Publications by authors named "Sarah Weckhuysen"

109 Publications

The Angelman Syndrome Online Registry - A multilingual approach to support global research.

Eur J Med Genet 2021 Oct 4;64(12):104349. Epub 2021 Oct 4.

Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany; Center for Rare Diseases, University of Leipzig Medical Center, Leipzig, Germany. Electronic address:

In collaboration with the German Angelman syndrome (AS) community, we developed a web-based AS Online Registry to congregate existing as well as future information and scientifically quantify observations made by parents, families and medical professionals. With its user-friendly design as well as its concise and multilingual questionnaire, the registry aims at families who had so far refrained from being recruited by other, more comprehensive and/or English-only, registries. Data can be entered by both parents/families and medical professionals. The study design allows for re-contacting individuals (e.g. to request additional information) enabling collection of longitudinal data. Since its launch in June 2020, more than 200 individuals with AS age 2 month to 83 years have registered and entered their clinical and genetic data. In addition to the German, Turkish, English, Dutch, Italian, Danish and Finnish versions of the registry, we aim for translation into further languages to enable international and user-friendly recruitment of AS individuals. This novel registry will allow for extensive genotype-phenotype correlations and facilitate sharing of de-identified information among clinicians, researchers as well as the Global AS Registry. Furthermore, the registry will allow for identification of individuals suitable for future clinical or pharmacologic trials according to particular genotypic and/or phenotypic properties.
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http://dx.doi.org/10.1016/j.ejmg.2021.104349DOI Listing
October 2021

Bi-allelic gephyrin variants impair GABAergic inhibition in a patient with epileptic encephalopathy.

Hum Mol Genet 2021 Oct 7. Epub 2021 Oct 7.

Institute of Biochemistry, Department of Chemistry, University of Cologne, 50674 Cologne, Germany.

Synaptic inhibition is essential for shaping the dynamics of neuronal networks, and aberrant inhibition is linked to epilepsy. Gephyrin (Geph) is the principal scaffolding protein at inhibitory synapses and is essential for postsynaptic clustering of glycine (GlyRs) and GABA type A receptors (GABAARs). Consequently, gephyrin is crucial for maintaining the relationship between excitation and inhibition in normal brain function and mutations in the gephyrin gene (GPHN) are associated with neurodevelopmental disorders and epilepsy. We identified bi-allelic variants in the GPHN gene, namely the missense mutation c.1264G > A and splice acceptor variant c.1315-2A > G, in a patient with developmental and epileptic encephalopathy (DEE). We demonstrate that the splice acceptor variant leads to nonsense-mediated mRNA decay (NMD). Furthermore, the missense variant (D422N) alters gephyrin structure, as examined by analytical size exclusion chromatography and CD-spectroscopy, thus leading to reduced receptor clustering and sensitivity towards calpain-mediated cleavage. Additionally, both alterations contribute to an observed reduction of inhibitory signal transmission in neurons, which likely contributes to the pathological encephalopathy.
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http://dx.doi.org/10.1093/hmg/ddab298DOI Listing
October 2021

Phenotypes and genotypes in non-consanguineous and consanguineous primary microcephaly: High incidence of epilepsy.

Mol Genet Genomic Med 2021 Sep 17;9(9):e1768. Epub 2021 Aug 17.

Department of Genetics, Hôpital Erasme, ULB Center of Human Genetics, Université Libre de Bruxelles, Brussels, Belgium.

Background: Primary microcephaly (PM) is defined as a significant reduction in occipitofrontal circumference (OFC) of prenatal onset. Clinical and genetic heterogeneity of PM represents a diagnostic challenge.

Methods: We performed detailed phenotypic and genomic analyses in a large cohort (n = 169) of patients referred for PM and could establish a molecular diagnosis in 38 patients.

Results: Pathogenic variants in ASPM and WDR62 were the most frequent causes in non-consanguineous patients in our cohort. In consanguineous patients, microarray and targeted gene panel analyses reached a diagnostic yield of 67%, which contrasts with a much lower rate in non-consanguineous patients (9%). Our series includes 11 novel pathogenic variants and we identify novel candidate genes including IGF2BP3 and DNAH2. We confirm the progression of microcephaly over time in affected children. Epilepsy was an important associated feature in our PM cohort, affecting 34% of patients with a molecular confirmation of the PM diagnosis, with various degrees of severity and seizure types.

Conclusion: Our findings will help to prioritize genomic investigations, accelerate molecular diagnoses, and improve the management of PM patients.
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http://dx.doi.org/10.1002/mgg3.1768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457702PMC
September 2021

KCNT1-related epilepsies and epileptic encephalopathies: phenotypic and mutational spectrum.

Brain 2021 Jun 11. Epub 2021 Jun 11.

Pediatric Neurology Department, Lyon University Hospital, 69500 Bron, France.

Variants in KCNT1, encoding a sodium-gated potassium channel (subfamily T member 1), have been associated with a spectrum of epilepsies and neurodevelopmental disorders. These range from familial autosomal dominant or sporadic sleep-related hypermotor epilepsy ((AD)SHE) to epilepsy of infancy with migrating focal seizures (EIMFS) and include developmental and epileptic encephalopathies (DEE). This study aims to provide a comprehensive overview of the phenotypic and genotypic spectrum of KCNT1 mutation-related epileptic disorders in 248 individuals, including 66 unpreviously published and 182 published cases, the largest cohort reported so far. Four phenotypic groups emerged from our analysis: i) EIMFS (152 individuals, 33 previously unpublished); ii) DEE other than EIMFS (non-EIMFS DEE) (37 individuals, 17 unpublished); iii) (AD)SHE (53 patients, 14 unpublished); iv) other phenotypes (6 individuals, 2 unpublished). In our cohort of 66 new cases, the most common phenotypic features were: a) in EIMFS, heterogeneity of seizure types, including epileptic spasms, epilepsy improvement over time, no epilepsy-related deaths; b) in non-EIMFS DEE, possible onset with West syndrome, occurrence of atypical absences, possible evolution to DEE with SHE features; one case of sudden unexplained death in epilepsy (SUDEP); c) in (AD)SHE, we observed a high prevalence of drug-resistance, although seizure frequency improved with age in some individuals, appearance of cognitive regression after seizure onset in all patients, no reported severe psychiatric disorders, although behavioural/psychiatric comorbidities were reported in about 50% of the patients, SUDEP in one individual; d) other phenotypes in individuals with mutation of KCNT1 included temporal lobe epilepsy, and epilepsy with tonic-clonic seizures and cognitive regression. Genotypic analysis of the whole cohort of 248 individuals showed only missense mutations and one inframe deletion in KCNT1. Although the KCNT1 mutations in affected individuals were seen to be distributed among the different domains of the KCNT1 protein, genotype-phenotype considerations showed many of the (AD)SHE-associated mutations to be clustered around the RCK2 domain in the C-terminus, distal to the NADP domain. Mutations associated with EIMFS/non-EIMFS DEE did not show a particular pattern of distribution in the KCNT1 protein. Recurrent KCNT1 mutations were seen to be associated with both severe and less severe phenotypes. Our study further defines and broadens the phenotypic and genotypic spectrums of KCNT1-related epileptic conditions and emphasizes the increasingly important role of this gene in the pathogenesis of early onset DEEs as well as in focal epilepsies, namely (AD)SHE.
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http://dx.doi.org/10.1093/brain/awab219DOI Listing
June 2021

