187 results on '"Scheffer, I.E."'
Search Results
2. Generation of an iPSC line (FINi001-A) from a female developmental and epileptic encephalopathy patient due to a heterozygous gain-of-function p.R1882Q variant in the voltage-gated sodium channel Nav1.2 protein encoded by the SCN2A gene
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Ovchinnikov, D.A., primary, Jong, S., additional, Cuddy, C., additional, Scheffer, I.E., additional, Maljevic, S., additional, and Petrou, S., additional
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- 2023
- Full Text
- View/download PDF
3. Genetic aetiologies for childhood speech disorder: novel pathways co-expressed during brain development
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Kaspi, A., Hildebrand, M.S., Jackson, V.E., Braden, R., Reyk, O. van, Howell, T., Debono, S., Lauretta, M., Morison, L., Coleman, M.J., Webster, R., Coman, D., Goel, H., Wallis, M., Dabscheck, G., Downie, L., Baker, E.K., Parry-Fielder, B., Ballard, K., Harrold, E., Ziegenfusz, S., Bennett, M.F., Robertson, E., Wang, L., Boys, A., Fisher, S.E., Amor, D.J., Scheffer, I.E., Bahlo, M., Morgan, A.T., Kaspi, A., Hildebrand, M.S., Jackson, V.E., Braden, R., Reyk, O. van, Howell, T., Debono, S., Lauretta, M., Morison, L., Coleman, M.J., Webster, R., Coman, D., Goel, H., Wallis, M., Dabscheck, G., Downie, L., Baker, E.K., Parry-Fielder, B., Ballard, K., Harrold, E., Ziegenfusz, S., Bennett, M.F., Robertson, E., Wang, L., Boys, A., Fisher, S.E., Amor, D.J., Scheffer, I.E., Bahlo, M., and Morgan, A.T.
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Item does not contain fulltext
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- 2023
4. Correction: Genetic aetiologies for childhood speech disorder: novel pathways co-expressed during brain development
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Kaspi, A., Hildebrand, M.S., Jackson, V.E., Braden, R., Reyk, O. van, Howell, T., Debono, S., Lauretta, M., Morison, L., Coleman, M.J., Webster, R., Coman, D., Goel, H., Wallis, M., Dabscheck, G., Downie, L., Baker, E.K., Parry-Fielder, B., Ballard, K., Harrold, E., Ziegenfusz, S., Bennett, M.F., Robertson, E., Wang, L., Boys, A., Fisher, S.E., Amor, D.J., Scheffer, I.E., Bahlo, M., Morgan, A.T., Kaspi, A., Hildebrand, M.S., Jackson, V.E., Braden, R., Reyk, O. van, Howell, T., Debono, S., Lauretta, M., Morison, L., Coleman, M.J., Webster, R., Coman, D., Goel, H., Wallis, M., Dabscheck, G., Downie, L., Baker, E.K., Parry-Fielder, B., Ballard, K., Harrold, E., Ziegenfusz, S., Bennett, M.F., Robertson, E., Wang, L., Boys, A., Fisher, S.E., Amor, D.J., Scheffer, I.E., Bahlo, M., and Morgan, A.T.
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Item does not contain fulltext
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- 2023
5. Movement Disorders in Patients With Genetic Developmental and Epileptic Encephalopathies
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Veen, S.W. van der, Tse, Gabrielle T.W., Ferretti, Alessandro, Garone, Giacomo, Post, B., Specchio, N., Trivisano, Marina, Scheffer, I.E., Veen, S.W. van der, Tse, Gabrielle T.W., Ferretti, Alessandro, Garone, Giacomo, Post, B., Specchio, N., Trivisano, Marina, and Scheffer, I.E.
- Abstract
Item does not contain fulltext
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- 2023
6. Distinctive Brain Malformations in Zhu-Tokita-Takenouchi-Kim Syndrome
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Halliday, B.J., primary, Baynam, G., additional, Ewans, L., additional, Greenhalgh, L., additional, Leventer, R.J., additional, Pilz, D.T., additional, Sachdev, R., additional, Scheffer, I.E., additional, Markie, D.M., additional, McGillivray, G., additional, Robertson, S.P., additional, and Mandelstam, S., additional
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- 2022
- Full Text
- View/download PDF
7. Severe childhood speech disorder: Gene discovery highlights transcriptional dysregulation.
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Hildebrand M.S., Jackson V.E., Scerri T.S., Van Reyk O., Coleman M., Braden R.O., Turner S., Rigbye K.A., Boys A., Barton S., Webster R., Fahey M., Saunders K., Parry-Fielder B., Paxton G., Hayman M., Coman D., Goel H., Baxter A., Ma A., Davis N., Reilly S., Delatycki M., Liegeois F.J., Connelly A., Gecz J., Fisher S.E., Amor D.J., Scheffer I.E., Bahlo M., Morgan A.T., Hildebrand M.S., Jackson V.E., Scerri T.S., Van Reyk O., Coleman M., Braden R.O., Turner S., Rigbye K.A., Boys A., Barton S., Webster R., Fahey M., Saunders K., Parry-Fielder B., Paxton G., Hayman M., Coman D., Goel H., Baxter A., Ma A., Davis N., Reilly S., Delatycki M., Liegeois F.J., Connelly A., Gecz J., Fisher S.E., Amor D.J., Scheffer I.E., Bahlo M., and Morgan A.T.
- Abstract
ObjectiveDetermining the genetic basis of speech disorders provides insight into the neurobiology of human communication. Despite intensive investigation over the past 2 decades, the etiology of most speech disorders in children remains unexplained. To test the hypothesis that speech disorders have a genetic etiology, we performed genetic analysis of children with severe speech disorder, specifically childhood apraxia of speech (CAS).MethodsPrecise phenotyping together with research genome or exome analysis were performed on children referred with a primary diagnosis of CAS. Gene coexpression and gene set enrichment analyses were conducted on high-confidence gene candidates.ResultsThirty-four probands ascertained for CAS were studied. In 11/34 (32%) probands, we identified highly plausible pathogenic single nucleotide (n = 10; CDK13, EBF3, GNAO1, GNB1, DDX3X, MEIS2, POGZ, SETBP1, UPF2, ZNF142) or copy number (n = 1; 5q14.3q21.1 locus) variants in novel genes or loci for CAS. Testing of parental DNA was available for 9 probands and confirmed that the variants had arisen de novo. Eight genes encode proteins critical for regulation of gene transcription, and analyses of transcriptomic data found CAS-implicated genes were highly coexpressed in the developing human brain.ConclusionWe identify the likely genetic etiology in 11 patients with CAS and implicate 9 genes for the first time. We find that CAS is often a sporadic monogenic disorder, and highly genetically heterogeneous. Highly penetrant variants implicate shared pathways in broad transcriptional regulation, highlighting the key role of transcriptional regulation in normal speech development. CAS is a distinctive, socially debilitating clinical disorder, and understanding its molecular basis is the first step towards identifying precision medicine approaches. Copyright © American Academy of Neurology.
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- 2022
8. Self-reported impact of developmental stuttering across the lifespan
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Boyce, J.O., Jackson, V.E., Reyk, O. van, Parker, R., Vogel, A.P., Eising, E., Horton, S.E., Gillespie, N.A., Scheffer, I.E., Amor, D.J., Hildebrand, M.S., Fisher, S.E., Martin, N.G., Reilly, S., Bahlo, M., Morgan, A.T., Boyce, J.O., Jackson, V.E., Reyk, O. van, Parker, R., Vogel, A.P., Eising, E., Horton, S.E., Gillespie, N.A., Scheffer, I.E., Amor, D.J., Hildebrand, M.S., Fisher, S.E., Martin, N.G., Reilly, S., Bahlo, M., and Morgan, A.T.
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Contains fulltext : 283563.pdf (Publisher’s version ) (Closed access)
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- 2022
9. Whole-genome linkage scan for epilepsy-related photosensitivity: A mega-analysis
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de Kovel, C.G.F., Pinto, D., Tauer, U., Lorenz, S., Muhle, H., Leu, C., Neubauer, B.A., Hempelmann, A., Callenbach, P.M.C., Scheffer, I.E., Berkovic, S.F., Rudolf, G., Striano, P., Siren, A., Baykan, B., Sander, T., Lindhout, D., Trenité, D.G. Kasteleijn-Nolst, Stephani, U., and Koeleman, B.P.C.
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- 2010
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10. Climate change and epilepsy: insights from clinical and basic science studies
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Gulcebi, M., Bartolini, E., Lee, O., Panagiotis Lisgaras, C., Onat, F., Mifsud, J., Striano, P., Vezzani, A., Hildebrand, M.S., Jimenez-Jimenez, D., Junck, L., Lewis-Smith, D., Scheffer, I.E., Thijs, R.D., Zuberi, S.M., Blenkinsop, S., Fowler, H.J., Foley, Aideen, and Sisodiya, S.M.
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geog - Abstract
Climate change is with us. As professionals who place value on evidence-based practice, climate change is something we cannot ignore. The current pandemic of the novel coronavirus, SARS-CoV-2, has demonstrated how global crises can arise suddenly and have a significant impact on public health. Global warming, a chronic process punctuated by acute episodes of extreme weather events, is an insidious global health crisis needing at least as much attention. Many neurological diseases are complex chronic conditions influenced at many levels by changes in the environment. This review aimed to collate and evaluate reports from clinical and basic science about the relationship between climate change and epilepsy. The keywords climate change, seasonal variation, temperature, humidity, thermoregulation, biorhythm, gene, circadian rhythm, heat, and weather were used to search the published evidence. A number of climatic variables are associated with increased seizure frequency in people with epilepsy. Climate change-induced increase in seizure precipitants such as fevers, stress, and sleep deprivation (e.g. as a result of more frequent extreme weather events) or vector-borne infections may trigger or exacerbate seizures, lead to deterioration of seizure control, and affect neurological, cerebrovascular, or cardiovascular comorbidities and risk of sudden unexpected death in epilepsy. Risks are likely to be modified by many factors, ranging from individual genetic variation and temperature-dependent channel function, to housing quality and global supply chains. According to the results of the limited number of experimental studies with animal models of seizures or epilepsy, different seizure types appear to have distinct susceptibility to seasonal influences. Increased body temperature, whether in the context of fever or not, has a critical role in seizure threshold and seizure-related brain damage. Links between climate change and epilepsy are likely to be multifactorial, complex, and often indirect, which makes predictions difficult. We need more data on possible climate-driven altered risks for seizures, epilepsy, and epileptogenesis, to identify underlying mechanisms at systems, cellular, and molecular levels for better understanding of the impact of climate change on epilepsy. Further focussed data would help us to develop evidence for mitigation methods to do more to protect people with epilepsy from the effects of climate change.
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- 2021
11. Genetic convergence of developmental and epileptic encephalopathies and intellectual disability
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Carvill, G.L., Jansen, S, Lacroix, A., Zemel, M., Mehaffey, M., Vries, P.F. de, Brunner, H.G., Scheffer, I.E., Vries, B.B. de, Vissers, L.E.L.M., Mefford, H.C., Carvill, G.L., Jansen, S, Lacroix, A., Zemel, M., Mehaffey, M., Vries, P.F. de, Brunner, H.G., Scheffer, I.E., Vries, B.B. de, Vissers, L.E.L.M., and Mefford, H.C.
