Forschung

Die Arbeitsgruppe Klinische und Pathophysiologische Epileptologie beschäftigt sich mit der Untersuchung von verschiedenen Ätiologien der Epilepsie mit einem Schwerpunkt auf genetischen Epilepsien. Die Epilepsie gehört zu den häufigsten neurologischen Erkrankungen. Die verschiedenen Ursachen umfassen neben läsionellen (z. B. zerebrale Ischämien) und entzündlichen (z. B. autoimmune Enzephalitiden) auch genetische Ursachen, wobei bis zu 30% der Epilepsien genetischen Einflussfaktoren unterliegen.

Ziel ist es, die Entstehung einer Epilepsie und verwandten Erkrankungen weiter zu verstehen und daraus individualisierte, krankheitsspezifische Therapiestrategien zu entwickeln.

Folgende Projekte werden aus dem Grunde derzeit verfolgt:

Publikationen

Tang S, Addis L, Smith A, Topp SD, Pendziwiat M, Mei D, Parker A, Agrawal S, Hughes E, Lascelles K, Williams RE, Fallon P, Robinson R, Cross HJ, Hedderly T, Eltze C, Kerr T, Desurkar A, Hussain N, Kinali M, Bagnasco I, Vassallo G, Whitehouse W, Goyal S, Absoud M, Møller RS, Helbig I, Weber YG, Marini C, Guerrini R, Simpson MA, Pal DK. 2020. Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures. Epilepsia 61:995–1007. doi:10.1111/epi.16508

Lal, D., May, P., Perez-Palma, E., Samocha, K.E., Kosmicki, J.A., Robinson, E.B., Møller, R.S., Krause, R., Nürnberg, P., Weckhuysen, S., et al. (2020). Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders. Genome Med. 12.

Moreau, C., Rébillard, R.-M., Wolking, S., Michaud, J., Tremblay, F., Girard, A., Bouchard, J., Minassian, B., Laprise, C., Cossette, P., et al. (2020). Polygenic risk scores of several subtypes of epilepsies in a founder population. Neurol. Genet. 6, e416.

Scherer, M., Milosevic, L., Guggenberger, R., Maus, V., Naros, G., Grimm, F., Bucurenciu, I., Steinhoff, B.J., Weber, Y.G., Lerche, H., et al. (2020). Desynchronization of temporal lobe theta-band activity during effective anterior thalamus deep brain stimulation in epilepsy. Neuroimage 116967.

Slavotinek, A., van Hagen, J.M., Kalsner, L., Pai, S., Davis-Keppen, L., Ohden, L., Weber, Y.G., Macke, E.L., Klee, E.W., Morava, E., et al. (2020). Jumonji domain containing 1C (JMJD1C) sequence variants in seven patients with autism spectrum disorder, intellectual disability and seizures. Eur. J. Med. Genet. 103850.

Wickham, J., Corna, A., Schwarz, N., Uysal, B., Layer, N., Honegger, J.B., Wuttke, T. V., Koch, H., and Zeck, G. (2020). Human Cerebrospinal Fluid Induces Neuronal Excitability Changes in Resected Human Neocortical and Hippocampal Brain Slices. Front. Neurosci. 14.

Wolking, S., Moreau, C., Nies, A.T., Schaeffeler, E., McCormack, M., Auce, P., Avbersek, A., Becker, F., Krenn, M., Møller, R.S., et al. (2020). Testing association of rare genetic variants with resistance to three common antiseizure medications. Epilepsia 61, 657–666.

Berghuis, B., Stapleton, C., Sonsma, A.C.M., Hulst, J., de Haan, G.-J., Lindhout, D., Demurtas, R., Krause, R., Depondt, C., Kunz, W.S., et al. (2019). A genome-wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine. Epilepsia Open 4, 102–109.

Czolk, R., Schwarz, N., Koch, H., Schötterl, S., Wuttke, T. V, Holm, P.S., Huber, S.M., and Naumann, U. (2019). Irradiation enhances the therapeutic effect of the oncolytic adenovirus XVir-N-31 in brain tumor initiating cells. Int. J. Mol. Med. 44, 1484–1494.

