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1. PLA2G6-associated neurodegeneration in three different populations-case series

Author

Milanowski, L., primary, Hanna AL-Shaikh, R., additional, Holla, V., additional, Kurihara, K., additional, Yadav, R., additional, Kamble, N., additional, Muthusamy, B., additional, Koziorowski, D., additional, Szlufik, S., additional, Hoffman-Zacharska, D., additional, Fujioka, S., additional, Ross, O.A., additional, Wierenga, K., additional, Wszolek, Z.K., additional, and Pal, P.K., additional

Published
2023
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2. Establishing an online resource to facilitate global collaboration and inclusion of underrepresented populations: Experience from the MJFF Global Genetic Parkinson's Disease Project.

Author

Vollstedt, E.J., Madoev, H., Aasly, A., Ahmad-Annuar, A., Al-Mubarak, B., Alcalay, R.N., Alvarez, V., Amorin, I., Annesi, G., Arkadir, D., Bardien, S., Barker, R.A., Barkhuizen, M., Basak, A.N., Bonifati, V., Boon, A., Brighina, L., Brockmann, K., Carmine Belin, A., Carr, J., Clarimon, J., Cornejo-Olivas, M., Correia Guedes, L., Corvol, J.C., Crosiers, D., Damásio, J., Das, P., Carvalho Aguiar, P. de, Rosa, A. De, Dorszewska, J., Ertan, S., Ferese, R., Ferreira, J., Gatto, E., Genç, G., Giladi, N., Gómez-Garre, P., Hanagasi, H., Hattori, N., Hentati, F., Hoffman-Zacharska, D., Illarioshkin, S.N., Jankovic, J., Jesús, S., Kaasinen, V., Kievit, A., Klivenyi, P., Kostic, V., Koziorowski, D., Kühn, A.A., Lang, A.E., Lim, S.Y., Lin, Chih-Yu, Lohmann, K., Markovic, V., Martikainen, M.H., Mellick, G., Merello, M., Milanowski, L., Mir, P., Öztop-Çakmak, Ö., Pimentel, M.M.G., Pulkes, T., Puschmann, A., Rogaeva, E., Sammler, E.M., Skaalum Petersen, M., Skorvanek, M., Spitz, M., Suchowersky, O., Tan, A.H., Termsarasab, P., Thaler, Avner, Tumas, V., Valente, E.M., Warrenburg, B.P.C. van de, Williams-Gray, C.H., Wu, R.M., Zhang, B., Zimprich, A., Solle, J., Padmanabhan, S., Klein, Christine, Vollstedt, E.J., Madoev, H., Aasly, A., Ahmad-Annuar, A., Al-Mubarak, B., Alcalay, R.N., Alvarez, V., Amorin, I., Annesi, G., Arkadir, D., Bardien, S., Barker, R.A., Barkhuizen, M., Basak, A.N., Bonifati, V., Boon, A., Brighina, L., Brockmann, K., Carmine Belin, A., Carr, J., Clarimon, J., Cornejo-Olivas, M., Correia Guedes, L., Corvol, J.C., Crosiers, D., Damásio, J., Das, P., Carvalho Aguiar, P. de, Rosa, A. De, Dorszewska, J., Ertan, S., Ferese, R., Ferreira, J., Gatto, E., Genç, G., Giladi, N., Gómez-Garre, P., Hanagasi, H., Hattori, N., Hentati, F., Hoffman-Zacharska, D., Illarioshkin, S.N., Jankovic, J., Jesús, S., Kaasinen, V., Kievit, A., Klivenyi, P., Kostic, V., Koziorowski, D., Kühn, A.A., Lang, A.E., Lim, S.Y., Lin, Chih-Yu, Lohmann, K., Markovic, V., Martikainen, M.H., Mellick, G., Merello, M., Milanowski, L., Mir, P., Öztop-Çakmak, Ö., Pimentel, M.M.G., Pulkes, T., Puschmann, A., Rogaeva, E., Sammler, E.M., Skaalum Petersen, M., Skorvanek, M., Spitz, M., Suchowersky, O., Tan, A.H., Termsarasab, P., Thaler, Avner, Tumas, V., Valente, E.M., Warrenburg, B.P.C. van de, Williams-Gray, C.H., Wu, R.M., Zhang, B., Zimprich, A., Solle, J., Padmanabhan, S., and Klein, Christine

Abstract

Item does not contain fulltext, Parkinson's disease (PD) is the fastest-growing neurodegenerative disorder, currently affecting ~7 million people worldwide. PD is clinically and genetically heterogeneous, with at least 10% of all cases explained by a monogenic cause or strong genetic risk factor. However, the vast majority of our present data on monogenic PD is based on the investigation of patients of European White ancestry, leaving a large knowledge gap on monogenic PD in underrepresented populations. Gene-targeted therapies are being developed at a fast pace and have started entering clinical trials. In light of these developments, building a global network of centers working on monogenic PD, fostering collaborative research, and establishing a clinical trial-ready cohort is imperative. Based on a systematic review of the English literature on monogenic PD and a successful team science approach, we have built up a network of 59 sites worldwide and have collected information on the availability of data, biomaterials, and facilities. To enable access to this resource and to foster collaboration across centers, as well as between academia and industry, we have developed an interactive map and online tool allowing for a quick overview of available resources, along with an option to filter for specific items of interest. This initiative is currently being merged with the Global Parkinson's Genetics Program (GP2), which will attract additional centers with a focus on underrepresented sites. This growing resource and tool will facilitate collaborative research and impact the development and testing of new therapies for monogenic and potentially for idiopathic PD patients.