Patients with -related intellectual disability without distinctive features of Zimmermann-Laband/Temple-Baraitser syndrome.

J Med Genet 2021 Apr 2. Epub 2021 Apr 2.

APHP.Sorbonne Université, Département de Génétique, Groupe Hospitalier Pitié Salpêtrière et Hôpital Trousseau, Paris, Île-de-France, France.

De novo missense variants in encoding Kv10.1 are responsible for two clinically recognisable phenotypes: Temple-Baraitser syndrome (TBS) and Zimmermann-Laband syndrome (ZLS). The clinical overlap between these two syndromes suggests that they belong to a spectrum of -related encephalopathies. Affected patients have severe intellectual disability (ID) with or without epilepsy, hypertrichosis and distinctive features such as gingival hyperplasia and nail hypoplasia/aplasia (present in 20/23 reported cases).We report a series of seven patients with ID and de novo pathogenic variants identified by whole-exome sequencing or an epilepsy gene panel in whom the diagnosis of TBS/ZLS had not been first considered. Four of these variants, p.(Thr294Met), p.(Ala492Asp), p.(Thr493Asn) and p.(Gly496Arg), were located in the transmembrane domains S3 and S6 of Kv10.1 and one, p.(Arg693Gln), in its C-terminal cyclic nucleotide-binding homology domain (CNBHD). Clinical reappraisal by the referring clinical geneticists confirmed the absence of the distinctive gingival and nail features of TBS/ZLS.Our study expands the phenotypical spectrum of -related encephalopathies to individuals with an attenuated extraneurological phenotype preventing a clinical diagnosis of TBS or ZLS. This subtype may be related to recurrent substitutions of the Gly496, suggesting a genotype-phenotype correlation and, possibly, to variants in the CNBHD domain.
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http://dx.doi.org/10.1136/jmedgenet-2020-107511DOI Listing
April 2021

Adult phenotype of encephalopathy.

J Med Genet 2021 Apr 2. Epub 2021 Apr 2.

Neurology Department, University Hospital Antwerp, Antwerp, Belgium

Background: Pathogenic variants are a frequent cause of developmental and epileptic encephalopathy.

Methods: We recruited 13 adults (between 18 years and 45 years of age) with encephalopathy and reviewed their clinical, EEG, neuroimaging and treatment history.

Results: While most patients had daily seizures at seizure onset, seizure frequency declined or remitted during childhood and adulthood. The most common seizure type was tonic seizures (early) infancy, and tonic-clonic and focal impaired awareness seizures later in life. Ten individuals (77%) were seizure-free at last follow-up. In 38% of the individuals, earlier periods of seizure freedom lasting a minimum of 2 years followed by seizure recurrence had occurred. Of the 10 seizure-free patients, 4 were receiving a single antiseizure medication (ASM, carbamazepine, lamotrigine or levetiracetam), and 2 had stopped taking ASM. Intellectual disability (ID) ranged from mild to profound, with the majority (54%) of individuals in the severe category. At last contact, six individuals (46%) remained unable to walk independently, six (46%) had limb spasticity and four (31%) tetraparesis/tetraplegia. Six (46%) remained non-verbal, 10 (77%) had autistic features/autism, 4 (31%) exhibited aggressive behaviour and 4 (31%) destructive behaviour with self-injury. Four patients had visual problems, thought to be related to prematurity in one. Sleep problems were seen in six (46%) individuals.

Conclusion: Seizure frequency declines over the years and most patients are seizure-free in adulthood. Longer seizure-free periods followed by seizure recurrence are common during childhood and adolescence. Most adult patients have severe ID. Motor, language and behavioural problems are an issue of continuous concern.
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http://dx.doi.org/10.1136/jmedgenet-2020-107449DOI Listing
April 2021

Genotype-phenotype correlations in patients with de novo pathogenic variants.

Neurol Genet 2020 Dec 30;6(6):e528. Epub 2020 Nov 30.

Department of Neurosciences (F. Malerba, G.B., E.A., A. Riva, V.S., L.N., C. Minetti, F.Z., P.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Università degli Studi di Genova; Pediatric Neurology and Muscular Diseases Unit (F. Malerba, G.B., F. Marchese, E.A., A. Riva, M.S.V., V.S., C. Minetti, P.S.), IRCCS Istituto G. Gaslini; Center for Synaptic Neuroscience and Technology ([email protected]) (G.A., L.M., F.B.), Istituto Italiano di Tecnologia; Department of Experimental Medicine (G.A.), Università degli Studi di Genova; Laboratory of Human Genetics (E.G.); Unit of Medical Genetics (F. Madia, F.Z.), IRCCS Istituto G. Gaslini, Genova, Italy; Child Neurology and Neurorehabilitation Unit (M.A.), Department of Pediatrics, Central Hospital of Bolzano, Bolzano; Child Neurology and Psychiatry Unit (L.G., P.A., P.M.), ASST Spedali Civili, Brescia; Neurology Unit (M. Trivisano, N.S.), Department of Neuroscience, Bambino Gesù Children's Hospital, IRCCS, Roma; Child Neurology Unit (A. Russo, G.G.), IRCCS, Institute of Neurological Sciences of Bologna; Child Neuropsychiatry Unit (F.R.), U.O.N.P.I.A. ASST-Rhodense, Rho, Milano; Neurology Unit and Laboratories (T.P.), A. Meyer Children's Hospital, Firenze; Child Neurology and Psychiatric Unit (C. Marini), Pediatric Hospital G. Salesi, United Hospital of Ancona; Child Neuropsychiatry Unit (M.M.M., L.N.), IRCCS Istituto G. Gaslini, Genova; Department of Pediatric Neuroscience (E.F.), Fondazione IRCCS Istituto Neurologico Carlo Besta; Unit of Genetics of Neurodegenerative and Metabolic Diseases (B. Castellotti), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano; Department of Child Neuropsychiatry (G.C.), Epilepsy Center, C. Poma Hospital, Mantova; Fondazione Poliambulanza Brescia (G.C.); Epilepsy Center (A.C.), Department of Neuroscience, Reproductive and Odontostomatological Sciences, Università degli Studi di Napoli Federico II, Napoli; Department of Pediatrics (A.V.), University of Perugia; Section of Pharmacology (F. Miceli, M. Taglialatela), Department of Neuroscience, Reproductive and Odontostomatological Sciences, Università degli Studi di Napoli Federico II, Napoli; IRCCS Ospedale Policlinico San Martino (L.M., F.B.), Genova, Italy; Division of Pediatric Neurology (M.R.C.), Saint-Luc University Hospital, and Institute of Experimental and Clinical Research (IREC), Université Catholique de Louvain, Brussels, Belgium; Department of Epilepsy Genetics and Personalized Treatment (K.M.J., R.S.M.), The Danish Epilepsy Center Filadelfia, Dianalund, Denmark; Institute for Regional Health Services (K.M.J., R.S.M.), University of Southern Denmark, Odense, Denmark; Department of Neurology (B. Ceulemans, S.W.), University Hospital Antwerp; Applied & Translational Neurogenomics Group (S.W.), VIB-Center for Molecular Neurology; Laboratory of Neurogenetics (S.W.), Institute Born-Bunge, University of Antwerp, Belgium; and Department of Life and Environmental Sciences (L.M.), Polytechnic University of Marche, Ancona, Italy.

Objective: Early identification of de novo variants in patients with epilepsy raises prognostic issues toward optimal management. We analyzed the clinical and genetic information from a cohort of patients with de novo pathogenic variants to dissect genotype-phenotype correlations.

Methods: Patients with de novo pathogenic variants were identified from Italy, Denmark, and Belgium. Atomic resolution Kv7.2 structures were also generated using homology modeling to map the variants.

Results: We included 34 patients with a mean age of 4.7 years. Median seizure onset was 2 days, mainly with focal seizures with autonomic signs. Twenty-two patients (65%) were seizure free at the mean age of 1.2 years. More than half of the patients (17/32) displayed severe/profound intellectual disability; however, 4 (13%) of them had a normal cognitive outcome.A total of 28 de novo pathogenic variants were identified, most missense (25/28), and clustered in conserved regions of the protein; 6 variants recurred, and 7 were novel. We did not identify a relationship between variant position and seizure offset or cognitive outcome in patients harboring missense variants. Besides, recurrent variants were associated with overlapping epilepsy features but also variable evolution regarding the intellectual outcome.

Conclusions: We highlight the complexity of variant interpretation to assess the impact of a class of de novo mutations. Genetic modifiers could be implicated, but the study paradigms to successfully address the impact of each single mutation need to be developed.
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http://dx.doi.org/10.1212/NXG.0000000000000528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803337PMC
December 2020

Impact of COVID-19 on the lives and psychosocial well-being of persons with epilepsy during the third trimester of the pandemic: Results from an international, online survey.

Epilepsy Behav 2021 03 29;116:107800. Epub 2021 Jan 29.

Global Health Institute, University of Antwerp, Belgium. Electronic address:

Objective: To evaluate the impact of the coronavirus disease 2019 (COVID-19) measures on the lives and psychosocial well-being of persons with epilepsy (PWE) during the third trimester of the COVID-19 pandemic.

Methods: A structured questionnaire investigating different aspects of the lives and psychosocial well-being of PWE during the COVID-19 pandemic was developed. Persons with epilepsy were invited via social media to anonymously respond to a secure web-based online questionnaire (www.icpcovid.com). Responses were collected between July 26th and December 3rd, 2020. Hospital anxiety and depression scales (HADS) were used to screen respondents for depression (HADS-D) and anxiety (HADS-A).

Results: Responses of 407 PWE were included in the analysis; 304 (74.7%) respondents were female and 245 (60.2%) living in Europe, 157 (38.6%) in South America, and 5 (1.2%) in Canada. Seventy-six (18.7%) reported a decrease of income during the COVID-19 lockdown, and 122 (30.0%) experienced difficulties in obtaining anti-seizure medication (ASM), mostly (72/122, 59.0%) due to unavailability. Seizure frequency increased in 122 (30.0%); 295 (72.5%) screened positive for anxiety, and 159 (39.1%) for depression. Hundred eighty-eight (46.2%) reported reluctance to seek medical care; 27.3% believed that epilepsy was associated with an increased risk of COVID-19 disease. Forty-six (74.2%) of 62 PWE who were followed up by telephone or video consult were satisfied with this consult. Fifty-five respondents, most (89.1%) of whom were from Europe, had also participated in a previous survey during the early months of the pandemic. In this subgroup, although there was no difference in prevalence of a positive screening for depression or anxiety, mean scores on HADS-A and HADS-D increased from 6.65 ± 3.99 to 7.27 ± 4.01 (p = 0.418), and from 5.84 ± 4.43 to 6.60 ± 4.45 (p = 0.371), respectively.

Conclusions: The COVID-19 pandemic continues to impact the psychosocial and somatic well-being of PWE. To minimize this impact, ensuring uninterrupted access to ASM is essential. Teleconsultations are valid alternatives for continued follow-up, but should include attention to psychosocial well-being. Persons with epilepsy should be more actively informed that epilepsy is not a risk factor for developing (more severe) COVID-19 disease.
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http://dx.doi.org/10.1016/j.yebeh.2021.107800DOI Listing
March 2021

Mutations Expand the Phenotypic Spectrum of Alternating Hemiplegia of Childhood.

Neurology 2021 03 27;96(11):e1539-e1550. Epub 2021 Jan 27.

From the UCL Queen Square Institute of Neurology (S.Z., S.K., L.H.-H., H.M.C., S.M.S.), London; Chalfont Centre for Epilepsy (S.Z., S.K., H.M.C., S.M.S.), Buckinghamshire; Department of Neurology (D.S., A.V., J.H.C., M.A.K.), Great Ormond Street Hospital; Clinical Neurosciences (A.V., J.H.C.), and Neurogenetics Group (D.S., M.A.K.), Developmental Neurosciences NIHR BRC UCL Great Ormond Street Institute of Child Health, London; School of Life Sciences (S.K.), Faculty of Science and Engineering, Anglia Ruskin University, Cambridge, UK; Department of Neurology and Clinical Neurophysiology (K.M.G., M.D.K., B.J.L.), Children's Health Ireland at Temple Street, Dublin 1; School of Medicine and Medical Sciences (K.M.G., M.D.K.), University College Dublin, Dublin 4, Ireland; Danish Epilepsy Centre (R.S.M., T.B.H.), Dianalund; Department of Regional Health Research (R.S.M.), University of Southern Denmark, Odense; Department of Paediatric Neurology (R.S., A.A.M., A.M.), Bristol Royal Hospital for Children, UK; Pediatric Neurology (W.F.), Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne; Institute of Human Genetics (T.B.), University of Leipzig Medical Center, Germany; Departement de Neuropediatrie (D.D.), Centre de Référence Neurogénetique Mouvements Anormaux, Hôpital Armand Trousseau, and Department of Genetics (B.K., C.M.), La Pitié-Salpêtrière Hospital, APHP, Sorbonne University, Paris; Centre de Référence Déficiences Intellectuelles de Causes Rares (C.M.); Departement de Pediatrie (N.B.), American Memorial Hospital, CHU Reims; CReSTIC (N.B.), University of Reims Champagne-Ardennes, France; University of Bristol (A.A.M.); Department of Haematology (A.S.-J.) and Cambridge Institute for Medical Research (F.L.R.), University of Cambridge; NIHR BioResource (A.S.-J., F.L.R.), Cambridge University Hospitals NHS Foundation Trust; Paediatric Neurology (A.B.), Great North Childrens Hospital, Newcastle upon Tyne; Population Health Sciences Institute (A.B.), Newcastle University, UK; Applied & Translational Genomics Group (H.S., S.W.), VIB-Center for Molecular Neurology, University of Antwerp; and Department of Neurology (H.S., S.W.), University Hospital Antwerp, Belgium.

Objective: To explore the phenotypic spectrum of -related disorders and specifically to determine whether patients fulfill criteria for alternating hemiplegia of childhood (AHC), we report the clinical features of 11 affected individuals.

Methods: Individuals with -related disorders were identified through a movement disorder clinic at a specialist pediatric center, with additional cases identified through collaboration with other centers internationally. Clinical data were acquired through retrospective case-note review.

Results: Eleven affected patients were identified. All had heterozygous missense variants involving exon 9 of , confirmed as de novo in 9 cases. All had a complex motor phenotype, including at least 2 different kinds of movement disorder, e.g., ataxia and dystonia. Many patients demonstrated several features fulfilling the criteria for AHC: 10 patients had a movement disorder including paroxysmal elements, and 8 experienced hemiplegic episodes. In contrast to classic AHC, commonly caused by mutations in , these events were reported later only in mutation-positive patients from 20 months of age. Seven patients had epilepsy, but of these, 4 patients achieved seizure freedom. All patients had intellectual disability, usually moderate to severe. Other features include episodes of marked skin color change and gastrointestinal symptoms, each in 4 patients.

Conclusion: Although heterozygous mutations were originally described in early infantile epileptic encephalopathy type 64, our study confirms that they account for a more expansive clinical phenotype, including a complex polymorphic movement disorder with paroxysmal elements resembling AHC. testing should therefore be considered in patients with an AHC-like phenotype, particularly those negative for mutations.
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http://dx.doi.org/10.1212/WNL.0000000000011543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032376PMC
March 2021

Variants in the SK2 channel gene (KCNN2) lead to dominant neurodevelopmental movement disorders.

Brain 2020 12;143(12):3564-3573

Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany.

KCNN2 encodes the small conductance calcium-activated potassium channel 2 (SK2). Rodent models with spontaneous Kcnn2 mutations show abnormal gait and locomotor activity, tremor and memory deficits, but human disorders related to KCNN2 variants are largely unknown. Using exome sequencing, we identified a de novo KCNN2 frameshift deletion in a patient with learning disabilities, cerebellar ataxia and white matter abnormalities on brain MRI. This discovery prompted us to collect data from nine additional patients with de novo KCNN2 variants (one nonsense, one splice site, six missense variants and one in-frame deletion) and one family with a missense variant inherited from the affected mother. We investigated the functional impact of six selected variants on SK2 channel function using the patch-clamp technique. All variants tested but one, which was reclassified to uncertain significance, led to a loss-of-function of SK2 channels. Patients with KCNN2 variants had motor and language developmental delay, intellectual disability often associated with early-onset movement disorders comprising cerebellar ataxia and/or extrapyramidal symptoms. Altogether, our findings provide evidence that heterozygous variants, likely causing a haploinsufficiency of the KCNN2 gene, lead to novel autosomal dominant neurodevelopmental movement disorders mirroring phenotypes previously described in rodents.
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http://dx.doi.org/10.1093/brain/awaa346DOI Listing
December 2020

The Role of Kv7.2 in Neurodevelopment: Insights and Gaps in Our Understanding.

Front Physiol 2020 28;11:570588. Epub 2020 Oct 28.

Applied and Translational Neurogenomics Group, VIB Center for Molecular Neurology, Vlaams Instituut voor Biotechnologie, Antwerp, Belgium.

Kv7.2 subunits encoded by the gene constitute a critical molecular component of the M-current, a subthreshold voltage-gated potassium current controlling neuronal excitability by dampening repetitive action potential firing. Pathogenic loss-of-function variants in have been linked to epilepsy since 1998, and there is ample functional evidence showing that dysfunction of the channel indeed results in neuronal hyperexcitability. The recent description of individuals with severe developmental delay with or without seizures due to pathogenic variants in (-encephalopathy) reveals that Kv7.2 channels also have an important role in neurodevelopment. Kv7.2 channels are expressed already very early in the developing brain when key developmental processes such as proliferation, differentiation, and synaptogenesis play a crucial role in brain morphogenesis and maturation. In this review, we will discuss the available evidence for a role of Kv7.2 channels in these neurodevelopmental processes, focusing in particular on insights derived from -related human phenotypes, from the spatio-temporal expression of Kv7.2 and other Kv7 family member, and from cellular and rodent models, highlighting critical gaps and research strategies to be implemented in the future. Lastly, we propose a model which divides the M-current activity in three different developmental stages, correlating with the cell characteristics during these particular periods in neuronal development, and how this can be linked with -related disorders. Understanding these mechanisms can create opportunities for new targeted therapies for -encephalopathy.
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http://dx.doi.org/10.3389/fphys.2020.570588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657400PMC
October 2020

Reply: Rational therapy with vigabatrin and a ketogenic diet in a patient with GAD1 deficiency.

Brain 2020 12;143(11):e92

School of Health Sciences, Division Biomedicine, University of Skovde, Skovde, Sweden.

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http://dx.doi.org/10.1093/brain/awaa290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719017PMC
December 2020

Recommendations for the treatment of epilepsy in adult and pediatric patients in Belgium: 2020 update.

Acta Neurol Belg 2021 Feb 13;121(1):241-257. Epub 2020 Oct 13.

Department of Neurology, Antwerp University Hospital, Antwerp, Belgium.

To guide health care professionals in Belgium in selecting the appropriate antiepileptic drugs (AEDs) for their epilepsy patients, a group of Belgian epilepsy experts developed recommendations for AED treatment in adults and children (initial recommendations in 2008, updated in 2012). As new drugs have become available, others have been withdrawn, new indications have been approved and recommendations for pregnant women have changed, a new update was pertinent. A group of Belgian epilepsy experts (partly overlapping with the group in charge of the 2008/2012 recommendations) evaluated the most recent international guidelines and relevant literature for their applicability to the Belgian situation (registration status, reimbursement, clinical practice) and updated the recommendations for initial monotherapy in adults and children and add-on treatment in adults. Recommendations for add-on treatment in children were also included (not covered in the 2008/2012 publications). Like the 2008/2012 publications, the current update also covers other important aspects related to the management of epilepsy, including the importance of early referral in drug-resistant epilepsy, pharmacokinetic properties and tolerability of AEDs, comorbidities, specific considerations in elderly and pregnant patients, generic substitution and the rapidly evolving field of precision medicine.
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http://dx.doi.org/10.1007/s13760-020-01488-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937601PMC
February 2021

Access to healthcare and prevalence of anxiety and depression in persons with epilepsy during the COVID-19 pandemic: A multicountry online survey.

Epilepsy Behav 2020 11 10;112:107350. Epub 2020 Sep 10.

Global Health Institute, University of Antwerp, Belgium. Electronic address:

Objective: The objective of this study was to assess access to healthcare and to estimate the prevalence of depression and anxiety among persons with epilepsy (PWE) during the ongoing coronavirus disease 2019 (COVID-19) pandemic.

Methods: We conducted a multicountry online survey among PWE. Persons with epilepsy were invited to participate through various social media channels. The Hospital Anxiety and Depression Scale (HADS) and 9-item Patient Health Questionnaire (PHQ-9) scale were used to score anxiety and depression. Logistic regression modeling was used to investigate factors associated with anxiety and depression.

Results: Three hundred ninety-nine PWE were included (mean age: 38.22 ± 12.09 years), the majority were female (80.2%) and living in high-income countries (83.2%). Two hundred three PWE reported symptoms of a cold since January 2020. Nine (25%) of the 36 PWE tested for COVID were positive. A total of 72 PWE (19.6%) reported problems to obtain antiseizure medication (ASM), which in 25% of cases was directly COVID-related. Of the 399 PWE, 201 (50.4%) screened positive for anxiety according to the HADS; 159 (39.8%) and 187 (46.9%) PWE screened positive for depression based on the HADS and PHQ-9 scale, respectively. Female gender and financial problems were associated with both depression and anxiety. A planned follow-up consultation with the treating physician was associated with a lower risk of depression, whereas difficulties to access ASM treatment increased the odds of depression. In 65/137 (47.4%) PWE with a planned follow-up visit with the treating physician, this consultation was canceled.

Conclusions: Innovative approaches are needed to ensure continuity in access to ASM treatment. Healthcare workers should ensure continued follow-up, either through inperson or telehealth appointments, to timely identify symptoms of anxiety and depression and act accordingly.
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http://dx.doi.org/10.1016/j.yebeh.2020.107350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481834PMC
November 2020

Cardiac phenotype in -related syndromes: A multicenter cohort study.

Neurology 2020 11 10;95(21):e2866-e2879. Epub 2020 Sep 10.

From the Department of Clinical and Experimental Epilepsy (S.B., S.M.S.), UCL Queen Square Institute of Neurology, London; Chalfont Centre for Epilepsy (S.B., S.M.S.), Bucks, UK; Division of Pediatric Neurology (M.A.M., A.S.H., B.K., M.M., L.P.), Department of Neurobiology, and Division of Cardiology (M.C.), Department of Pediatrics, Duke University, School of Medicine, Durham, NC; Centre for Inherited Cardiovascular Diseases (R.A.G.-R., J.P.K.), Great Ormond Street Hospital for Children NHS Foundation Trust; Institute of Cardiovascular Science(R.A.G.-R., J.P.K.), University College London, London, UK; Child Neuropsychiatry Unit (E.D.G., A.G., L.P., M.S., E.V.), IRCCs Istituto Giannina Gaslini, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health, DINOG-MI, University of Genoa; Department of Pediatric Neuroscience (A.G., T.G., N.N., F.R.), Fondazione IRCCS Istituto Neurologico Carlo Besta; Unit of Child Neuropsychiatry (L.P.), ASST Fatebenefratelli Sacco, Milan, Italy; Paediatric Neurology Department (J.C., C.F., L.P.-P., A.A.), Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona University, Member of the International Alternating Hemiplegia in Childhood Research Consortium IAHCRC and of the European Reference Network ERN EpiCARE, Barcelona, Spain; Department of Neurology (A.B., C.M.), Wake Forest School of Medicine, Winston-Salem, NC; Neurology Department (R.S.), Centro Hospitalar e Universitario do Porto-Hospital de Santo António, Porto, Portugal; Clinic for Child Neurology and Psychiatry (V.B., A.P.), Department of Child Neurology, Medical Faculty University of Belgrade, Serbia; Department of Human Genetics (Q.S.P.), Graduate School of Public Health, University of Pittsburgh, PA; Department of Pediatric Neurology (J.P.), Medical University of Silesia, Katowice, Poland; Clinical Neurosciences (K.V., J.H.C.), Developmental Neuroscience Programme, UCL Great Ormond Street Institute of Child Health, and Great Ormond Street Hospital for Children NHS Foundation Trust, Member of the International Alternating Hemiplegia in Childhood Research Consortium IAHCRC and of the European Reference Network ERN EpiCARE, London, UK; Sydney Children's Hospital (A.M.E.B.), Randwick; Department of Cardiology (A.M.D.), The Royal Children's Hospital, Melbourne, University of Melbourne; Department of Neurology (M.M.R.), Royal Children's Hospital, Melbourne; Agnes Ginges Centre for Molecular Cardiology (C.S.), Centenary Institute, University of Sydney; Epilepsy Research Centre (G.H., I.E.S.), Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC; Department of Paediatrics (I.E.S.), University of Melbourne, Royal Children's Hospital, Florey and Murdoch Children's Research Institutes, Melbourne, Australia; Department of Clinical Epileptology, Sleep Disorders and Functional Neurology in Children (A.A., E.P.), University Hospitals of Lyon (HCL), Member of the International Alternating Hemiplegia in Childhood Research Consortium IAHCRC and of the European Reference Network ERN EpiCARE, Lyon, France; Paediatric Neurology Unit (I.C.), CMIN, Centro Hospitalar e Universitario Porto, Porto, Portugal; Clinical Neurophysiology Unit (C.Z.), IRCCS "E. Medea," Bosisio Parini (LC), Italy; Department of Neurology (J.N.), CHUV and Université de Lausanne, Switzerland; Second Department of Neurology (K.D.), Institute Psychiatry and Neurology, Warsaw, Poland; Association AHC18+ e. V. (Germany) and Polish Association for People Affected by AHC, ahc-pl (M.P.); Department of Developmental Neurology (M.M.B.), Medical University of Gdańsk, Poland; Neurology Department (S.W.), University Hospital Antwerp; Neurogenetics Group (S.W.), University Antwerp, Belgium; First Department of Pediatrics (R.P.), "Agia Sofia" Children Hospital, National & Kapodistrian University of Athens, Greece; Department of Neurology (S.G.), University Medical Center of the Johannes Gutenberg University Mainz, Germany; Ion Channel Research Unit (D.S.S.), Department of Medicine/Cardiology and Pharmacology, Duke University Medical Center, Durham, NC; Cardiovascular Research Institute (G.S.P.), Weill Cornell Medical College, New York, NY; The Heart Centre (A.T.), Queen Mary University of London; Department of Pathology (M.A.), Great Ormond Street Hospital for Children NHS Foundation Trust; Department of Neuropathology (Z.M., M.T.), Institute of Neurology, University College London, UK; and ICT and Data Analysis Section (R.V.), Euro-Mediterranean Institute of Science and Technology (I.E.ME.S.T.), Palermo, Italy.

Objective: To define the risks and consequences of cardiac abnormalities in -related syndromes.

Methods: Patients meeting clinical diagnostic criteria for rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) with genetic analysis and at least 1 cardiac assessment were included. We evaluated the cardiac phenotype in an knock-in mouse (Mashl) to determine the sequence of events in seizure-related cardiac death.

Results: Ninety-eight patients with AHC, 9 with RDP, and 3 with CAPOS (63 female, mean age 17 years) were included. Resting ECG abnormalities were found in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%) with RDP. Serial ECGs showed dynamic changes in 10 of 18 patients with AHC. The first Holter ECG was abnormal in 24 of 65 (37%) cases with AHC and RDP with either repolarization or conduction abnormalities. Echocardiography was normal. Cardiac intervention was required in 3 of 98 (≈3%) patients with AHC. In the mouse model, resting ECGs showed intracardiac conduction delay; during induced seizures, heart block or complete sinus arrest led to death.

Conclusions: We found increased prevalence of ECG dynamic abnormalities in all -related syndromes, with a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies (≈3%). Sudden cardiac death due to conduction abnormality emerged as a seizure-related outcome in murine -related disease. -related syndromes are cardiac diseases and neurologic diseases. We provide guidance to identify patients potentially at higher risk of sudden cardiac death who may benefit from insertion of a pacemaker or implantable cardioverter-defibrillator.
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http://dx.doi.org/10.1212/WNL.0000000000010794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734736PMC
November 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

Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders.

Genome Med 2020 03 17;12(1):28. Epub 2020 Mar 17.

Stanley Center for Psychiatric Research, The Broad Institute of Harvard and M.I.T, Cambridge, MA, USA.

Background: Classifying pathogenicity of missense variants represents a major challenge in clinical practice during the diagnoses of rare and genetic heterogeneous neurodevelopmental disorders (NDDs). While orthologous gene conservation is commonly employed in variant annotation, approximately 80% of known disease-associated genes belong to gene families. The use of gene family information for disease gene discovery and variant interpretation has not yet been investigated on a genome-wide scale. We empirically evaluate whether paralog-conserved or non-conserved sites in human gene families are important in NDDs.

Methods: Gene family information was collected from Ensembl. Paralog-conserved sites were defined based on paralog sequence alignments; 10,068 NDD patients and 2078 controls were statistically evaluated for de novo variant burden in gene families.

Results: We demonstrate that disease-associated missense variants are enriched at paralog-conserved sites across all disease groups and inheritance models tested. We developed a gene family de novo enrichment framework that identified 43 exome-wide enriched gene families including 98 de novo variant carrying genes in NDD patients of which 28 represent novel candidate genes for NDD which are brain expressed and under evolutionary constraint.

Conclusion: This study represents the first method to incorporate gene family information into a statistical framework to interpret variant data for NDDs and to discover new NDD-associated genes.
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http://dx.doi.org/10.1186/s13073-020-00725-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079346PMC
March 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

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy.

Nat Commun 2020 01 30;11(1):595. Epub 2020 Jan 30.

Department of Pediatrics, Department of Neurology, & the Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients' primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy.
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http://dx.doi.org/10.1038/s41467-020-14360-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992768PMC
January 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

Three novel patients with epileptic encephalopathy due to biallelic mutations in the PLCB1 gene.

Clin Genet 2020 03 15;97(3):477-482. Epub 2020 Jan 15.

APHP, Département de Génétique, GH Pitié-Salpêtrière, Paris, France.

Biallelic mutations in the PLCB1 gene, encoding for a phospholipase C beta isoform strongly expressed in the brain, have been reported to cause infantile epileptic encephalopathy in only four children to date. We report here three additional patients to delineate the phenotypic and genotypic characteristics of the disease. Our three patients were one sporadic case with an intragenic homozygous deletion and two cousins with the homozygous p.(Arg222*) nonsense variant in PLCB1. These patients had severe to profound intellectual disability, epileptic spasms at age 3-5 months concomitant with developmental arrest or regression, other seizure types and drug-resistant epilepsy. With this report, we expand the clinical, radiologic and electroencephalographic knowledge about the extremely rare PLCB1-related encephalopathy. Since the first report in 2010, the overall number of reported patients with our additional patients is currently limited to seven. All seven patients had epileptic encephalopathy, mainly infantile spasms and 6/7 had profound intellectual disability, with one only being able to walk. Truncal hypotonia was the most frequent neurological sign, sometimes associated with pyramidal and/or extrapyramidal hypertonia of limbs. Microcephaly was inconstant. In conclusion, the phenotypical spectrum of PLCB1-related encephalopathy is relatively narrow, comprises infantile spasms and severe to profound intellectual disability, and does not seem to define a recognizable clinical entity.
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http://dx.doi.org/10.1111/cge.13696DOI Listing
March 2020

Re-annotation of 191 developmental and epileptic encephalopathy-associated genes unmasks de novo variants in .

NPJ Genom Med 2019 2;4:31. Epub 2019 Dec 2.

20Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY UK.

The developmental and epileptic encephalopathies (DEE) are a group of rare, severe neurodevelopmental disorders, where even the most thorough sequencing studies leave 60-65% of patients without a molecular diagnosis. Here, we explore the incompleteness of transcript models used for exome and genome analysis as one potential explanation for a lack of current diagnoses. Therefore, we have updated the GENCODE gene annotation for 191 epilepsy-associated genes, using human brain-derived transcriptomic libraries and other data to build 3,550 putative transcript models. Our annotations increase the transcriptional 'footprint' of these genes by over 674 kb. Using as a case study, due to its close phenotype/genotype correlation with Dravet syndrome, we screened 122 people with Dravet syndrome or a similar phenotype with a panel of exon sequences representing eight established genes and identified two de novo variants that now - through improved gene annotation - are ascribed to residing among our exons. These two (from 122 screened people, 1.6%) molecular diagnoses carry significant clinical implications. Furthermore, we identified a previously classified intronic Dravet syndrome-associated variant that now lies within a deeply conserved exon. Our findings illustrate the potential gains of thorough gene annotation in improving diagnostic yields for genetic disorders.
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http://dx.doi.org/10.1038/s41525-019-0106-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889285PMC
December 2019

Clinical presentation of epilepsy in six villages in an onchocerciasis endemic area in Mahenge, Tanzania.

Epileptic Disord 2019 Oct;21(5):425-435

Global Health Institute, University of Antwerp, Antwerp, Belgium.

To describe the clinical manifestations of epilepsy and access to antiseizure treatment in Mahenge in Central Tanzania, an onchocerciasis endemic area with a high prevalence of epilepsy. A door-to-door epilepsy prevalence survey was conducted in four rural and two sub-urban villages. Trained community workers used five screening questions to identify persons suspected to have epilepsy. Such individuals were interviewed and examined by a neurologist or a medical doctor with additional training in epilepsy, and were tested for Onchocerca volvulus antibodies. A total of 221 out of 8,062 (2.74%) surveyed individuals were confirmed to have epilepsy. The median age at seizure onset was 12 years (interquartile range: 7-16). Seventy-nine persons with epilepsy (PWE) (36.1%) had a family member with epilepsy, which was a sibling in 52.1%. Tonic-clonic seizures (142 individuals; 64.2%) were the most common seizure type. Nodding seizures were reported in 12.7% of PWE; the majority of them living in rural villages. Persons with nodding seizures reported more frequent seizures, presented with more psychiatric symptoms, and more often had onchocerciasis antibodies than those with other seizure types. The high rate of individuals with a seizure onset at between seven and 16 years is characteristic of onchocerciasis-associated epilepsy (OAE). Of the PWE, 77.9% met the criteria for the clinical case definition of OAE. Eighty-three PWE (37.6%) were not taking any antiepileptic medication. Phenobarbital was the antiepileptic drug most commonly prescribed in 76.1% of treated PWE. The high prevalence of epilepsy in rural villages in Mahenge most likely is related to the high prevalence of OAE. To prevent children developing OAE, strengthening the onchocerciasis elimination programme in Mahenge is urgently needed. Moreover, a decentralised epilepsy treatment programme is also needed to provide uninterrupted access to affordable antiepileptic drugs for the many PWE living in rural villages in the Mahenge area.
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http://dx.doi.org/10.1684/epd.2019.1093DOI Listing
October 2019

Women with epilepsy in sub-Saharan Africa: A review of the reproductive health challenges and perspectives for management.

Seizure 2019 Oct 6;71:312-317. Epub 2019 Sep 6.

Global Health Institute, University of Antwerp, Antwerp, Belgium. Electronic address:

Background: Epilepsy is one of the commonest neurological conditions affecting women of reproductive age. Epilepsy management during pregnancy is a clinical conundrum, requiring a balance between seizure control and risk minimization for the women with epilepsy (WWE) as well as for their fetuses. The objective of this comprehensive review is to explore the reproductive health challenges of WWE in sub-Saharan Africa (SSA) and ways to address them.

Method: Relevant documentation published until June 2019 were retrieved via literature searches performed in PubMed and Google Scholar, as well as a manual search to identify grey literature.

Results: WWE in SSA are generally more stigmatized and sexually exploited than women without epilepsy. Contraception use among WWE was reported only in Senegal (51%) and Kenya (14.7%). Only two prospective studies (one in Senegal and one in Nigeria) investigated pregnancy outcomes for a total of 97 WWE. The prevalence of convulsive epilepsy in pregnancy was estimated at 3.33 per 1000. Among pregnant WWE treated with first line anti-epileptic drugs, 16.2% had miscarriages, 41.9% premature births, and 4.1% had babies with malformations. Carbamazepine, which is frequently prescribed to pregnant WWE in SSA, still entails a 2.1-fold increased risk of congenital malformation. No reports were found concerning pre-conceptual counseling and post-natal outcomes in WWE in SSA.

Conclusion: Our review underscores the need for contextualized evidence-based clinical guidelines and a collaborative approach to treat WWE in SSA. High risks of congenital malformations and drug interactions with first line AED warrant the provision of safer second line alternatives.
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http://dx.doi.org/10.1016/j.seizure.2019.08.016DOI Listing
October 2019

Dissecting the genetic basis of focal cortical dysplasia: a large cohort study.

Acta Neuropathol 2019 12 23;138(6):885-900. Epub 2019 Aug 23.

Sorbonne Université, UPMC Univ Paris 06, UMR S 1127, Paris, France.