Feng, Y.-C.A., Howrigan, D., Abbott, L., Tashman, K., Cerrato, F., Singh, T., Heyne, H., Byrnes, A., Churchhouse, C., Lal, D., et al. (2019). Ultra-rare genetic variation in the epilepsies: a whole-exome sequencing study of 17,606 individuals. BioRxiv 525683.

Heavin, S.B., McCormack, M., Wolking, S., Slattery, L., Walley, N., Avbersek, A., Novy, J., Sinha, S.R., Radtke, R., Doherty, C., et al. (2019). Genomic and clinical predictors of lacosamide response in refractory epilepsies. Epilepsia Open 4, 563–571.

Hedrich, U.B.S., Koch, H., Becker, A., and Lerche, H. (2019). Epileptogenesis and consequences for treatment. Nervenarzt 90, 773–780.

Helbig, I., Lopez-Hernandez, T., Shor, O., Galer, P., Ganesan, S., Pendziwiat, M., Rademacher, A., Ellis, C.A., Hümpfer, N., Schwarz, N., et al. (2019). A Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Causes Developmental and Epileptic Encephalopathy. Am. J. Hum. Genet.

Heyne, H.O., Artomov, M., Battke, F., Bianchini, C., Smith, D.R., Liebmann, N., Tadigotla, V., Stanley, C.M., Lal, D., Rehm, H., et al. (2019). Targeted gene sequencing in 6994 individuals with neurodevelopmental disorder with epilepsy. Genet. Med. 21, 2496–2503.

Koch, H., and Weber, Y.G. (2019). The glucose transporter type 1 (Glut1) syndromes. Epilepsy Behav. 91, 90–93.

Koch, H., Niturad, C.E., Theiss, S., Bien, C.G., Elger, C., Wandinger, K., Vincent, A., Malter, M., Körtvelyessy, P., Lerche, H., et al. (2019). In vitro neuronal network activity as a new functional diagnostic system to detect effects of Cerebrospinal fluid from autoimmune encephalitis patients. Sci. Rep. 1–8.

Kruszynski, S., Stanaitis, K., Brandes, J., Poets, C.F., and Koch, H. (2019). Doxapram stimulates respiratory activity through distinct activation of neurons in the nucleus hypoglossus and the pre-Bötzinger complex. J. Neurophysiol. 121, 1102–1110.

Lerche, H., Berkovic, S.F., and Lowenstein, D.H. (2019). Intestinal-Cell Kinase and Juvenile Myoclonic Epilepsy. N. Engl. J. Med. 380, e24.

Liu, Y., Schubert, J., Sonnenberg, L., Helbig, K.L., Hoei-Hansen, C.E., Koko, M., Rannap, M., Lauxmann, S., Huq, M., Schneider, M.C., et al. (2019). Neuronal mechanisms of mutations in SCN8A causing epilepsy or intellectual disability. Brain 142, 376–390.

Niestroj, L.M., May, P., Artomov, M., Kobow, K., Coras, R., Pérez-Palma, E., Altmüller, J., Thiele, H., Nürnberg, P., Leu, C., et al. (2019). Assessment of genetic variant burden in epilepsy-associated brain lesions. Eur. J. Hum. Genet. 27, 1738–1744.

O’Donnell-Luria, A.H., Pais, L.S., Faundes, V., Wood, J.C., Sveden, A., Luria, V., Abou Jamra, R., Accogli, A., Amburgey, K., Anderlid, B.M., et al. (2019). Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy. Am. J. Hum. Genet. 104, 1210–1222.

Reinhardt, F., Weber, Y.G., Mayer, T., Luef, G., Joeres, L., Tennigkeit, F., Dedeken, P., De Backer, M., Hellot, S., Lauterbach, T., et al. (2019). Changes in drug load during lacosamide combination therapy: A noninterventional, observational study in German and Austrian clinical practice. Epilepsia Open 4, 409–419.

Schulz, H., Ruppert, A.K., Zara, F., Madia, F., Iacomino, M., S. Vari, M., Balagura, G., Minetti, C., Striano, P., Bianchi, A., et al. (2019). No evidence for a BRD2 promoter hypermethylation in blood leukocytes of Europeans with juvenile myoclonic epilepsy. Epilepsia 60, e31–e36.