Published
2023

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

Author

Lal, D., May, P., Perez-Palma, E., Samocha, K. E., Kosmicki, J. A., Robinson, E. B., Moller, R. S., Krause, R., Nurnberg, P., Weckhuysen, S., De Jonghe, P., Guerrini, R., Niestroj, L. M., Du, J., Marini, C., Balling, R., Barisic, N., Baulac, S., Caglayan, H., Craiu, D. C., Depienne, C., Helbig, I., Hjalgrim, H., Hoffman-Zacharska, D., Jahn, J., Klein, K. M., Koeleman, B. P. C., Komarek, V., Leguern, E., Lehesjoki, A. -E., Lemke, J. R., Lerche, H., Linnankivi, T., Muhle, H., Pal, D. K., Palotie, A., Rosenow, F., Schubert-Bast, S., Selmer, K., Serratosa, J. M., Stephani, U., Sterbova, K., Striano, P., Suls, A., Talvik, T., Von Spiczak, S., Weber, Y. G., Zara, F., Ware, J. S., Kurki, M., Gormley, P., Tang, S., Wu, S., Biskup, S., Poduri, A., Neubauer, B. A., Helbig, K. L., Majithia, A. R., Daly, M. J., EuroEPINOMICS-RES Consortium, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, University of Helsinki, Department of Medical and Clinical Genetics, Medicum, HUS Helsinki and Uusimaa Hospital District, and Wellcome Trust

Subjects
Candidate gene, lcsh:QH426-470, Developmental Disabilities, Mutation, Missense, Sequence Homology, lcsh:Medicine, ORTHOLOGS, Computational biology, Conservation, Gene family, Missense variants, Neurodevelopmental disorders, Paralogs, Biology, 03 medical and health sciences, MULTIPLE SEQUENCE ALIGNMENT, PHYLOGENETIC TREES, Genetics, Missense mutation, Ensembl, Molecular Biology, Gene, Genetics (clinical), Phylogeny, 030304 developmental biology, 0303 health sciences, 0604 Genetics, Phylogenetic tree, Research, 030305 genetics & heredity, lcsh:R, 1184 Genetics, developmental biology, physiology, 1103 Clinical Sciences, EuroEPINOMICS-RES Consortium, Human genetics, lcsh:Genetics, Genetic Loci, DE-NOVO MUTATIONS, Multigene Family, Molecular Medicine, Human medicine, Orthologous Gene, Genome-Wide Association Study
Abstract

Background Classifying pathogenicity of missense variants represents a major challenge in clinical practice during the diagnoses of rare and genetic heterogeneous neurodevelopmental disorders (NDDs). While orthologous gene conservation is commonly employed in variant annotation, approximately 80% of known disease-associated genes belong to gene families. The use of gene family information for disease gene discovery and variant interpretation has not yet been investigated on a genome-wide scale. We empirically evaluate whether paralog-conserved or non-conserved sites in human gene families are important in NDDs. Methods Gene family information was collected from Ensembl. Paralog-conserved sites were defined based on paralog sequence alignments; 10,068 NDD patients and 2078 controls were statistically evaluated for de novo variant burden in gene families. Results We demonstrate that disease-associated missense variants are enriched at paralog-conserved sites across all disease groups and inheritance models tested. We developed a gene family de novo enrichment framework that identified 43 exome-wide enriched gene families including 98 de novo variant carrying genes in NDD patients of which 28 represent novel candidate genes for NDD which are brain expressed and under evolutionary constraint. Conclusion This study represents the first method to incorporate gene family information into a statistical framework to interpret variant data for NDDs and to discover new NDD-associated genes.

Published
2020
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7. De novo variants in neurodevelopmental disorders with epilepsy

Author

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., Kosmicki, J. A., Linnankivi, T., May, P., Muhle, H., Moller, R. S., Neubauer, B. A., Palotie, A., Pendziwiat, M., Striano, P., Tang, S., Wu, S., Afawi, Z., De Kovel, C., Dimova, P., Djemie, T., Endziniene, M., Hoffman-Zacharska, D., Jahn, J., Korff, C., Lehesjoki, A. -E., Marini, C., Muller, S. H., Pal, D., Schwarz, N., Selmer, K., Serratosa, J., Stephani, U., Sterbova, K., Suls, A., Syrbe, S., Talvik, I., Von Spiczak, S., Zara, F., Poduri, A., Weber, Y. G., Weckhuysen, S., Sisodiya, S. M., Daly, M. J., Helbig, I., Lal, D., Lemke, J. R., Children's Hospital, Lastenneurologian yksikkö, Clinicum, University of Helsinki, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Research Programme for Molecular Neurology, Neuroscience Center, HUS Children and Adolescents, Genomics of Neurological and Neuropsychiatric Disorders, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], University of Luxembourg: High Performance Computing - ULHPC [research center], Korff, Christian, and EuroEPINOMICS RES Consortium