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Item does not contain fulltext, AIM: To determine whether genes that cause developmental and epileptic encephalopathies (DEEs) are more commonly implicated in intellectual disability with epilepsy as a comorbid feature than in intellectual disability only. METHOD: We performed targeted resequencing of 18 genes commonly implicated in DEEs in a cohort of 830 patients with intellectual disability (59% male) and 393 patients with DEEs (52% male). RESULTS: We observed a significant enrichment of pathogenic/likely pathogenic variants in patients with epilepsy and intellectual disability (16 out of 159 in seven genes) compared with intellectual disability only (2 out of 671) (p<1.86×10(-10) , odds ratio 37.22, 95% confidence interval 8.60-337.0). INTERPRETATION: We identified seven genes that are more likely to cause epilepsy and intellectual disability than intellectual disability only. Conversely, two genes, GRIN2B and SCN2A, can be implicated in intellectual disability without epilepsy; in these instances intellectual disability is not a secondary consequence of ongoing seizures but rather a primary cause. What this paper adds A subset of genes are more commonly implicated in epilepsy than other neurodevelopmental disorders. GRIN2B and SCN2A are implicated in intellectual disability and epilepsy independently.
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- 2021
12. NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns
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Stamberger, H., Hammer, T.B., Gardella, E., Vlaskamp, D.R.M., Bertelsen, B., Mandelstam, S., Lange, I. de, Zhang, J., Myers, C.T., Fenger, C., Afawi, Z., Fuerte, E.P. Almanza, Andrade, D.M., Balcik, Y., Zeev, B. Ben, Bennett, M.F., Berkovic, S.F., Isidor, B., Bouman, A., Brilstra, E., Ø, L. Busk, Cairns, A., Caumes, R., Chatron, N., Dale, R.C., Geus, C. de, Edery, P., Gill, D., Granild-Jensen, J.B., Gunderson, L., Gunning, B., Heimer, G., Helle, J.R., Hildebrand, M.S., Hollingsworth, G., Kharytonov, V., Klee, E.W., Koeleman, B.P.C., Koolen, D.A., Korff, C., Küry, S., Lesca, G., Lev, D., Leventer, R.J., Mackay, M.T., Macke, E.L., McEntagart, M., Mohammad, S.S., Monin, P., Montomoli, M., Morava, E., Moutton, S., Muir, A.M., Parrini, E., Procopis, P., Ranza, E., Reed, L., Reif, P.S., Rosenow, F., Rossi, M., Sadleir, L.G., Sadoway, T., Schelhaas, H.J., Schneider, A.L., Shah, K., Shalev, R., Sisodiya, S.M., Smol, T., Stumpel, C., Stuurman, K., Symonds, J.D., Mau-Them, F.T., Verbeek, N., Verhoeven, J.S., Wallace, G., Yosovich, K., Zarate, Y.A., Zerem, A., Zuberi, S.M., Guerrini, R., Mefford, H.C., Patel, C., Zhang, Y.H., Møller, R.S., Scheffer, I.E., Stamberger, H., Hammer, T.B., Gardella, E., Vlaskamp, D.R.M., Bertelsen, B., Mandelstam, S., Lange, I. de, Zhang, J., Myers, C.T., Fenger, C., Afawi, Z., Fuerte, E.P. Almanza, Andrade, D.M., Balcik, Y., Zeev, B. Ben, Bennett, M.F., Berkovic, S.F., Isidor, B., Bouman, A., Brilstra, E., Ø, L. Busk, Cairns, A., Caumes, R., Chatron, N., Dale, R.C., Geus, C. de, Edery, P., Gill, D., Granild-Jensen, J.B., Gunderson, L., Gunning, B., Heimer, G., Helle, J.R., Hildebrand, M.S., Hollingsworth, G., Kharytonov, V., Klee, E.W., Koeleman, B.P.C., Koolen, D.A., Korff, C., Küry, S., Lesca, G., Lev, D., Leventer, R.J., Mackay, M.T., Macke, E.L., McEntagart, M., Mohammad, S.S., Monin, P., Montomoli, M., Morava, E., Moutton, S., Muir, A.M., Parrini, E., Procopis, P., Ranza, E., Reed, L., Reif, P.S., Rosenow, F., Rossi, M., Sadleir, L.G., Sadoway, T., Schelhaas, H.J., Schneider, A.L., Shah, K., Shalev, R., Sisodiya, S.M., Smol, T., Stumpel, C., Stuurman, K., Symonds, J.D., Mau-Them, F.T., Verbeek, N., Verhoeven, J.S., Wallace, G., Yosovich, K., Zarate, Y.A., Zerem, A., Zuberi, S.M., Guerrini, R., Mefford, H.C., Patel, C., Zhang, Y.H., Møller, R.S., and Scheffer, I.E.
- Abstract
Contains fulltext : 231688.pdf (Publisher’s version ) (Closed access), PURPOSE: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy. METHODS: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy. RESULTS: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism. CONCLUSION: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants.
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- 2021
13. The severe epilepsy syndromes of infancy: A population-based study.
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Dabscheck G., McMahon J.M., Mefford H.C., Panetta J., Riseley J., Rodriguez-Casero V., Ryan M.M., Schneider A.L., Smith L.J., Stark Z., Wong F., Yiu E.M., Scheffer I.E., Harvey A.S., Howell K.B., Freeman J.L., Mackay M.T., Fahey M.C., Archer J., Berkovic S.F., Chan E., Eggers S., Hayman M., Holberton J., Hunt R.W., Jacobs S.E., Kornberg A.J., Leventer R.J., Mandelstam S., Dabscheck G., McMahon J.M., Mefford H.C., Panetta J., Riseley J., Rodriguez-Casero V., Ryan M.M., Schneider A.L., Smith L.J., Stark Z., Wong F., Yiu E.M., Scheffer I.E., Harvey A.S., Howell K.B., Freeman J.L., Mackay M.T., Fahey M.C., Archer J., Berkovic S.F., Chan E., Eggers S., Hayman M., Holberton J., Hunt R.W., Jacobs S.E., Kornberg A.J., Leventer R.J., and Mandelstam S.
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Objective: To study the epilepsy syndromes among the severe epilepsies of infancy and assess their incidence, etiologies, and outcomes. Method(s): A population-based cohort study was undertaken of severe epilepsies with onset before age 18 months in Victoria, Australia. Two epileptologists reviewed clinical features, seizure videos, and electroencephalograms to diagnose International League Against Epilepsy epilepsy syndromes. Incidence, etiologies, and outcomes at age 2 years were determined. Result(s): Seventy-three of 114 (64%) infants fulfilled diagnostic criteria for epilepsy syndromes at presentation, and 16 (14%) had "variants" of epilepsy syndromes in which there was one missing or different feature, or where all classical features had not yet emerged. West syndrome (WS) and "WS-like" epilepsy (infantile spasms without hypsarrhythmia or modified hypsarrhythmia) were the most common syndromes, with a combined incidence of 32.7/100 000 live births/year. The incidence of epilepsy of infancy with migrating focal seizures (EIMFS) was 4.5/100 000 and of early infantile epileptic encephalopathy (EIEE) was 3.6/100 000. Structural etiologies were common in "WS-like" epilepsy (100%), unifocal epilepsy (83%), and WS (39%), whereas single gene disorders predominated in EIMFS, EIEE, and Dravet syndrome. Eighteen (16%) infants died before age 2 years. Development was delayed or borderline in 85 of 96 (89%) survivors, being severe-profound in 40 of 96 (42%). All infants with EIEE or EIMFS had severe-profound delay or were deceased, but only 19 of 64 (30%) infants with WS, "WS-like," or "unifocal epilepsy" had severe-profound delay, and only two of 64 (3%) were deceased. Significance: Three quarters of severe epilepsies of infancy could be assigned an epilepsy syndrome or "variant syndrome" at presentation. In this era of genomic testing and advanced brain imaging, diagnosing epilepsy syndromes at presentation remains clinically useful for guiding etiologic investigation, i
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- 2021
14. Severe speech impairment is a distinguishing feature of FOXP1-related disorder
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Braden, R.O., Amor, D.J., Fisher, S.E., Mei, Christina, Myers, C.T., Mefford, Heather C., Gill, D., Srivastava, S., Swanson, L.C., Goel, H., Scheffer, I.E., Morgen, A.T., Braden, R.O., Amor, D.J., Fisher, S.E., Mei, Christina, Myers, C.T., Mefford, Heather C., Gill, D., Srivastava, S., Swanson, L.C., Goel, H., Scheffer, I.E., and Morgen, A.T.
- Abstract
Item does not contain fulltext
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- 2021
15. Generation of an iPSC line (FINi001-A) from a girl with developmental and epileptic encephalopathy due to a heterozygous gain-of-function p.R1882Q variant in the voltage-gated sodium channel Nav1.2 protein encoded by the SCN2A gene
- Author
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Ovchinnikov, D.A., Jong, S., Cuddy, C., Scheffer, I.E., Maljevic, S., and Petrou, S.
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- 2023
- Full Text
- View/download PDF
16. Revidierte Terminologie und Konzepte zur Einteilung von epileptischen Anfällen und Epilepsien: Bericht der Klassifikations- und Terminologiekommission der Internationalen Liga gegen Epilepsie, 2005–2009
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Berg, A.T., Berkovic, S.F., Brodie, M., Buchhalter, J., Cross, J.H., van Emde Boas, W., Engel Jr, J., French, J., Glauser, T.A., Mathern, G.W., Moshé, S.L., Nordli, D., Plouin, P., and Scheffer, I.E.
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- 2010
- Full Text
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17. Glut1 Deficiency Syndrome (Glut1DS): State of the art in 2020 and recommendations of the international Glut1DS study group
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Klepper, J. Akman, C. Armeno, M. Auvin, S. Cervenka, M. Cross, H.J. De Giorgis, V. Della Marina, A. Engelstad, K. Heussinger, N. Kossoff, E.H. Leen, W.G. Leiendecker, B. Monani, U.R. Oguni, H. Neal, E. Pascual, J.M. Pearson, T.S. Pons, R. Scheffer, I.E. Veggiotti, P. Willemsen, M. Zuberi, S.M. De Vivo, D.C.
- Abstract
Glut1 deficiency syndrome (Glut1DS) is a brain energy failure syndrome caused by impaired glucose transport across brain tissue barriers. Glucose diffusion across tissue barriers is facilitated by a family of proteins including glucose transporter type 1 (Glut1). Patients are treated effectively with ketogenic diet therapies (KDT) that provide a supplemental fuel, namely ketone bodies, for brain energy metabolism. The increasing complexity of Glut1DS, since its original description in 1991, now demands an international consensus statement regarding diagnosis and treatment. International experts (n = 23) developed a consensus statement utilizing their collective professional experience, responses to a standardized questionnaire, and serial discussions of wide-ranging issues related to Glut1DS. Key clinical features signaling the onset of Glut1DS are eye-head movement abnormalities, seizures, neurodevelopmental impairment, deceleration of head growth, and movement disorders. Diagnosis is confirmed by the presence of these clinical signs, hypoglycorrhachia documented by lumbar puncture, and genetic analysis showing pathogenic SLC2A1 variants. KDT represent standard choices with Glut1DS-specific recommendations regarding duration, composition, and management. Ongoing research has identified future interventions to restore Glut1 protein content and function. Clinical manifestations are influenced by patient age, genetic complexity, and novel therapeutic interventions. All clinical phenotypes will benefit from a better understanding of Glut1DS natural history throughout the life cycle and from improved guidelines facilitating early diagnosis and prompt treatment. Often, the presenting seizures are treated initially with antiseizure drugs before the cause of the epilepsy is ascertained and appropriate KDT are initiated. Initial drug treatment fails to treat the underlying metabolic disturbance during early brain development, contributing to the long-term disease burden. Impaired development of the brain microvasculature is one such complication of delayed Glut1DS treatment in the postnatal period. This international consensus statement should facilitate prompt diagnosis and guide best standard of care for Glut1DS throughout the life cycle. © 2020 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.