Schwarz, N., Uysal, B., Welzer, M., Bahr, J.C., Layer, N., Loffler, H., Stanaitis, K., Pa, H., Weber, Y.G., Hedrich, U.B., et al. (2019b). Long-term adult human brain slice cultures as a model system to study human CNS circuitry and disease. Elife 8.

Silvennoinen, K., de Lange, N., Zagaglia, S., Balestrini, S., Androsova, G., Wassenaar, M., Auce, P., Avbersek, A., Becker, F., Berghuis, B., et al. (2019). Comparative effectiveness of antiepileptic drugs in juvenile myoclonic epilepsy. Epilepsia Open 4, 420–430.

Truong, V.T., Palmer, C., Wolking, S., Sheets, B., Young, M., Ngo, T.N.M., Taylor, M., Nagueh, S.F., Zareba, K.M., Raman, S., et al. (2019). Normal left atrial strain and strain rate using cardiac magnetic resonance feature tracking in healthy volunteers. Eur. Heart J. Cardiovasc. Imaging.

Willikens, S., and Wolking, S. (2019). A case of DRESS (drug reaction with eosinophilia and systemic symptoms) under treatment with eslicarbazepine. Seizure 72, 11–12.

Wolking, S., May, P., Mei, D., Møller, R.S., Balestrini, S., Helbig, K.L., Altuzarra, C.D., Chatron, N., Kaiwar, C., Stöhr, K., et al. (2019). Clinical spectrum of STX1B-related epileptic disorders. Neurology 92, e1238–e1249.

Bernhard, F.P., Sartor, J., Bettecken, K., Hobert, M.A., Arnold, C., Weber, Y.G., Poli, S., Margraf, N.G., Schlenstedt, C., Hansen, C., et al. (2018). Wearables for gait and balance assessment in the neurological ward - study design and first results of a prospective cross-sectional feasibility study with 384 inpatients. BMC Neurol. 18, 114.

Dubey, M., Brouwers, E., Hamilton, E.M.C., Stiedl, O., Bugiani, M., Koch, H., Kole, M.H.P., Boschert, U., Wykes, R.C., Mansvelder, H.D., et al. (2018). Seizures and disturbed brain potassium dynamics in the leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts. Ann. Neurol. 83, 636–649.

Epilepsies, T.I.L.A.E.C. on C. (2018). Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies. Nat. Commun. 9, 5269.

Hamer, H.M., Pfafflin, M., Baier, H., Bosebeck, F., Franz, M., Holtkamp, M., Kurlemann, G., May, T.W., Mayer, T., Metzner, M., et al. (2018). Characteristics and healthcare situation of adult patients with tuberous sclerosis complex in German epilepsy centers. Epilepsy Behav. 82, 64–67.

Heyne, H.O., Singh, T., Stamberger, H., Abou Jamra, R., Caglayan, H., Craiu, D., De Jonghe, P., Guerrini, R., Helbig, K.L., Koeleman, B.P.C., et al. (2018). De novo variants in neurodevelopmental disorders with epilepsy. Nat. Genet. 50, 1048–1053.

Jabbari, K., Bobbili, D.R., Lal, D., Reinthaler, E.M., Schubert, J., Wolking, S., Sinha, V., Motameny, S., Thiele, H., Kawalia, A., et al. (2018). Rare gene deletions in genetic generalized and Rolandic epilepsies. PLoS One 13, e0202022.

Johannesen, K.M., Gardella, E., Linnankivi, T., Courage, C., de Saint Martin, A., Lehesjoki, A.-E., Mignot, C., Afenjar, A., Lesca, G., Abi-Warde, M.-T., et al. (2018). Defining the phenotypic spectrum of SLC6A1 mutations. Epilepsia 59, 389–402.

Koch, H., and Weber, Y.G. (2018). The glucose transporter type 1 (Glut1) syndromes. Epilepsy Behav. 1, 4–7.