Subjects
Exome/genetics, Male, 0301 basic medicine, ILAE COMMISSION, Joint analysis, Neurodevelopmental Disorders/genetics, Bioinformatics, Epilepsy/genetics, Epilepsy, 0302 clinical medicine, Intellectual disability, SEQUENCE VARIANTS, Missense mutation, Epilepsy is a frequent feature, Exome, TERMINOLOGY, Disease gene, 0303 health sciences, ddc:618, medicine.diagnostic_test, Genetic Predisposition to Disease/genetics, Neurodevelopmental disorders, 1184 Genetics, developmental biology, physiology, HUMAN-DISEASE, PREVALENCE, 3. Good health, Genetic Variation/genetics, De novo variants, Female, Genetics & genetic processes [F10] [Life sciences], Génétique & processus génétiques [F10] [Sciences du vivant], Genetic Testing/methods, Disease Association, Biology, CLASSIFICATION, 03 medical and health sciences, Intellectual Disability, Genetics, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Limited evidence, 030304 developmental biology, Genetic testing, business.industry, MUTATIONS, AUTISM SPECTRUM DISORDER, Genetic Variation, medicine.disease, Intellectual Disability/genetics, 030104 developmental biology, Neurodevelopmental Disorders, epilepsy, KCNQ2 ENCEPHALOPATHY, Human medicine, 3111 Biomedicine, business, Genetic diagnosis, 030217 neurology & neurosurgery
Abstract

Epilepsy is a frequent feature of neurodevelopmental disorders (NDD) but little is known about genetic differences between NDD with and without epilepsy. We analyzed de novo variants (DNV) in 6753 parent-offspring trios ascertained for different NDD. In the subset of 1942 individuals with NDD with epilepsy, we identified 33 genes with a significant excess of DNV, of which SNAP25 and GABRB2 had previously only limited evidence for disease association. Joint analysis of all individuals with NDD also implicated CACNA1E as a novel disease gene. Comparing NDD with and without epilepsy, we found missense DNV, DNV in specific genes, age of recruitment and severity of intellectual disability to be associated with epilepsy. We further demonstrate to what extent our results impact current genetic testing as well as treatment, emphasizing the benefit of accurate genetic diagnosis in NDD with epilepsy.

Published
2018
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10. Diagnostic implications of genetic copy number variation in epilepsy plus

Author

Coppola, A., Cellini, E., Stamberger, H., Saarentaus, E., Cetica, V., Lal, D., Djemie, T., Bartnik-Glaska, M., Ceulemans, B., Helen Cross, J., Deconinck, T., Masi, S. D., Dorn, T., Guerrini, R., Hoffman-Zacharska, D., Kooy, F., Lagae, L., Lench, N., Lemke, J. R., Lucenteforte, E., Madia, F., Mefford, H. C., Morrogh, D., Nuernberg, P., Palotie, A., Schoonjans, A. -S., Striano, P., Szczepanik, E., Tostevin, A., Vermeesch, J. R., Van Esch, H., Van Paesschen, W., Waters, J. J., Weckhuysen, S., Zara, F., Jonghe, P. D., Sisodiya, S. M., Marini, C., Lehesjioki, A. -E., Craiu, D., Talvik, T., Caglayan, H., Serratosa, J., Sterbova, K., Moller, R. S., Hjalgrim, H., Lerche, H., Weber, Y., Helbig, I., von Spiczak, S., Barba, C., Bogaerts, A., Boni, A., Galizia, E. C., Chiari, S., Di Gacomo, G., Ferrari, A., Guarducci, S., Giglio, S., Holmgren, P., Leu, C., Melani, F., Novara, F., Pantaleo, M., Peeters, E., Pisano, T., Rosati, A., Sander, J., Schoeler, N., Stankiewicz, P., Striano, S., Suls, A., Traverso, M., Vandeweyer, G., Van Dijck, A., Zuffardi, O., Coppola, Antonietta, Cellini, Elena, Stamberger, Hannah, Saarentaus, Elmo, Cetica, Valentina, Lal, Denni, Djémié, Tania, Bartnik-Glaska, Magdalena, Ceulemans, Berten, Helen Cross, J., Deconinck, Tine, Masi, Salvatore De, Dorn, Thoma, Guerrini, Renzo, Hoffman-Zacharska, Dorotha, Kooy, Frank, Lagae, Lieven, Lench, Nichola, Lemke, Johannes R., Lucenteforte, Ersilia, Madia, Francesca, Mefford, Heather C., Morrogh, Deborah, Nuernberg, Peter, Palotie, Aarno, Schoonjans, An-Sofie, Striano, Pasquale, Szczepanik, Elzbieta, Tostevin, Anna, Vermeesch, Joris R., Van Esch, Hilde, