dominant SLC2A1 mutations were found in rare autosomal dominant families with various forms of epilepsy including early onset absence epilepsy (EOAE), myoclonic astatic epilepsy (MAE), and genetic generalized epilepsy (GGE). Our study aimed to investigate the possible role of SLC2A1 in various forms of epilepsy including MAE and absence epilepsy with early onset. We also aimed to estimate the frequency of GLUT1 deficiency syndrome in the Danish population. One hundred twenty patients with MAE, 50 patients with absence epilepsy, and 37 patients with unselected epilepsies, intellectual disability (ID), and/or various movement disorders were screened for mutations in SLC2A1. Mutations in SLC2A1 were detected in 5 (10%) of 50 patients with absence epilepsy, and in one (2.7%) of 37 patient with unselected epilepsies, ID, and/or various movement disorders. None of the 120 MAE patients harbored SLC2A1 mutations. We estimated the frequency of SLC2A1 mutations in the Danish population to be approximately 1:83,000. Our study confirmed the role of SLC2A1 mutations in absence epilepsy with early onset. However, our study failed to support the notion that SLC2A1 aberrations are a cause of MAE without associated features such as movement disorders.
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http://dx.doi.org/10.1111/epi.13222DOI Listing
December 2015

Investigation of GRIN2A in common epilepsy phenotypes.

Epilepsy Res 2015 Sep 2;115:95-9. Epub 2015 Jun 2.

Division of Human Genetics, University Children's Hospital Inselspital, Bern, Switzerland; Institute of Human Genetics, University Medical Center Leipzig, Leipzig, Germany. Electronic address:

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.
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http://dx.doi.org/10.1016/j.eplepsyres.2015.05.010DOI Listing
September 2015

Investigating the genetic basis of fever-associated syndromic epilepsies using copy number variation analysis.

Epilepsia 2015 Mar 17;56(3):e26-32. Epub 2015 Feb 17.

Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany.

Fever-associated syndromic epilepsies ranging from febrile seizures plus (FS+) to Dravet syndrome have a significant genetic component. However, apart from SCN1A mutations in >80% of patients with Dravet syndrome, the genetic underpinnings of these epilepsies remain largely unknown. Therefore, we performed a genome-wide screening for copy number variations (CNVs) in 36 patients with SCN1A-negative fever-associated syndromic epilepsies. Phenotypes included Dravet syndrome (n = 23; 64%), genetic epilepsy with febrile seizures plus (GEFS+) and febrile seizures plus (FS+) (n = 11; 31%) and unclassified fever-associated epilepsies (n = 2; 6%). Array comparative genomic hybridization (CGH) was performed using Agilent 4 × 180K arrays. We identified 13 rare CNVs in 8 (22%) of 36 individuals. These included known pathogenic CNVs in 4 (11%) of 36 patients: a 1q21.1 duplication in a proband with Dravet syndrome, a 14q23.3 deletion in a proband with FS+, and two deletions at 16p11.2 and 1q44 in two individuals with fever-associated epilepsy with concomitant autism and/or intellectual disability. In addition, a 3q13.11 duplication in a patient with FS+ and two de novo duplications at 7p14.2 and 18q12.2 in a patient with atypical Dravet syndrome were classified as likely pathogenic. Six CNVs were of unknown significance. The identified genomic aberrations overlap with known neurodevelopmental disorders, suggesting that fever-associated epilepsy syndromes may be a recurrent clinical presentation of known microdeletion syndromes.
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http://dx.doi.org/10.1111/epi.12920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4363163PMC
March 2015

GABRA1 and STXBP1: novel genetic causes of Dravet syndrome.

Neurology 2014 Apr 12;82(14):1245-53. Epub 2014 Mar 12.

From the Division of Genetic Medicine, Department of Pediatrics (G.L.C., C.H., J.C., E.G., H.C.M.), and the Department of Genome Sciences (J.S.), University of Washington, Seattle; Neurogenetics Group (S.W.), Department of Molecular Genetics, VIB, Antwerp; Laboratory of Neurogenetics (S.W., A.S., P.D.J.), Institute Born-Bunge, University of Antwerp, Belgium; Epilepsy Centre Kempenhaeghe (S.W.), Oosterhout, the Netherlands; Epilepsy Research Centre (J.M.M., S.F.B., I.E.S.), Department of Medicine, University of Melbourne, Austin Health, Australia; Department of Neuropediatrics (C.H., H.M., S.v.S., I.H.), University Medical Center, Schleswig-Holstein, Christian-Albrechts University, Kiel, Germany; Danish Epilepsy Centre (R.S.M., H.H., M.N.), Dianalund; Institute for Regional Health Services (H.H., M.N.), University of Southern Denmark, Odense, Denmark; Department of Molecular and Medical Genetics (B.J.O.), Oregon Health and Science University, Portland; Florey Institute (S.P., A.C., E.V.G., I.E.S.), Victoria; TY Nelson Department of Neurology (D.G.), The Children's Hospital at Westmead, Sydney, NSW, Australia; Department of Paediatrics (L.G.S.), School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand; Epilepsy Research Program (B.L.H., L.M.D.), School of Pharmacy and Medical Sciences, University of South Australia, Adelaide; Division of Neurology (P.D.J.), Antwerp University Hospital, Belgium; and the Department of Paediatrics (I.E.S.), University of Melbourne, Royal Children's Hospital, Australia.

Objective: To determine the genes underlying Dravet syndrome in patients who do not have an SCN1A mutation on routine testing.

Methods: We performed whole-exome sequencing in 13 SCN1A-negative patients with Dravet syndrome and targeted resequencing in 67 additional patients to identify new genes for this disorder.

Results: We detected disease-causing mutations in 2 novel genes for Dravet syndrome, with mutations in GABRA1 in 4 cases and STXBP1 in 3. Furthermore, we identified 3 patients with previously undetected SCN1A mutations, suggesting that SCN1A mutations occur in even more than the currently accepted ∼ 75% of cases.

Conclusions: We show that GABRA1 and STXBP1 make a significant contribution to Dravet syndrome after SCN1A abnormalities have been excluded. Our results have important implications for diagnostic testing, clinical management, and genetic counseling of patients with this devastating disorder and their families.
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http://dx.doi.org/10.1212/WNL.0000000000000291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4001207PMC
April 2014

Structural genomic variation in childhood epilepsies with complex phenotypes.

Eur J Hum Genet 2014 Jul 27;22(7):896-901. Epub 2013 Nov 27.

Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.

A genetic contribution to a broad range of epilepsies has been postulated, and particularly copy number variations (CNVs) have emerged as significant genetic risk factors. However, the role of CNVs in patients with epilepsies with complex phenotypes is not known. Therefore, we investigated the role of CNVs in patients with unclassified epilepsies and complex phenotypes. A total of 222 patients from three European countries, including patients with structural lesions on magnetic resonance imaging (MRI), dysmorphic features, and multiple congenital anomalies, were clinically evaluated and screened for CNVs. MRI findings including acquired or developmental lesions and patient characteristics were subdivided and analyzed in subgroups. MRI data were available for 88.3% of patients, of whom 41.6% had abnormal MRI findings. Eighty-eight rare CNVs were discovered in 71 out of 222 patients (31.9%). Segregation of all identified variants could be assessed in 42 patients, 11 of which were de novo. The frequency of all structural variants and de novo variants was not statistically different between patients with or without MRI abnormalities or MRI subcategories. Patients with dysmorphic features were more likely to carry a rare CNV. Genome-wide screening methods for rare CNVs may provide clues for the genetic etiology in patients with a broader range of epilepsies than previously anticipated, including in patients with various brain anomalies detectable by MRI. Performing genome-wide screens for rare CNVs can be a valuable contribution to the routine diagnostic workup in patients with a broad range of childhood epilepsies.
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http://dx.doi.org/10.1038/ejhg.2013.262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4060113PMC
July 2014

Iterative phenotyping of 15q11.2, 15q13.3 and 16p13.11 microdeletion carriers in pediatric epilepsies.

Epilepsy Res 2014 Jan 26;108(1):109-16. Epub 2013 Oct 26.

Department of Neuropediatrics, University Medical Center Schleswig-Holstein (UKSH, Campus Kiel), Kiel, Germany. Electronic address:

Microdeletions at 15q11.2, 15q13.3 and 16p13.11 are known genetic risk factors for idiopathic generalized epilepsies and other neurodevelopmental disorders. The full phenotypic range of this microdeletion triad in pediatric epilepsies is unknown. We attempted to describe associated phenotypes in a cohort of pediatric epilepsy patients. We screened 570 patients with pediatric epilepsies including idiopathic generalized epilepsies, focal epilepsies and fever-associated epilepsy syndromes for microdeletions at 15q11.2, 15q13.3 and 16p13.11 using quantitative polymerase chain reaction. Identified microdeletions were confirmed using array comparative hybridization. Ten microdeletions in 15q11.2 (n=3), 15q13.3 (n=3) and 16p13.11 (n=4) were identified (1.8%). 9/10 microdeletions were identified in patients with IGE (6/101, 6.0%) or patients with generalized EEG patterns without seizures (3/122, 2.5%). 6/10 microdeletion carriers had various degrees of ID; the frequency of microdeletions in patients with epilepsy and ID was higher (4.6%) compared to patients with normal intellect (0.9%). Iterative phenotyping revealed a wide range of generalized epilepsy phenotypes. In our pediatric cohort, recurrent microdeletions at 15q11.2, 15q13.3 and 16p13.11 are mainly associated with phenotypes related to idiopathic generalized epilepsies or related EEG patterns. In contrast to previous reports, these recurrent microdeletions are virtually absent in focal epilepsies, FS, FS+ and GEFS+. Microdeletion carriers have a five-fold risk to present with various degrees of ID compared to patients without these risk factors. This microdeletion triad might help delineate a novel spectrum of epilepsy phenotypes classifiable through clinical, electrographic and genetic data.
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http://dx.doi.org/10.1016/j.eplepsyres.2013.10.001DOI Listing
January 2014

De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with Dravet syndrome.

Am J Hum Genet 2013 Nov 24;93(5):967-75. Epub 2013 Oct 24.

Neurogenetics group, Department of Molecular Genetics, VIB, 2610 Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, 2610 Antwerp, Belgium.

Dravet syndrome is a severe epilepsy syndrome characterized by infantile onset of therapy-resistant, fever-sensitive seizures followed by cognitive decline. Mutations in SCN1A explain about 75% of cases with Dravet syndrome; 90% of these mutations arise de novo. We studied a cohort of nine Dravet-syndrome-affected individuals without an SCN1A mutation (these included some atypical cases with onset at up to 2 years of age) by using whole-exome sequencing in proband-parent trios. In two individuals, we identified a de novo loss-of-function mutation in CHD2 (encoding chromodomain helicase DNA binding protein 2). A third CHD2 mutation was identified in an epileptic proband of a second (stage 2) cohort. All three individuals with a CHD2 mutation had intellectual disability and fever-sensitive generalized seizures, as well as prominent myoclonic seizures starting in the second year of life or later. To explore the functional relevance of CHD2 haploinsufficiency in an in vivo model system, we knocked down chd2 in zebrafish by using targeted morpholino antisense oligomers. chd2-knockdown larvae exhibited altered locomotor activity, and the epileptic nature of this seizure-like behavior was confirmed by field-potential recordings that revealed epileptiform discharges similar to seizures in affected persons. Both altered locomotor activity and epileptiform discharges were absent in appropriate control larvae. Our study provides evidence that de novo loss-of-function mutations in CHD2 are a cause of epileptic encephalopathy with generalized seizures.
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http://dx.doi.org/10.1016/j.ajhg.2013.09.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3824114PMC
November 2013

Atypical vitamin B6 deficiency: a rare cause of unexplained neonatal and infantile epilepsies.

J Child Neurol 2014 May 10;29(5):704-7. Epub 2013 Oct 10.

1Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Kiel, Germany.

ALDH7A1 and PNPO deficiencies are rare inborn errors of vitamin B6 metabolism causing perinatal seizure disorders. The phenotypic variability, however, is broad. To assess the frequency of these deficiencies in unexplained infantile epilepsy, we screened 113 patients for mutations in both genes. We identified 1 patient with an epilepsy phenotype resembling Dravet syndrome and likely pathogenic mutations in ALDH7A1. Presenting features were highly atypical of pyridoxine-dependent epilepsy, including febrile seizures, response to anticonvulsive drugs, and periods of seizure freedom without pyridoxine treatment. "Hidden" vitamin B6 deficiencies might be rare but treatable causes of unexplained epilepsy extending beyond the classical phenotypes.
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http://dx.doi.org/10.1177/0883073813505354DOI Listing
May 2014

Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes.

Nat Genet 2013 Sep 11;45(9):1067-72. Epub 2013 Aug 11.

Division of Human Genetics, University Children's Hospital Inselspital, Bern, Switzerland.

Idiopathic focal epilepsy (IFE) with rolandic spikes is the most common childhood epilepsy, comprising a phenotypic spectrum from rolandic epilepsy (also benign epilepsy with centrotemporal spikes, BECTS) to atypical benign partial epilepsy (ABPE), Landau-Kleffner syndrome (LKS) and epileptic encephalopathy with continuous spike and waves during slow-wave sleep (CSWS). The genetic basis is largely unknown. We detected new heterozygous mutations in GRIN2A in 27 of 359 affected individuals from 2 independent cohorts with IFE (7.5%; P = 4.83 × 10(-18), Fisher's exact test). Mutations occurred significantly more frequently in the more severe phenotypes, with mutation detection rates ranging from 12/245 (4.9%) in individuals with BECTS to 9/51 (17.6%) in individuals with CSWS (P = 0.009, Cochran-Armitage test for trend). In addition, exon-disrupting microdeletions were found in 3 of 286 individuals (1.0%; P = 0.004, Fisher's exact test). These results establish alterations of the gene encoding the NMDA receptor NR2A subunit as a major genetic risk factor for IFE.
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http://dx.doi.org/10.1038/ng.2728DOI Listing
September 2013
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