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- 2020
18. Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders
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Wang, T., Hoekzema, K., Vecchio, D., Wu, H., Sulovari, A., Coe, B.P., Gillentine, M.A., Wilfert, A.B., Perez-Jurado, L.A., Kvarnung, M., Sleyp, Y., Earl, R.K., Rosenfeld, J.A., Geisheker, M.R., Han, L., Du, B., Barnett, C., Thompson, E., Shaw, M., Carroll, R., Friend, K., Catford, R., Palmer, E.E., Zou, X., Ou, J., Li, H., Guo, H, Gerdts, J., Avola, E., Calabrese, G., Elia, M., Greco, D., Lindstrand, A., Nordgren, A., Anderlid, B.M., Vandeweyer, G., Dijck, A. Van, Aa, N. van der, McKenna, B., Hancarova, M., Bendova, S., Havlovicova, M., Malerba, G., Bernardina, B.D., Muglia, P., Haeringen, A. van, Hoffer, M.J.V., Franke, B., Cappuccio, G., Delatycki, M., Lockhart, P.J., Manning, M.A., Liu, P, Scheffer, I.E., Brunetti-Pierri, N., Rommelse, N.N.J., Amaral, D.G., Santen, G.W.E., Trabetti, E., Sedláček, Z., Michaelson, J.J., Pierce, K., Courchesne, E., Kooy, R.F., Nordenskjöld, M., Romano, C, Peeters, H, Bernier, R.A., Gecz, J., Xia, K., Eichler, E.E., Wang, T., Hoekzema, K., Vecchio, D., Wu, H., Sulovari, A., Coe, B.P., Gillentine, M.A., Wilfert, A.B., Perez-Jurado, L.A., Kvarnung, M., Sleyp, Y., Earl, R.K., Rosenfeld, J.A., Geisheker, M.R., Han, L., Du, B., Barnett, C., Thompson, E., Shaw, M., Carroll, R., Friend, K., Catford, R., Palmer, E.E., Zou, X., Ou, J., Li, H., Guo, H, Gerdts, J., Avola, E., Calabrese, G., Elia, M., Greco, D., Lindstrand, A., Nordgren, A., Anderlid, B.M., Vandeweyer, G., Dijck, A. Van, Aa, N. van der, McKenna, B., Hancarova, M., Bendova, S., Havlovicova, M., Malerba, G., Bernardina, B.D., Muglia, P., Haeringen, A. van, Hoffer, M.J.V., Franke, B., Cappuccio, G., Delatycki, M., Lockhart, P.J., Manning, M.A., Liu, P, Scheffer, I.E., Brunetti-Pierri, N., Rommelse, N.N.J., Amaral, D.G., Santen, G.W.E., Trabetti, E., Sedláček, Z., Michaelson, J.J., Pierce, K., Courchesne, E., Kooy, R.F., Nordenskjöld, M., Romano, C, Peeters, H, Bernier, R.A., Gecz, J., Xia, K., and Eichler, E.E.
- Abstract
Contains fulltext : 229260.pdf (publisher's version ) (Open Access), Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E-06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E-07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype-genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.
- Published
- 2020
19. Severe childhood speech disorder: Gene discovery highlights transcriptional dysregulation
- Author
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Hildebrandt, M.S., Jackson, V.E., Scerri, T.S., Reyk, O. van, Coleman, M., Braden, R.O., Turner, S., Rigbye, K.A., Boys, A., Barton, S., Webster, R., Fahey, M., Saunders, K., Parry-Fielder, B., Paxton, G., Hayman, M., Coman, D., Goel, H., Baxter, A., Ma, A., Davis, N., Reilly, S., Delatycki, M., Liégeois, F.J., Connelly, A., Gecz, J., Fisher, S.E., Amor, D.J., Scheffer, I.E., Bahlo, M., Morgan, A.T., Hildebrandt, M.S., Jackson, V.E., Scerri, T.S., Reyk, O. van, Coleman, M., Braden, R.O., Turner, S., Rigbye, K.A., Boys, A., Barton, S., Webster, R., Fahey, M., Saunders, K., Parry-Fielder, B., Paxton, G., Hayman, M., Coman, D., Goel, H., Baxter, A., Ma, A., Davis, N., Reilly, S., Delatycki, M., Liégeois, F.J., Connelly, A., Gecz, J., Fisher, S.E., Amor, D.J., Scheffer, I.E., Bahlo, M., and Morgan, A.T.
- Abstract
Contains fulltext : 229004.pdf (publisher's version ) (Closed access)
- Published
- 2020
20. Predominant and novel de novo variants in 29 individuals with ALG13 deficiency: Clinical description, biomarker status, biochemical analysis, and treatment suggestions.
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Tuite A., Rowe L.J., Serrano Russi A.H., Russo R.S., Thabet F., Villanueva M.M., Wang R.Y., Webster R.I., Wilson D., Zalan A., Wolfe L.A., Rosenfeld J.A., Rhodes L., Freeze H.H., Ng B.G., Eklund E.A., Shiryaev S.A., Dong Y.Y., Abbott M.-A., Asteggiano C., Bamshad M.J., Barr E., Bernstein J.A., Chelakkadan S., Christodoulou J., Chung W.K., Ciliberto M.A., Cousin J., Gardiner F., Ghosh S., Graf W.D., Grunewald S., Hammond K., Hauser N.S., Hoganson G.E., Houck K.M., Kohler J.N., Morava E., Larson A.A., Liu P., Madathil S., McCormack C., Meeks N.J.L., Miller R., Monaghan K.G., Nickerson D.A., Palculict T.B., Papazoglu G.M., Pletcher B.A., Scheffer I.E., Schenone A.B., Schnur R.E., Si Y., Tuite A., Rowe L.J., Serrano Russi A.H., Russo R.S., Thabet F., Villanueva M.M., Wang R.Y., Webster R.I., Wilson D., Zalan A., Wolfe L.A., Rosenfeld J.A., Rhodes L., Freeze H.H., Ng B.G., Eklund E.A., Shiryaev S.A., Dong Y.Y., Abbott M.-A., Asteggiano C., Bamshad M.J., Barr E., Bernstein J.A., Chelakkadan S., Christodoulou J., Chung W.K., Ciliberto M.A., Cousin J., Gardiner F., Ghosh S., Graf W.D., Grunewald S., Hammond K., Hauser N.S., Hoganson G.E., Houck K.M., Kohler J.N., Morava E., Larson A.A., Liu P., Madathil S., McCormack C., Meeks N.J.L., Miller R., Monaghan K.G., Nickerson D.A., Palculict T.B., Papazoglu G.M., Pletcher B.A., Scheffer I.E., Schenone A.B., Schnur R.E., and Si Y.
- Abstract
Asparagine-linked glycosylation 13 homolog (ALG13) encodes a nonredundant, highly conserved, X-linked uridine diphosphate (UDP)-N-acetylglucosaminyltransferase required for the synthesis of lipid linked oligosaccharide precursor and proper N-linked glycosylation. De novo variants in ALG13 underlie a form of early infantile epileptic encephalopathy known as EIEE36, but given its essential role in glycosylation, it is also considered a congenital disorder of glycosylation (CDG), ALG13-CDG. Twenty-four previously reported ALG13-CDG cases had de novo variants, but surprisingly, unlike most forms of CDG, ALG13-CDG did not show the anticipated glycosylation defects, typically detected by altered transferrin glycosylation. Structural homology modeling of two recurrent de novo variants, p.A81T and p.N107S, suggests both are likely to impact the function of ALG13. Using a corresponding ALG13-deficient yeast strain, we show that expressing yeast ALG13 with either of the highly conserved hotspot variants rescues the observed growth defect, but not its glycosylation abnormality. We present molecular and clinical data on 29 previously unreported individuals with de novo variants in ALG13. This more than doubles the number of known cases. A key finding is that a vast majority of the individuals presents with West syndrome, a feature shared with other CDG types. Among these, the initial epileptic spasms best responded to adrenocorticotropic hormone or prednisolone, while clobazam and felbamate showed promise for continued epilepsy treatment. A ketogenic diet seems to play an important role in the treatment of these individuals.Copyright © 2020 SSIEM
- Published
- 2020
21. Severe childhood speech disorder: Gene discovery highlights transcriptional dysregulation.
- Author
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Barton S., Hildebrand M.S., Jackson V.E., Scerri T.S., Van Reyk O., Coleman M., Braden R.O., Rigbye K.A., Ma A., Boys A., Reilly S., Delatycki M., Liegeois F.J., Connelly A., Gecz J., Fisher S.E., Amor D.J., Scheffer I.E., Bahlo M., Morgan A.T., Turner S., Fahey M., Webster R., Saunders K., Parry-Fielder B., Paxton G., Hayman M., Coman D., Goel H., Baxter A., Davis N., Barton S., Hildebrand M.S., Jackson V.E., Scerri T.S., Van Reyk O., Coleman M., Braden R.O., Rigbye K.A., Ma A., Boys A., Reilly S., Delatycki M., Liegeois F.J., Connelly A., Gecz J., Fisher S.E., Amor D.J., Scheffer I.E., Bahlo M., Morgan A.T., Turner S., Fahey M., Webster R., Saunders K., Parry-Fielder B., Paxton G., Hayman M., Coman D., Goel H., Baxter A., and Davis N.
- Abstract
OBJECTIVE: Determining the genetic basis of speech disorders provides insight into the neurobiology of human communication. Despite intensive investigation over the past 2 decades, the etiology of most speech disorders in children remains unexplained. To test the hypothesis that speech disorders have a genetic etiology, we performed genetic analysis of children with severe speech disorder, specifically childhood apraxia of speech (CAS). METHOD(S): Precise phenotyping together with research genome or exome analysis were performed on children referred with a primary diagnosis of CAS. Gene coexpression and gene set enrichment analyses were conducted on high-confidence gene candidates. RESULT(S): Thirty-four probands ascertained for CAS were studied. In 11/34 (32%) probands, we identified highly plausible pathogenic single nucleotide (n = 10; CDK13, EBF3, GNAO1, GNB1, DDX3X, MEIS2, POGZ, SETBP1, UPF2, ZNF142) or copy number (n = 1; 5q14.3q21.1 locus) variants in novel genes or loci for CAS. Testing of parental DNA was available for 9 probands and confirmed that the variants had arisen de novo. Eight genes encode proteins critical for regulation of gene transcription, and analyses of transcriptomic data found CAS-implicated genes were highly coexpressed in the developing human brain. CONCLUSION(S): We identify the likely genetic etiology in 11 patients with CAS and implicate 9 genes for the first time. We find that CAS is often a sporadic monogenic disorder, and highly genetically heterogeneous. Highly penetrant variants implicate shared pathways in broad transcriptional regulation, highlighting the key role of transcriptional regulation in normal speech development. CAS is a distinctive, socially debilitating clinical disorder, and understanding its molecular basis is the first step towards identifying precision medicine approaches.Copyright © 2020 American Academy of Neurology.
- Published
- 2020
22. Protocol for a single patient therapy plan: A randomised, double-blind, placebo-controlled N-of-1 trial to assess the efficacy of cannabidiol in patients with intractable epilepsy.
- Author
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Freeman J.L., Legge D., Huque M.H., Anderson M., Gillam L., Ong K.S., Carlin J.B., Fahey M., Scheffer I.E., Cranswick N., Slota-Kan S., Lilley B., Dirnbauer N., Freeman J.L., Legge D., Huque M.H., Anderson M., Gillam L., Ong K.S., Carlin J.B., Fahey M., Scheffer I.E., Cranswick N., Slota-Kan S., Lilley B., and Dirnbauer N.
- Abstract
Aim: This paper describes the use of the single patient therapy plan (SPTP). The SPTP has been designed to assess the efficacy at an individual level of a commercially available cannabinoid product, cannabidiol, in reducing seizure frequency in paediatric patients with intractable epilepsy. Method(s): The SPTP is a randomised, double-blind, placebo-controlled N-of-1 trial designed to assess the efficacy of treatment in a neurology outpatient setting. The primary objective of the SPTP is to assess the efficacy of cannabidiol in reducing seizure frequency in each patient with intractable epilepsy, with change in seizure frequency being the primary outcome of interest. The analysis adopts a Bayesian approach, which provides results in the form of posterior probabilities that various levels of benefit (based on the primary outcome measure, seizure frequency) have been achieved under active treatment compared to placebo, accompanied by decision rules that provide thresholds for deciding whether treatment has been successful in the individual patient. The SPTP arrangement is most accurately considered part of clinical practice rather than research, since it is aimed at making clinical treatment decisions for individual patients and is not testing a hypothesis or collecting aggregate data. Therefore, Human Research Ethics Committee approval was considered not to be required, although it is recommended that hospital Clinical Ethics Committees provide ethical oversight. Conclusion(s): These SPTP resources are made available so that they may inform clinical practice in the treatment of severe epilepsy or adapted for use in other conditions.Copyright © 2020, Commonwealth of Australia. Journal of Paediatrics and Child Health © 2020 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).
- Published
- 2020
23. SCN1A Variants in vaccine-related febrile seizures: A prospective study.
- Author
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Hildebrand M.S., Richmond P., Macartney K.K., Scheffer I.E., Berkovic S.F., Wood N., Damiano J.A., Deng L., Li W., Burgess R., Schneider A.L., Crawford N.W., Buttery J., Gold M., Hildebrand M.S., Richmond P., Macartney K.K., Scheffer I.E., Berkovic S.F., Wood N., Damiano J.A., Deng L., Li W., Burgess R., Schneider A.L., Crawford N.W., Buttery J., and Gold M.
- Abstract
Objective: Febrile seizures may follow vaccination. Common variants in the sodium channel gene, SCN1A, are associated with febrile seizures, and rare pathogenic variants in SCN1A cause the severe developmental and epileptic encephalopathy Dravet syndrome. Following vaccination, febrile seizures may raise the specter of poor outcome and inappropriately implicate vaccination as the cause. We aimed to determine the prevalence of SCN1A variants in children having their first febrile seizure either proximal to vaccination or unrelated to vaccination compared to controls. Method(s): We performed SCN1A sequencing, blind to clinical category, in a prospective cohort of children presenting with their first febrile seizure as vaccine proximate (n = 69) or as non-vaccine proximate (n = 75), and children with no history of seizures (n = 90) recruited in Australian pediatric hospitals. Result(s): We detected 2 pathogenic variants in vaccine-proximate cases (p.R568X and p.W932R), both of whom developed Dravet syndrome, and 1 in a non-vaccine-proximate case (p.V947L) who had febrile seizures plus from 9 months. All had generalized tonic-clonic seizures lasting >15 minutes. We also found enrichment of a reported risk allele, rs6432860-T, in children with febrile seizures compared to controls (odds ratio = 1.91, 95% confidence interval = 1.31-2.81). Interpretation(s): Pathogenic SCN1A variants may be identified in infants with vaccine-proximate febrile seizures. As early diagnosis of Dravet syndrome is essential for optimal management and outcome, SCN1A sequencing in infants with prolonged febrile seizures, proximate to vaccination, should become routine. ANN NEUROL 2020;87:281-288.Copyright © 2019 American Neurological Association
- Published
- 2020
24. GENETICS | Clinical Genetics of Epilepsy
- Author
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Berkovic, S.F., primary and Scheffer, I.E., additional
- Published
- 2009
- Full Text
- View/download PDF
25. Detection of cryptic pathogenic copy number variations and constitutional loss of heterozygosity using high resolution SNP microarray analysis in 117 patients referred to cytogenetic analysis and impact on clinical practice
- Author
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Bruno, D.L., Ganesamoorthy, D., Schoumans, J., Bankier, A., Coman, D., Delatycki, M., Gardner, R.J.M., Hunter, M., James, P.A., Kannu, P., McGillivray, G., Pachter, N., Peters, H., Rieubland, C., Savarirayan, R., Scheffer, I.E., Sheffield, L., Tan, T., White, S.M., Yeung, A., Bowman, Zho, Ngo, C., Choy, K.W., Cacheux, V., Wong, L., Amor, D.J., and Slater, H.R.
- Subjects
DNA microarrays -- Usage ,DNA microarrays -- Research ,Genetic disorders -- Diagnosis ,Genetic disorders -- Research ,Genetic variation -- Analysis ,Single nucleotide polymorphisms -- Analysis ,Health - Published
- 2009
26. Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3
- Author
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Florian, R.T., Kraft, F., Leitao, E., Kaya, S., Klebe, S., Magnin, E., Rootselaar, A.F. van, Buratti, J., Kuhnel, T., Schroder, C., Giesselmann, S., Tschernoster, N., Altmueller, J., Lamiral, A., Keren, B., Nava, C., Bouteiller, D., Forlani, S., Jornea, L., Kubica, R., Ye, T., Plassard, D., Jost, B., Meyer, V., Deleuze, J.F., Delpu, Y., Avarello, M.D.M., Vijfhuizen, L.S., Rudolf, G., Hirsch, E., Kroes, T., Reif, P.S., Rosenow, F., Ganos, C., Vidailhet, M., Thivard, L., Mathieu, A., Bourgeron, T., Kurth, I., Rafehi, H., Steenpass, L., Horsthemke, B., Berkovic, S.F., Bisulli, F., Brancati, F., Canafoglia, L., Casari, G., Guerrini, R., Ishiura, H., Licchetta, L., Mei, D., Pippucci, T., Sadleir, L., Scheffer, I.E., Striano, P., Tinuper, P., Tsuji, S., Zara, F., LeGuern, E., Klein, K.M., Labauge, P., Bennett, M.F., Bahlo, M., Gecz, J., Corbett, M.A., Tijssen, M.A.J., Maagdenberg, A.M.J.M. van den, Depienne, C., and FAME Consortium
- Abstract
Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same individual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements.
- Published
- 2019
27. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders
- Author
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Salpietro, V. Dixon, C.L. Guo, H. Bello, O.D. Vandrovcova, J. Efthymiou, S. Maroofian, R. Heimer, G. Burglen, L. Valence, S. Torti, E. Hacke, M. Rankin, J. Tariq, H. Colin, E. Procaccio, V. Striano, P. Mankad, K. Lieb, A. Chen, S. Pisani, L. Bettencourt, C. Männikkö, R. Manole, A. Brusco, A. Grosso, E. Ferrero, G.B. Armstrong-Moron, J. Gueden, S. Bar-Yosef, O. Tzadok, M. Monaghan, K.G. Santiago-Sim, T. Person, R.E. Cho, M.T. Willaert, R. Yoo, Y. Chae, J.-H. Quan, Y. Wu, H. Wang, T. Bernier, R.A. Xia, K. Blesson, A. Jain, M. Motazacker, M.M. Jaeger, B. Schneider, A.L. Boysen, K. Muir, A.M. Myers, C.T. Gavrilova, R.H. Gunderson, L. Schultz-Rogers, L. Klee, E.W. Dyment, D. Osmond, M. Parellada, M. Llorente, C. Gonzalez-Peñas, J. Carracedo, A. Van Haeringen, A. Ruivenkamp, C. Nava, C. Heron, D. Nardello, R. Iacomino, M. Minetti, C. Skabar, A. Fabretto, A. Hanna, M.G. Bugiardini, E. Hostettler, I. O’Callaghan, B. Khan, A. Cortese, A. O’Connor, E. Yau, W.Y. Bourinaris, T. Kaiyrzhanov, R. Chelban, V. Madej, M. Diana, M.C. Vari, M.S. Pedemonte, M. Bruno, C. Balagura, G. Scala, M. Fiorillo, C. Nobili, L. Malintan, N.T. Zanetti, M.N. Krishnakumar, S.S. Lignani, G. Jepson, J.E.C. Broda, P. Baldassari, S. Rossi, P. Fruscione, F. Madia, F. Traverso, M. De-Marco, P. Pérez-Dueñas, B. Munell, F. Kriouile, Y. El-Khorassani, M. Karashova, B. Avdjieva, D. Kathom, H. Tincheva, R. Van-Maldergem, L. Nachbauer, W. Boesch, S. Gagliano, A. Amadori, E. Goraya, J.S. Sultan, T. Kirmani, S. Ibrahim, S. Jan, F. Mine, J. Banu, S. Veggiotti, P. Zuccotti, G.V. Ferrari, M.D. Van Den Maagdenberg, A.M.J. Verrotti, A. Marseglia, G.L. Savasta, S. Soler, M.A. Scuderi, C. Borgione, E. Chimenz, R. Gitto, E. Dipasquale, V. Sallemi, A. Fusco, M. Cuppari, C. Cutrupi, M.C. Ruggieri, M. Cama, A. Capra, V. Mencacci, N.E. Boles, R. Gupta, N. Kabra, M. Papacostas, S. Zamba-Papanicolaou, E. Dardiotis, E. Maqbool, S. Rana, N. Atawneh, O. Lim, S.Y. Shaikh, F. Koutsis, G. Breza, M. Coviello, D.A. Dauvilliers, Y.A. AlKhawaja, I. AlKhawaja, M. Al-Mutairi, F. Stojkovic, T. Ferrucci, V. Zollo, M. Alkuraya, F.S. Kinali, M. Sherifa, H. Benrhouma, H. Turki, I.B.Y. Tazir, M. Obeid, M. Bakhtadze, S. Saadi, N.W. Zaki, M.S. Triki, C.C. Benfenati, F. Gustincich, S. Kara, M. Belcastro, V. Specchio, N. Capovilla, G. Karimiani, E.G. Salih, A.M. Okubadejo, N.U. Ojo, O.O. Oshinaike, O.O. Oguntunde, O. Wahab, K. Bello, A.H. Abubakar, S. Obiabo, Y. Nwazor, E. Ekenze, O. Williams, U. Iyagba, A. Taiwo, L. Komolafe, M. Senkevich, K. Shashkin, C. Zharkynbekova, N. Koneyev, K. Manizha, G. Isrofilov, M. Guliyeva, U. Salayev, K. Khachatryan, S. Rossi, S. Silvestri, G. Haridy, N. Ramenghi, L.A. Xiromerisiou, G. David, E. Aguennouz, M. Fidani, L. Spanaki, C. Tucci, A. Raspall-Chaure, M. Chez, M. Tsai, A. Fassi, E. Shinawi, M. Constantino, J.N. De Zorzi, R. Fortuna, S. Kok, F. Keren, B. Bonneau, D. Choi, M. Benzeev, B. Zara, F. Mefford, H.C. Scheffer, I.E. Clayton-Smith, J. Macaya, A. Rothman, J.E. Eichler, E.E. Kullmann, D.M. Houlden, H. SYNAPS Study Group
- Abstract
AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission. © 2019, The Author(s).