May, P., Girard, S., Harrer, M., Bobbili, D.R., Schubert, J., Wolking, S., Becker, F., Lachance-Touchette, P., Meloche, C., Gravel, M., et al. (2018). Rare coding variants in genes encoding GABAA receptors in genetic generalised epilepsies: an exome-based case-control study. Lancet Neurol. 17, 699–708.

McCormack, M., Gui, H., Ingason, A., Speed, D., Wright, G.E.B., Zhang, E.J., Secolin, R., Yasuda, C., Kwok, M., Wolking, S., et al. (2018). Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients. Neurology 90, e332–e341.

Zaman, S.M., Mullen, S.A., Petrovski, S., Maljevic, S., Gazina, E. V, Phillips, A.M., Jones, G.D., Hildebrand, M.S., Damiano, J., Auvin, S., et al. (2018). Development of a rapid functional assay that predicts GLUT1 disease severity. Neurol. Genet. 4, e297.

(2018). Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies. Nat. Commun. 9, 5269.

Androsova, G., Krause, R., Borghei, M., Wassenaar, M., Auce, P., Avbersek, A., Becker, F., Berghuis, B., Campbell, E., Coppola, A., et al. (2017). Comparative effectiveness of antiepileptic drugs in patients with mesial temporal lobe epilepsy with hippocampal sclerosis. Epilepsia 58, 1734–1741.

Becker, F., Reid, C.A., Hallmann, K., Tae, H.-S., Phillips, A.M., Teodorescu, G., Weber, Y.G., Kleefuss-Lie, A., Elger, C., Perez-Reyes, E., et al. (2017). Functional variants in HCN4 and CACNA1H may contribute to genetic generalized epilepsy. Epilepsia Open 2, 334–342.

Berghuis, B., van der Palen, J., de Haan, G.-J., Lindhout, D., Koeleman, B.P.C., and Sander, J.W. (2017). Carbamazepine- and oxcarbazepine-induced hyponatremia in people with epilepsy. Epilepsia 58, 1227–1233.

Dohrn, M.F., Glockle, N., Mulahasanovic, L., Heller, C., Mohr, J., Bauer, C., Riesch, E., Becker, A., Battke, F., Hortnagel, K., et al. (2017). Frequent genes in rare diseases: panel-based next generation sequencing to disclose causal mutations in hereditary neuropathies. J. Neurochem. 143, 507–522.

Grimm, A., Winter, N., Wolking, S., Vittore, D., Biskup, S., and Axer, H. (2017). Nerve enlargement in an unusual case of inflammatory neuropathy and new gene mutation-morphology is the key. Neurol. Sci.  Off. J. Ital. Neurol. Soc.  Ital. Soc. Clin. Neurophysiol. 38, 1525–1527.

Perez-Palma, E., Helbig, I., Klein, K.M., Anttila, V., Horn, H., Reinthaler, E.M., Gormley, P., Ganna, A., Byrnes, A., Pernhorst, K., et al. (2017). Heterogeneous contribution of microdeletions in the development of common generalised and focal epilepsies. J. Med. Genet. 54, 598–606.

Schwarz, N., Hedrich, U.B.S., Schwarz, H., Harshad, P.A., Dammeier, N., Auffenberg, E., Bedogni, F., Honegger, J.B., Lerche, H., Wuttke, T. V., et al. (2017). Human Cerebrospinal fluid promotes long-term neuronal viability and network function in human neocortical organotypic brain slice cultures. Sci. Rep. 7, 1–12.

Theiss, S., Maetzler, W., Deuschle, C., Lerche, H., Koch, H., and Dihné, M. (2017). Dementia with Lewy bodies: Cerebrospinal fluid suppresses neuronal network activity. Neuroreport 28.

Weber, Y.G., Biskup, S., Helbig, K.L., Von Spiczak, S., and Lerche, H. (2017). The role of genetic testing in epilepsy diagnosis and management. Expert Rev. Mol. Diagn. 17, 739–750.

Weiss, D., Zrenner, B., Wolking, S., Freilinger, T., and Grimm, A. (2017). Macrodactylia lipomatosa with fibrolipomatous hamartomas: Macroscopic and ultrasound clues. Clin. Neurophysiol. 128, 1315–1316.