Genetic malformations of cortical development (MCDs), such as mild MCDs (mMCD), focal cortical dysplasia (FCD), and hemimegalencephaly (HME), are major causes of severe pediatric refractory epilepsies subjected to neurosurgery. FCD2 are characterized by neuropathological hallmarks that include enlarged dysmorphic neurons (DNs) and balloon cells (BCs). Here, we provide a comprehensive assessment of the contribution of germline and somatic variants in a large cohort of surgical MCD cases. We enrolled in a monocentric study 80 children with drug-resistant epilepsy and a postsurgical neuropathological diagnosis of mMCD, FCD1, FCD2, or HME. We performed targeted gene sequencing ( ≥ 2000X read depth) on matched blood-brain samples to search for low-allele frequency variants in mTOR pathway and FCD genes. We were able to elucidate 29% of mMCD/FCD1 patients and 63% of FCD2/HME patients. Somatic loss-of-function variants in the N-glycosylation pathway-associated SLC35A2 gene were found in mMCD/FCD1 cases. Somatic gain-of-function variants in MTOR and its activators (AKT3, PIK3CA, RHEB), as well as germline, somatic and two-hit loss-of-function variants in its repressors (DEPDC5, TSC1, TSC2) were found exclusively in FCD2/HME cases. We show that panel-negative FCD2 cases display strong pS6-immunostaining, stressing that all FCD2 are mTORopathies. Analysis of microdissected cells demonstrated that DNs and BCs carry the pathogenic variants. We further observed a correlation between the density of pathological cells and the variant-detection likelihood. Single-cell microdissection followed by sequencing of enriched pools of DNs unveiled a somatic second-hit loss-of-heterozygosity in a DEPDC5 germline case. In conclusion, this study indicates that mMCD/FCD1 and FCD2/HME are two distinct genetic entities: while all FCD2/HME are mosaic mTORopathies, mMCD/FCD1 are not caused by mTOR-pathway-hyperactivating variants, and ~ 30% of the cases are related to glycosylation defects. We provide a framework for efficient genetic testing in FCD/HME, linking neuropathology to genetic findings and emphasizing the usefulness of molecular evaluation in the pediatric epileptic neurosurgical population.
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http://dx.doi.org/10.1007/s00401-019-02061-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851393PMC
December 2019

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

encephalopathy: Connecting neurodevelopmental disorders with α-synucleinopathies?

Neurology 2019 07 20;93(3):114-123. Epub 2019 Jun 20.

From the Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute (V.L., Y.J.C., J.Z.B., F.A.M.), the University of Queensland, St. Lucia Campus, Brisbane, Australia; Neurogenetics Group (S.W.), University of Antwerp, Belgium; Laboratory of Neurogenetics (S.W.), Institute Born-Bunge, University of Antwerp; Department of Neurology (S.W.), Antwerp University Hospital, Belgium; School of Women's and Children's Health (E.E.P.), University of New South Wales, Sydney; Genetics of Learning Disability Service (E.E.P.), Hunter New England Health, Newcastle; Department of Clinical Genetics (E.E.P.), Sydney Children's Hospital; and Institute for Molecular Bioscience (B.M.C.), the University of Queensland, Brisbane, Australia.

De novo pathogenic variants in encoding syntaxin1-binding protein (STXBP1, also known as Munc18-1) lead to a range of early-onset neurocognitive conditions, most commonly early infantile epileptic encephalopathy type 4 (EIEE4, also called STXBP1 encephalopathy), a severe form of epilepsy associated with developmental delay/intellectual disability. Other neurologic features include autism spectrum disorder and movement disorders. The progression of neurologic symptoms has been reported in a few older affected individuals, with the appearance of extrapyramidal features, reminiscent of early onset parkinsonism. Understanding the pathologic process is critical to improving therapies, as currently available antiepileptic drugs have shown limited success in controlling seizures in EIEE4 and there is no precision medication approach for the other neurologic features of the disorder. Basic research shows that genetic knockout of STXBP1 or other presynaptic proteins of the exocytic machinery leads to widespread perinatal neurodegeneration. The mechanism that regulates this effect is under scrutiny but shares intriguing hallmarks with classical neurodegenerative diseases, albeit appearing early during brain development. Most critically, recent evidence has revealed that STXBP1 controls the self-replicating aggregation of α-synuclein, a presynaptic protein involved in various neurodegenerative diseases that are collectively known as synucleinopathies, including Parkinson disease. In this review, we examine the tantalizing link among STXBP1 function, EIEE, and the neurodegenerative synucleinopathies, and suggest that neural development in EIEE could be further affected by concurrent synucleinopathic mechanisms.
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http://dx.doi.org/10.1212/WNL.0000000000007786DOI Listing
July 2019

Autism and developmental disability caused by KCNQ3 gain-of-function variants.

Ann Neurol 2019 08 26;86(2):181-192. Epub 2019 Jun 26.

Division of Neurology, Department of Pediatrics, Children's Hospital of Pittsburgh and University of Pittsburgh School of Medicine, Pittsburgh, PA.

Objective: Recent reports have described single individuals with neurodevelopmental disability (NDD) harboring heterozygous KCNQ3 de novo variants (DNVs). We sought to assess whether pathogenic variants in KCNQ3 cause NDD and to elucidate the associated phenotype and molecular mechanisms.

Methods: Patients with NDD and KCNQ3 DNVs were identified through an international collaboration. Phenotypes were characterized by clinical assessment, review of charts, electroencephalographic (EEG) recordings, and parental interview. Functional consequences of variants were analyzed in vitro by patch-clamp recording.

Results: Eleven patients were assessed. They had recurrent heterozygous DNVs in KCNQ3 affecting residues R230 (R230C, R230H, R230S) and R227 (R227Q). All patients exhibited global developmental delay within the first 2 years of life. Most (8/11, 73%) were nonverbal or had a few words only. All patients had autistic features, and autism spectrum disorder (ASD) was diagnosed in 5 of 11 (45%). EEGs performed before 10 years of age revealed frequent sleep-activated multifocal epileptiform discharges in 8 of 11 (73%). For 6 of 9 (67%) recorded between 1.5 and 6 years of age, spikes became near-continuous during sleep. Interestingly, most patients (9/11, 82%) did not have seizures, and no patient had seizures in the neonatal period. Voltage-clamp recordings of the mutant KCNQ3 channels revealed gain-of-function (GoF) effects.

Interpretation: Specific GoF variants in KCNQ3 cause NDD, ASD, and abundant sleep-activated spikes. This new phenotype contrasts both with self-limited neonatal epilepsy due to KCNQ3 partial loss of function, and with the neonatal or infantile onset epileptic encephalopathies due to KCNQ2 GoF. ANN NEUROL 2019;86:181-192.
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http://dx.doi.org/10.1002/ana.25522DOI Listing
August 2019
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