- Published
- 2019
28. Autosomal dominant nocturnal frontal-lobe epilepsy: genetic heterogeneity and evidence for a second locus at 15q24
- Author
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Phillips, H.A., Scheffer, I.E., Crossland, K.M., Bhatia, K.P., Fish, D.R., Marsden, C.D., Howell, S.J.L., Stephenson, J.B.P., Tolmie, J., Plazzi, G., Eeg-Olofsson, O., Singh, R., Lopes-Cendes, I., Andermann, E., Andermann, F., Berkovic, S.F., and Mulley, J.C.
- Subjects
Epilepsy -- Research ,Genetic disorders -- Research ,Biological sciences - Abstract
Further research is needed to determine causal factors for autosomal dominant nocturnal frontal-lobe epilepsy. While evidence suggests a second locus for the disorder at chromosome 15q24 in addition to 20q13.2 with a clinically homogeneous phenotype, a wide range of molecular defects that contribute to the disorder are complicating accurate causal determination.
- Published
- 1998
29. Deletions or duplications in KCNQ2 can cause benign familial neonatal seizures
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Heron, S.E., Cox, K., Grinton, B.E., Zuberi, S.M., Kivity, S., Afawi, Z., Straussberg, R., Berkovic, S.F., Scheffer, I.E., and Mulley, J.C.
- Subjects
Convulsions -- Causes of ,Convulsions -- Demographic aspects ,Potassium channels -- Genetic aspects ,Potassium channels -- Health aspects ,Familial diseases -- Genetic aspects ,Familial diseases -- Research ,Gene mutations -- Health aspects ,Infants (Newborn) -- Diseases ,Infants (Newborn) -- Research ,Health - Published
- 2007
30. Repeat expansion disorders enriched in an Australian and New Zealand Epi25 Year 1 epilepsy cohort
- Author
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Bennett, M.F., Tankard, R.M., Bennett, C.A., Schneider, A.L., Regan, B.M., Damiano, J.A., Hildebrand, M.S., Sadleir, L.G., Scheffer, I.E., Berkovic, S.F., Bahlo, M., Bennett, M.F., Tankard, R.M., Bennett, C.A., Schneider, A.L., Regan, B.M., Damiano, J.A., Hildebrand, M.S., Sadleir, L.G., Scheffer, I.E., Berkovic, S.F., and Bahlo, M.
- Abstract
Meeting abstract: 33rd International Epilepsy Congress Bangkok, Thailand 22 – 26 June 2019
- Published
- 2019
31. The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures.
- Author
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Guerrini R., Marini C., Zhang Y.-H., Mefford H.C., Kurian M.A., Poduri A.H., Scheffer I.E., Burgess R., Wang S., McTague A., Boysen K.E., Yang X., Zeng Q., Myers K.A., Rochtus A., Trivisano M., Gill D., Sadleir L.G., Specchio N., Guerrini R., Marini C., Zhang Y.-H., Mefford H.C., Kurian M.A., Poduri A.H., Scheffer I.E., Burgess R., Wang S., McTague A., Boysen K.E., Yang X., Zeng Q., Myers K.A., Rochtus A., Trivisano M., Gill D., Sadleir L.G., and Specchio N.
- Abstract
Objective: Epilepsy of infancy with migrating focal seizures (EIMFS) is one of the most severe developmental and epileptic encephalopathies. We delineate the genetic causes and genotype-phenotype correlations of a large EIMFS cohort. Method(s): Phenotypic and molecular data were analyzed on patients recruited through an international collaborative study. Result(s): We ascertained 135 patients from 128 unrelated families. Ninety-three of 135 (69%) had causative variants (42/55 previously reported) across 23 genes, including 9 novel EIMFS genes: de novo dominant GABRA1, GABRB1, ATP1A3; X-linked CDKL5, PIGA; and recessive ITPA, AIMP1, KARS, WWOX. The most frequently implicated genes were KCNT1 (36/135, 27%) and SCN2A (10/135, 7%). Mosaicism occurred in 2 probands (SCN2A, GABRB3) and 3 unaffected mothers (KCNT1). Median age at seizure onset was 4 weeks, with earlier onset in the SCN2A, KCNQ2, and BRAT1 groups. Epileptic spasms occurred in 22% patients. A total of 127 patients had severe to profound developmental impairment. All but 7 patients had ongoing seizures. Additional features included microcephaly, movement disorders, spasticity, and scoliosis. Mortality occurred in 33% at median age 2 years 7 months. Interpretation(s): We identified a genetic cause in 69% of patients with EIMFS. We highlight the genetic heterogeneity of EIMFS with 9 newly implicated genes, bringing the total number to 33. Mosaicism was observed in probands and parents, carrying critical implications for recurrence risk. EIMFS pathophysiology involves diverse molecular processes from gene and protein regulation to ion channel function and solute trafficking. ANN NEUROL 2019;86:821-831.Copyright © 2019 American Neurological Association
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- 2019
32. Clinical and molecular characterization ofKCNT1-related severe early-onset epilepsy
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McTague, A., Nair, U., Malhotra, S., Meyer, E., Trump, N., Gazina, E.V., Papandreou, A., Ngoh, A., Ackermann, S., Ambegaonkar, G., Appleton, R., Desurkar, A., Eltze, C., Kneen, R., Kumar, A.V., Lascelles, K., Montgomery, T., Ramesh, V., Samanta, R., Scott, R.H., Tan, J., Whitehouse, W., Poduri, A., Scheffer, I.E., Chong, W.K., Cross, J.H., Topf, Maya, Petrou, S., and Kurian, M.A.
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bcs - Abstract
Objective: To characterize the phenotypic spectrum, molecular genetic findings, and functional consequences of pathogenic variants in early-onset KCNT1 epilepsy.\ud \ud Methods: We identified a cohort of 31 patients with epilepsy of infancy with migrating focal seizures (EIMFS) and screened for variants in KCNT1 using direct Sanger sequencing, a multiple-gene next-generation sequencing panel, and whole-exome sequencing. Additional patients with non-EIMFS early-onset epilepsy in whom we identified KCNT1 variants on local diagnostic multiple gene panel testing were also included. When possible, we performed homology modeling to predict the putative effects of variants on protein structure and function. We undertook electrophysiologic assessment of mutant KCNT1 channels in a xenopus oocyte model system.\ud \ud Results: We identified pathogenic variants in KCNT1 in 12 patients, 4 of which are novel. Most variants occurred de novo. Ten patients had a clinical diagnosis of EIMFS, and the other 2 presented with early-onset severe nocturnal frontal lobe seizures. Three patients had a trial of quinidine with good clinical response in 1 patient. Computational modeling analysis implicates abnormal pore function (F346L) and impaired tetramer formation (F502V) as putative disease mechanisms. All evaluated KCNT1 variants resulted in marked gain of function with significantly increased channel amplitude and variable blockade by quinidine.\ud \ud Conclusions: Gain-of-function KCNT1 pathogenic variants cause a spectrum of severe focal epilepsies with onset in early infancy. Currently, genotype-phenotype correlations are unclear, although clinical outcome is poor for the majority of cases. Further elucidation of disease mechanisms may facilitate the development of targeted treatments, much needed for this pharmacoresistant genetic epilepsy.
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- 2018
33. Clinical and molecular characterisation of KCNT1-related severe early onset epilepsy
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McTague, A., Nair, U., Malhotra, S., Meyer, E., Trump, N., Gazina, E.V., Papandreou, A., Ngoh, A., Ackermann, S., Ambegaonkar, G., Appleton, R., Desurkar, A., Eltze, C., Kneen, R., Kumar, A.V., Lascelles, K., Montgomery, T., Ramesh, V., Samanta, R., Scott, R.H., Tan, J., Whitehouse, W., Poduri, A., Scheffer, I.E., Chong, W.K. \\'Kling\\', Cross, H.K., Topf, Maya, Petrou, S., and Kurian, M.A.
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bcs - Abstract
Objective: To characterise the phenotypic spectrum, molecular genetic findings and\ud functional consequences of pathogenic variants in early onset KCNT1-epilepsy.\ud Methods: We identified a cohort of 31 patients with epilepsy of infancy with\ud migrating focal seizures (EIMFS) and screened for variants in KCNT1 using direct\ud Sanger sequencing, a multiple gene next generation sequencing panel and whole\ud exome sequencing. Additional patients with non-EIMFS early onset epilepsy in\ud whom we identified KCNT1 variants on local diagnostic multiple gene panel testing\ud were also included. Where possible, we performed homology modelling to predict\ud putative effects of variants on protein structure and function. We undertook\ud electrophysiological assessment of mutant KCNT1 channels in a Xenopus oocyte\ud model system.\ud Results: We identified pathogenic variants in KCNT1 in 12 patients, four of which\ud are novel. Most variants occurred de novo. Ten had a clinical diagnosis of EIMFS\ud and the other two presented with early onset severe nocturnal frontal lobe seizures.\ud Three patients had a trial of quinidine with good clinical response in one.\ud Computational modelling analysis implicates abnormal pore function (F346L) and\ud impaired tetramer formation (F502V) as putative disease mechanisms. All evaluated\ud KCNT1 variants resulted in marked gain-of-function, with significantly increased\ud channel amplitude and variable blockade by quinidine.\ud Conclusions: Gain-of-function KCNT1 pathogenic variants cause a spectrum of\ud severe focal epilepsies with onset in early infancy. Currently, genotype-phenotype\ud correlations are unclear, though clinical outcome is poor for the majority of cases.\ud Further elucidation of disease mechanisms may facilitate the development of\ud targeted treatments, much needed for this pharmacoresistant genetic epilepsy.
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- 2017
34. De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias
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Helbig, K.L., Lauerer, R.J., Bahr, J.C., Souza, I.A., Myers, C.T., Uysal, B., Schwarz, N., Gandini, M.A., Huang, S., Keren, B., Mignot, C., Afenjar, A., Villemeur, T. Billette de, Heron, D., Nava, C., Valence, S., Buratti, J., Fagerberg, C.R., Soerensen, K.P., Kibaek, M., Kamsteeg, E.J., Koolen, D.A., Gunning, B., Schelhaas, H.J., Kruer, M.C., Fox, J., Bakhtiari, S., Jarrar, R., Padilla-Lopez, S., Lindstrom, K., Jin, S.C., Zeng, X., Bilguvar, K., Papavasileiou, A., Xin, Q., Zhu, C., Boysen, K., Vairo, F., Lanpher, B.C., Klee, E.W., Tillema, J.M., Payne, E.T., Cousin, M.A., Kruisselbrink, T.M., Wick, M.J., Baker, J., Haan, E., Smith, N., Corbett, M.A., MacLennan, A.H., Gecz, J., Biskup, S., Goldmann, E., Rodan, L.H., Kichula, E., Segal, E., Jackson, K.E., Asamoah, A., Dimmock, D., McCarrier, J., Botto, L.D., Filloux, F., Tvrdik, T., Cascino, G.D., Klingerman, S., Neumann, C., Wang, R., Jacobsen, J.C., Nolan, M.A., Snell, R.G., Lehnert, K., Sadleir, L.G., Anderlid, B.M., Kvarnung, M., Guerrini, R., Friez, M.J., Lyons, M.J., Leonhard, J., Kringlen, G., Casas, K., Achkar, C.M. El, Smith, L.A., Rotenberg, A., Poduri, A., Sanchis-Juan, A., Carss, K.J., Rankin, J., Zeman, A., Raymond, F.L., Blyth, M., Kerr, B., Ruiz, K., Urquhart, J., Hughes, I., Banka, S., Hedrich, U.B.S., Scheffer, I.E., Helbig, I., Zamponi, G.W., Lerche, H., et al., Helbig, K.L., Lauerer, R.J., Bahr, J.C., Souza, I.A., Myers, C.T., Uysal, B., Schwarz, N., Gandini, M.A., Huang, S., Keren, B., Mignot, C., Afenjar, A., Villemeur, T. Billette de, Heron, D., Nava, C., Valence, S., Buratti, J., Fagerberg, C.R., Soerensen, K.P., Kibaek, M., Kamsteeg, E.J., Koolen, D.A., Gunning, B., Schelhaas, H.J., Kruer, M.C., Fox, J., Bakhtiari, S., Jarrar, R., Padilla-Lopez, S., Lindstrom, K., Jin, S.C., Zeng, X., Bilguvar, K., Papavasileiou, A., Xin, Q., Zhu, C., Boysen, K., Vairo, F., Lanpher, B.C., Klee, E.W., Tillema, J.M., Payne, E.T., Cousin, M.A., Kruisselbrink, T.M., Wick, M.J., Baker, J., Haan, E., Smith, N., Corbett, M.A., MacLennan, A.H., Gecz, J., Biskup, S., Goldmann, E., Rodan, L.H., Kichula, E., Segal, E., Jackson, K.E., Asamoah, A., Dimmock, D., McCarrier, J., Botto, L.D., Filloux, F., Tvrdik, T., Cascino, G.D., Klingerman, S., Neumann, C., Wang, R., Jacobsen, J.C., Nolan, M.A., Snell, R.G., Lehnert, K., Sadleir, L.G., Anderlid, B.M., Kvarnung, M., Guerrini, R., Friez, M.J., Lyons, M.J., Leonhard, J., Kringlen, G., Casas, K., Achkar, C.M. El, Smith, L.A., Rotenberg, A., Poduri, A., Sanchis-Juan, A., Carss, K.J., Rankin, J., Zeman, A., Raymond, F.L., Blyth, M., Kerr, B., Ruiz, K., Urquhart, J., Hughes, I., Banka, S., Hedrich, U.B.S., Scheffer, I.E., Helbig, I., Zamponi, G.W., and Lerche, H., et al.
- Abstract
Item does not contain fulltext, Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the alpha1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.
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- 2018
35. Randomized controlled trial of melatonin for sleep disturbance in dravet syndrome: The DREAMS study.
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Lightfoot P.A., Scheffer I.E., Myers K.A., Davey M.J., Ching M., Ellis C., Grinton B.E., Roten A., Lightfoot P.A., Scheffer I.E., Myers K.A., Davey M.J., Ching M., Ellis C., Grinton B.E., and Roten A.
- Abstract
Study Objectives: Dravet syndrome is a severe developmental and epileptic encephalopathy, in which 75% of patients have sleep disturbance. Melatonin is often used for sleep problems in childhood; however, there is no quality evidence supporting its use in Dravet syndrome. We hypothesized that melatonin would increase total sleep and quality of life for patients with Dravet syndrome. Method(s): A double-blind crossover randomized placebo-controlled trial was conducted, comparing 6 mg regular-release melatonin to placebo for patients with Dravet syndrome and sleep disturbance. The primary outcome measure was total sleep measured by actigraphy, with secondary outcomes including wakefulness after sleep onset (WASO), Sleep Disturbance Scale in Children and Quality of Life in Children with Epilepsy 55 questionnaires, caregiver reports of clinical change, seizure diary and serum antiepileptic drug levels. We also compared actigraphy data of patients with Dravet syndrome to an age-matched healthy control group. Result(s): A total of 13 patients completed the study. There was no difference in total sleep or WASO between melatonin and placebo. However, of the 11 patients for whom caregivers reported a clear clinical difference between treatments (blinded), 8 reported improvement on melatonin (P < .05). Interestingly, when compared to patients in the control group, patients with Dravet syndrome had significantly increased total sleep (P = .002). Conclusion(s): Melatonin did not increase total sleep; however, blinded caregiver reports indicate treatment with melatonin provided considerable clinical benefit for some patients with Dravet syndrome and sleep disturbance.Copyright © 2018 American Academy of Sleep Medicine. All right reserved.
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- 2018
36. Sleep problems in Dravet syndrome: a modifiable comorbidity.
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Scheffer I.E., Licheni S.H., Mcmahon J.M., Schneider A.L., Davey M.J., Scheffer I.E., Licheni S.H., Mcmahon J.M., Schneider A.L., and Davey M.J.
- Abstract
Aim: Many children with severe developmental and epileptic encephalopathies experience significant sleep disturbance, causing major disruption to the family's quality of life. We aimed to determine the frequency and nature of sleep problems in individuals with Dravet syndrome. Method(s): The Sleep Disturbance Scale for Children and a seizure questionnaire were distributed to the parents/guardians of 96 patients with Dravet syndrome. Sixteen patients had two nights of home oximetry. Result(s): Fifty-seven out of 96 questionnaires were completed. Forty-three out of 57 (75%) individuals had sleep problems. Twenty-five out of 57 (44%) individuals had an abnormal total sleep score, with difficulty initiating and maintaining sleep (22 out of 57, 39%), sleep-wake transition disorders (20 out of 57, 35%), and sleep breathing disorders (19 out of 57, 33%). Twenty-two out of 57 (39%) individuals took medication to assist sleep, predominantly melatonin (n=14). Thirty out of 57 (53%) recently had nocturnal seizures. Overnight oximetry showed 14 out of 16 (88%) had a higher oxygen desaturation index (>3%), and six out of 16 (38%) had higher mean pulse rates than normative values. Home oximetry was normal or inconclusive in all patients. Interpretation(s): Seventy-five per cent of individuals with Dravet syndrome had sleep problems, highlighting the importance of routinely assessing sleep and initiating appropriate behavioural and pharmacological interventions to improve the patient and family's quality of life. A high oxygen desaturation index and mean pulse rates on pulse oximetry may reflect unrecognized nocturnal seizures. What this paper adds: More than 70% of patients with Dravet syndrome have sleep problems. Difficulty initiating and maintaining sleep was most common, particularly in those older than 20 years. Second most common were sleep-wake transition disorders, affecting more than 50% of those younger than 5 years. Sleep breathing disorders were a frequent problem acr
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- 2018
37. Optimal clinical management of children receiving dietary therapies for epilepsy: Updated recommendations of the International Ketogenic Diet Study Group
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Kossoff, E.H., Zupec-Kania, B.A., Auvin, S., Ballaban-Gil, K.R., Christina Bergqvist, A.G., Blackford, R., Buchhalter, J.R., Caraballo, R.H., Cross, JH, Dahlin, M.G., Donner, E.J., Guzel, O., Jehle, R.S., Klepper, J., Kang, H.C., Lambrechts, D.A., Liu, Y. (YongMei), Nathan, J.K., Nordli, D.R., Jr., Pfeifer, H.H., Rho, J.M., Scheffer, I.E., Sharma, S., Stafstrom, C.E., Thiele, EA, Turner, Z., Vaccarezza, M.M., Louw, E.J.T.M. (Elles) van der, Veggiotti, P., Wheless, J.W., Wirrell, E.C., Kossoff, E.H., Zupec-Kania, B.A., Auvin, S., Ballaban-Gil, K.R., Christina Bergqvist, A.G., Blackford, R., Buchhalter, J.R., Caraballo, R.H., Cross, JH, Dahlin, M.G., Donner, E.J., Guzel, O., Jehle, R.S., Klepper, J., Kang, H.C., Lambrechts, D.A., Liu, Y. (YongMei), Nathan, J.K., Nordli, D.R., Jr., Pfeifer, H.H., Rho, J.M., Scheffer, I.E., Sharma, S., Stafstrom, C.E., Thiele, EA, Turner, Z., Vaccarezza, M.M., Louw, E.J.T.M. (Elles) van der, Veggiotti, P., Wheless, J.W., and Wirrell, E.C.
- Abstract
Ketogenic dietary therapies (KDTs) are established, effective nonpharmacologic treatments for intractable childhood epilepsy. For many years KDTs were implemented differently throughout the world due to lack of consistent protocols. In 2009, an expert consensus guideline for the management of children on KDT was published, focusing on topics of patient selection, pre-KDT counseling and evaluation, diet choice and attributes, implementation, supplementation, follow-up, side events, and KDT discontinuation. It has been helpful in outlining a state-of-the-art protocol, standardizing KDT for multicenter clinical trials, and identifying areas of controversy and uncertainty for future research. Now one decade later, the organizers and authors of this guideline present a revised version with additional authors, in order to include recent research, especially regarding other dietary treatments, clarifying indications for use, side effects during initiation and ongoing use, value of supplements, and methods of KDT discontinuation. In addition, authors completed a survey of their institution’s practices, which was compared to responses from the original consensus survey, to show trends in management over the last 10 years.
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- 2018
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38. Not all SCN1A epileptic encephalopathies are Dravet syndrome
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Sadleir, L.G., Mountier, E.I., Gill, D., Davis, S., Joshi, C., DeVile, C., Kurian, M.A., Mandelstam, S., Wirrell, E., Nickels, K.C., Murali, H.R., Carvill, G., Myers, C.T., Mefford, H.C., Scheffer, I.E., and Study, DDD.
- Abstract
Objective: To define a distinct SCN1A developmental and epileptic encephalopathy with early onset, profound impairment, and movement disorder.\ud \ud Methods: A case series of 9 children were identified with a profound developmental and epileptic encephalopathy and SCN1A mutation.\ud \ud Results: We identified 9 children 3 to 12 years of age; 7 were male. Seizure onset was at 6 to 12 weeks with hemiclonic seizures, bilateral tonic-clonic seizures, or spasms. All children had profound developmental impairment and were nonverbal and nonambulatory, and 7 of 9 required a gastrostomy. A hyperkinetic movement disorder occurred in all and was characterized by dystonia and choreoathetosis with prominent oral dyskinesia and onset from 2 to 20 months of age. Eight had a recurrent missense SCN1A mutation, p.Thr226Met. The remaining child had the missense mutation p.Pro1345Ser. The mutation arose de novo in 8 of 9; for the remaining case, the mother was negative and the father was unavailable.\ud \ud Conclusions: Here, we present a phenotype-genotype correlation for SCN1A. We describe a distinct SCN1A phenotype, early infantile SCN1A encephalopathy, which is readily distinguishable from the well-recognized entities of Dravet syndrome and genetic epilepsy with febrile seizures plus. This disorder has an earlier age at onset, profound developmental impairment, and a distinctive hyperkinetic movement disorder, setting it apart from Dravet syndrome. Remarkably, 8 of 9 children had the recurrent missense mutation p.Thr226Met.
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- 2017
39. Severe microcephaly associated with congenital varicella infection
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Scheffer, I.E., Baraitser, M., and Brett, E.M.
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Microcephaly -- Causes of ,Communicable diseases in pregnancy -- Complications ,Chickenpox -- Complications ,Health - Abstract
Only a small portion of newborn infants show any adverse effects when their mothers develop chickenpox sometime during pregnancy. When adverse effects do occur, they usually involve the infant's skin. Mental retardation and brain atrophy have only been described in exposed infants in conjunction with other abnormalities that comprise the congenital varicella syndrome. Many researchers believe exposure to chickenpox during the first trimester of pregnancy poses the most danger to the fetus. This study examined the case of a female infant born with severe microcephaly (small head), but with none of the other abnormalities associated with congenital varicella syndrome. The infant's mother had chickenpox during the second trimester of pregnancy. She was born to healthy parents who had a normal eight-year-old son. The mother contracted chickenpox from the son at the 16th week of pregnancy and was given penicillin. The infant was born in good condition at 39 weeks. She became more microcephalic over time, but had no other dysmorphic features. X-ray and computerized tomography (CT) examinations showed that the infant had an extremely small skull vault and calcified brain matter. Antibodies to varicella-zoster (chickenpox) were found in the infant at 5 and 11 months of age, indicating congenital varicella infection. These results demonstrate that although exposure to chickenpox during pregnancy poses a small risk for severe fetal abnormalities, such abnormalities can occur, even when exposure is later than the first trimester. (Consumer Summary produced by Reliance Medical Information, Inc.)
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- 1991
40. Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases
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Stessman, H.A., Xiong, B., Coe, B.P., Wang, T., Hoekzema, K., Fenckova, M., Kvarnung, M., Gerdts, J., Trinh, S., Cosemans, N., Vives, L., Lin, J., Turner, T.N., Santen, G., Ruivenkamp, C., Kriek, M., Haeringen, A. van, Aten, E., Friend, K., Liebelt, J., Barnett, C., Haan, E., Shaw, M., Gecz, J., Anderlid, B.M., Nordgren, A., Lindstrand, A., Schwartz, C., Kooy, R.F., Vandeweyer, G., Helsmoortel, C., Romano, C, Alberti, A., Vinci, M., Avola, E., Giusto, S., Courchesne, E., Pramparo, T., Pierce, K., Nalabolu, S., Amaral, D.G., Scheffer, I.E., Delatycki, M.B., Lockhart, P.J., Hormozdiari, F., Harich, B., Castells Nobau, A., Xia, K., Peeters, H., Nordenskjold, M., Schenck, A., Bernier, R.A., Eichler, E.E., Stessman, H.A., Xiong, B., Coe, B.P., Wang, T., Hoekzema, K., Fenckova, M., Kvarnung, M., Gerdts, J., Trinh, S., Cosemans, N., Vives, L., Lin, J., Turner, T.N., Santen, G., Ruivenkamp, C., Kriek, M., Haeringen, A. van, Aten, E., Friend, K., Liebelt, J., Barnett, C., Haan, E., Shaw, M., Gecz, J., Anderlid, B.M., Nordgren, A., Lindstrand, A., Schwartz, C., Kooy, R.F., Vandeweyer, G., Helsmoortel, C., Romano, C, Alberti, A., Vinci, M., Avola, E., Giusto, S., Courchesne, E., Pramparo, T., Pierce, K., Nalabolu, S., Amaral, D.G., Scheffer, I.E., Delatycki, M.B., Lockhart, P.J., Hormozdiari, F., Harich, B., Castells Nobau, A., Xia, K., Peeters, H., Nordenskjold, M., Schenck, A., Bernier, R.A., and Eichler, E.E.
- Abstract
Item does not contain fulltext, Gene-disruptive mutations contribute to the biology of neurodevelopmental disorders (NDDs), but most of the related pathogenic genes are not known. We sequenced 208 candidate genes from >11,730 cases and >2,867 controls. We identified 91 genes, including 38 new NDD genes, with an excess of de novo mutations or private disruptive mutations in 5.7% of cases. Drosophila functional assays revealed a subset with increased involvement in NDDs. We identified 25 genes showing a bias for autism versus intellectual disability and highlighted a network associated with high-functioning autism (full-scale IQ >100). Clinical follow-up for NAA15, KMT5B, and ASH1L highlighted new syndromic and nonsyndromic forms of disease.
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- 2017
41. The epileptology of Koolen-de Vries syndrome: Electro-clinico-radiologic findings in 31 patients
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Myers, K.A., Mandelstam, S.A., Ramantani, G., Rushing, E.J., Vries, B.B. de, Koolen, D.A., Scheffer, I.E., Myers, K.A., Mandelstam, S.A., Ramantani, G., Rushing, E.J., Vries, B.B. de, Koolen, D.A., and Scheffer, I.E.
- Abstract
Item does not contain fulltext, OBJECTIVE: This study was designed to describe the spectrum of epilepsy phenotypes in Koolen-de Vries syndrome (KdVS), a genetic syndrome involving dysmorphic features, intellectual disability, hypotonia, and congenital malformations, that occurs secondary to 17q21.31 microdeletions and heterozygous mutations in KANSL1. METHODS: We were invited to attend a large gathering of individuals with KdVS and their families. While there, we recruited individuals with KdVS and seizures, and performed thorough phenotyping. Additional subjects were included who approached us after the family support group brought attention to our research via social media. Inclusion criteria were genetic testing results demonstrating 17q21.31 deletion or KANSL1 mutation, and at least one seizure. RESULTS: Thirty-one individuals were studied, aged 2-35 years. Median age at seizure onset was 3.5 years, and 9 of 22 had refractory seizures 2 years after onset. Focal impaired awareness seizures were the most frequent seizure type occurring in 20 of 31, usually with prominent autonomic features. Twenty-one patients had prolonged seizures and, at times, refractory status epilepticus. Electroencephalography (EEG) showed focal/multifocal epileptiform discharges in 20 of 26. MRI studies of 13 patients were reviewed, and all had structural anomalies. Corpus callosum dysgenesis, abnormal hippocampi, and dilated ventricles were the most common, although periventricular nodular heterotopia, focal cortical dysplasia, abnormal sulcation, and brainstem and cerebellum abnormalities were also observed. One patient underwent epilepsy surgery for a lesion that proved to be an angiocentric glioma. SIGNIFICANCE: The typical epilepsy phenotype of KdVS involves childhood-onset focal seizures that are prolonged and have prominent autonomic features. Multifocal epileptiform discharges are the typical EEG pattern. Structural brain abnormalities may be universal, including signs of abnormal neuroblast migration and abnorma
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- 2017
42. Neonatal nonepileptic myoclonus is a prominent clinical feature of KCNQ2 gain-of-function variants R201C and R201H
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Mulkey, S.B., Ben-Zeev, B., Nicolai, J., Carroll, J.L., Gronborg, S., Jiang, Y.H., Joshi, N., Kelly, M., Koolen, D.A., Mikati, M.A., Park, K., Pearl, P.L., Scheffer, I.E., Spillmann, R.C., Taglialatela, M., Vieker, S., Weckhuysen, S., Cooper, E.C., Cilio, M.R., Mulkey, S.B., Ben-Zeev, B., Nicolai, J., Carroll, J.L., Gronborg, S., Jiang, Y.H., Joshi, N., Kelly, M., Koolen, D.A., Mikati, M.A., Park, K., Pearl, P.L., Scheffer, I.E., Spillmann, R.C., Taglialatela, M., Vieker, S., Weckhuysen, S., Cooper, E.C., and Cilio, M.R.
- Abstract
Item does not contain fulltext, OBJECTIVE: To analyze whether KCNQ2 R201C and R201H variants, which show atypical gain-of-function electrophysiologic properties in vitro, have a distinct clinical presentation and outcome. METHODS: Ten children with heterozygous, de novo KCNQ2 R201C or R201H variants were identified worldwide, using an institutional review board (IRB)-approved KCNQ2 patient registry and database. We reviewed medical records and, where possible, interviewed parents and treating physicians using a structured, detailed phenotype inventory focusing on the neonatal presentation and subsequent course. RESULTS: Nine patients had encephalopathy from birth and presented with prominent startle-like myoclonus, which could be triggered by sound or touch. In seven patients, electroencephalography (EEG) was performed in the neonatal period and showed a burst-suppression pattern. However, myoclonus did not have an EEG correlate. In many patients the paroxysmal movements were misdiagnosed as seizures. Seven patients developed epileptic spasms in infancy. In all patients, EEG showed a slow background and multifocal epileptiform discharges later in life. Other prominent features included respiratory dysfunction (perinatal respiratory failure and/or chronic hypoventilation), hypomyelination, reduced brain volume, and profound developmental delay. One patient had a later onset, and sequencing indicated that a low abundance (~20%) R201C variant had arisen by postzygotic mosaicism. SIGNIFICANCE: Heterozygous KCNQ2 R201C and R201H gain-of-function variants present with profound neonatal encephalopathy in the absence of neonatal seizures. Neonates present with nonepileptic myoclonus that is often misdiagnosed and treated as seizures. Prognosis is poor. This clinical presentation is distinct from the phenotype associated with loss-of-function variants, supporting the value of in vitro functional screening. These findings suggest that gain-of-function and loss-of-function variants need different targeted th
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- 2017
43. Severe cognitive impairment and early-onset epilepsy in six patients with the de novo p.Glu590Lys variant of CUX2
- Author
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Chatron, N., primary, Møller, R.S., additional, Champaigne, N.L., additional, Kuechler, A., additional, Labalme, A., additional, Baggett, L., additional, Wieczorek, D., additional, Portes, V. des, additional, Edery, P., additional, Gardella, E., additional, Scheffer, I.E., additional, Mefford, H., additional, Sanlaville, D., additional, Carvill, G.L., additional, and Lesca, G., additional
- Published
- 2017
- Full Text
- View/download PDF
44. Generalised epilepsy with febrile seizures plus: Mutation of the sodium channel subunit SCN1B and evidence for a founder effect
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Wallace, R.H., Scheffer, I.E., Barnett, S., Berkovic, S.F., and Sutherland, G.R.
- Subjects
Genetic research -- Analysis ,Human genetics -- Research ,Epilepsy -- Genetic aspects ,Biological sciences - Published
- 2000
45. Familial neonatal seizures in 36 families: Clinical and genetic features correlate with outcome.
- Author
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Mulley J.C., Malone S., Bassan H., Goldberg-Stern H., Stanley T., Hayman M., Calvert S., Korczyn A.D., Lev D., Lerman-Sagie T., Shevell M., Scheffer I.E., Berkovic S.F., Grinton B.E., Heron S.E., Pelekanos J.T., Zuberi S.M., Kivity S., Afawi Z., Williams T.C., Casalaz D.M., Yendle S., Linder I., Mulley J.C., Malone S., Bassan H., Goldberg-Stern H., Stanley T., Hayman M., Calvert S., Korczyn A.D., Lev D., Lerman-Sagie T., Shevell M., Scheffer I.E., Berkovic S.F., Grinton B.E., Heron S.E., Pelekanos J.T., Zuberi S.M., Kivity S., Afawi Z., Williams T.C., Casalaz D.M., Yendle S., and Linder I.
- Abstract
Objective We evaluated seizure outcome in a large cohort of familial neonatal seizures (FNS), and examined phenotypic overlap with different molecular lesions. Methods Detailed clinical data were collected from 36 families comprising two or more individuals with neonatal seizures. The seizure course and occurrence of seizures later in life were analyzed. Families were screened for KCNQ2, KCNQ3, SCN2A, and PRRT2 mutations, and linkage studies were performed in mutation-negative families to exclude known loci. Results Thirty-three families fulfilled clinical criteria for benign familial neonatal epilepsy (BFNE); 27 of these families had KCNQ2 mutations, one had a KCNQ3 mutation, and two had SCN2A mutations. Seizures persisting after age 6 months were reported in 31% of individuals with KCNQ2 mutations; later seizures were associated with frequent neonatal seizures. Linkage mapping in two mutation-negative BFNE families excluded linkage to KCNQ2, KCNQ3, and SCN2A, but linkage to KCNQ2 could not be excluded in the third mutation-negative BFNE family. The three remaining families did not fulfill criteria of BFNE due to developmental delay or intellectual disability; a molecular lesion was identified in two; the other family remains unsolved. Significance Most families in our cohort of familial neonatal seizures fulfill criteria for BFNE; the molecular cause was identified in 91%. Most had KCNQ2 mutations, but two families had SCN2A mutations, which are normally associated with a mixed picture of neonatal and infantile onset seizures. Seizures later in life are more common in BFNE than previously reported and are associated with a greater number of seizures in the neonatal period. Linkage studies in two families excluded known loci, suggesting a further gene is involved in BFNE.Copyright © Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.
- Published
- 2015
46. PRIMA1 mutation: A new cause of nocturnal frontal lobe epilepsy
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Hildebrand, M.S., Tankard, R., Gazina, E.V., Damiano, J.A., Lawrence, K.M., Dahl, H-H.M., Regan, B.M., Shearer, A.E., Smith, R.J.H., Marini, C., Guerrini, R., Labate, A., Gambardella, A., Tinuper, P., Lichetta, L., Baldassari, S., Bisulli, F., Pippucci, T., Scheffer, I.E., Reid, C.A., Petrou, S., Bahlo, M., Berkovic, S.F., Hildebrand, M.S., Tankard, R., Gazina, E.V., Damiano, J.A., Lawrence, K.M., Dahl, H-H.M., Regan, B.M., Shearer, A.E., Smith, R.J.H., Marini, C., Guerrini, R., Labate, A., Gambardella, A., Tinuper, P., Lichetta, L., Baldassari, S., Bisulli, F., Pippucci, T., Scheffer, I.E., Reid, C.A., Petrou, S., Bahlo, M., and Berkovic, S.F.
- Abstract
Objective Nocturnal frontal lobe epilepsy (NFLE) can be sporadic or autosomal dominant; some families have nicotinic acetylcholine receptor subunit mutations. We report a novel autosomal recessive phenotype in a single family and identify the causative gene. Methods Whole exome sequencing data was used to map the family, thereby narrowing exome search space, and then to identify the mutation. Results Linkage analysis using exome sequence data from two affected and two unaffected subjects showed homozygous linkage peaks on chromosomes 7, 8, 13, and 14 with maximum LOD scores between 1.5 and 1.93. Exome variant filtering under these peaks revealed that the affected siblings were homozygous for a novel splice site mutation (c.93+2T>C) in the PRIMA1 gene on chromosome 14. No additional PRIMA1 mutations were found in 300 other NFLE cases. The c.93+2T>C mutation was shown to lead to skipping of the first coding exon of the PRIMA1 mRNA using a minigene system. Interpretation PRIMA1 is a transmembrane protein that anchors acetylcholinesterase (AChE), an enzyme hydrolyzing acetycholine, to membrane rafts of neurons. PRiMA knockout mice have reduction of AChE and accumulation of acetylcholine at the synapse; our minigene analysis suggests that the c.93+2T>C mutation leads to knockout of PRIMA1. Mutations with gain of function effects in acetylcholine receptor subunits cause autosomal dominant NFLE. Thus, enhanced cholinergic responses are the likely cause of the severe NFLE and intellectual disability segregating in this family, representing the first recessive case to be reported and the first PRIMA1 mutation implicated in disease.
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- 2015
47. Absence epilepsies with widely variable onset are a key feature of autosomal dominant Glut1 deficiency
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Mullen, S.A., Suls, Arvid, Weber, Y., Lerche, H., De Jonghe, Peter, Berkovic, S.F., and Scheffer, I.E.
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Human medicine - Abstract
AB Background: Familial glucose transporter type 1 (GLUT1) deficiency due to autosomal dominant inheritance of SLC2A1 mutations is associated with paroxysmal exertional dyskinesia; epilepsy and intellectual disability occur in some family members. We recently demonstrated that GLUT1 deficiency occurs in over 10% of patients with early-onset absence epilepsy. Methods: This family study analyses the phenotypes in 2 kindreds segregating SLC2A1 mutations identified through probands with early-onset absence epilepsy. One comprised 9 individuals with mutations over 3 generations; the other had 6 individuals over 2 generations. Results: Of 15 subjects with SLC2A1 mutations, epilepsy occurred in 12. Absence seizures were the most prevalent seizure type (10/12), with onset from 3 to 34 years of age. Epilepsy phenotypes varied widely, including idiopathic generalized epilepsies (IGE) with absence (8/12), myoclonic-astatic epilepsy (2/12), and focal epilepsy (2/12). Paroxysmal exertional dyskinesia occurred in 7, and was subtle and universally undiagnosed prior to molecular diagnosis. There were 2 unaffected mutation carriers. Conclusions: GLUT1 deficiency is an important monogenic cause of absence epilepsies with onset from early childhood to adult life. Individual cases may be phenotypically indistinguishable from common forms of IGE. Although subtle paroxysmal exertional dyskinesia is a helpful diagnostic clue, it is far from universal. The phenotypic spectrum of GLUT1 deficiency is considerably greater than previously recognized. Diagnosis of GLUT1 deficiency has important treatment and genetic counseling implications.
- Published
- 2010
48. Refining analyses of copy number variation identifies specific genes associated with developmental delay.
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Coe, B.P., Witherspoon, K., Rosenfeld, J.A., Bon, B.W.M. van, Silfhout, A.T. van, Bosco, P., Friend, K.L., Baker, C., Buono, S., Vissers, L.E.L.M., Schuurs-Hoeijmakers, J.H.M., Hoischen, A., Pfundt, R., Krumm, N., Carvill, G.L., Li, D., Amaral, D., Brown, N., Lockhart, P.J., Scheffer, I.E., Alberti, A., Shaw, M., Pettinato, R., Tervo, R., Leeuw, N. de, Reijnders, M.R., Torchia, B.S., Peeters, H., Thompson, E., O'Roak, B.J., Fichera, M., Hehir-Kwa, J.Y., Shendure, J., Mefford, H.C., Haan, E., Gécz, J., Vries, L.B.A. de, Romano, C, Eichler, E.E., Coe, B.P., Witherspoon, K., Rosenfeld, J.A., Bon, B.W.M. van, Silfhout, A.T. van, Bosco, P., Friend, K.L., Baker, C., Buono, S., Vissers, L.E.L.M., Schuurs-Hoeijmakers, J.H.M., Hoischen, A., Pfundt, R., Krumm, N., Carvill, G.L., Li, D., Amaral, D., Brown, N., Lockhart, P.J., Scheffer, I.E., Alberti, A., Shaw, M., Pettinato, R., Tervo, R., Leeuw, N. de, Reijnders, M.R., Torchia, B.S., Peeters, H., Thompson, E., O'Roak, B.J., Fichera, M., Hehir-Kwa, J.Y., Shendure, J., Mefford, H.C., Haan, E., Gécz, J., Vries, L.B.A. de, Romano, C, and Eichler, E.E.
- Abstract
Contains fulltext : 136682.pdf (publisher's version ) (Closed access)
- Published
- 2014
49. Analyzing the etiology of benign Rolandic epilepsy:A multi-center twin collaboration
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Vadlamudi, L., Kjeldsen, Marianne Juel, Corey, L.A., Solaas, M.H., Friis, Mogens Laue, Pellock, JM, Nakken, K.O., Milne, R.L., Scheffer, I.E., Harvey, A.S., Hopper, J.L., and Berkovic, S.F.
- Published
- 2006
50. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.
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Mefford H.C., Andrade D.M., Freeman J.L., Sadleir L.G., Shendure J., Berkovic S.F., Scheffer I.E., Carvill G.L., Heavin S.B., Yendle S.C., McMahon J.M., O'Roak B.J., Cook J., Khan A., Dorschner M.O., Weaver M., Calvert S., Malone S., Wallace G., Stanley T., Bye A.M.E., Bleasel A., Howell K.B., Kivity S., Mackay M.T., Rodriguez-Casero V., Webster R., Korczyn A., Afawi Z., Zelnick N., Lerman-Sagie T., Lev D., Moller R.S., Gill D., Mefford H.C., Andrade D.M., Freeman J.L., Sadleir L.G., Shendure J., Berkovic S.F., Scheffer I.E., Carvill G.L., Heavin S.B., Yendle S.C., McMahon J.M., O'Roak B.J., Cook J., Khan A., Dorschner M.O., Weaver M., Calvert S., Malone S., Wallace G., Stanley T., Bye A.M.E., Bleasel A., Howell K.B., Kivity S., Mackay M.T., Rodriguez-Casero V., Webster R., Korczyn A., Afawi Z., Zelnick N., Lerman-Sagie T., Lev D., Moller R.S., and Gill D.
- Abstract
Epileptic encephalopathies are a devastating group of epilepsies with poor prognosis, of which the majority are of unknown etiology. We perform targeted massively parallel resequencing of 19 known and 46 candidate genes for epileptic encephalopathy in 500 affected individuals (cases) to identify new genes involved and to investigate the phenotypic spectrum associated with mutations in known genes. Overall, we identified pathogenic mutations in 10% of our cohort. Six of the 46 candidate genes had 1 or more pathogenic variants, collectively accounting for 3% of our cohort. We show that de novo CHD2 and SYNGAP1 mutations are new causes of epileptic encephalopathies, accounting for 1.2% and 1% of cases, respectively. We also expand the phenotypic spectra explained by SCN1A, SCN2A and SCN8A mutations. To our knowledge, this is the largest cohort of cases with epileptic encephalopathies to undergo targeted resequencing. Implementation of this rapid and efficient method will change diagnosis and understanding of the molecular etiologies of these disorders. © 2013 Nature America, Inc. All rights reserved.
- Published
- 2013
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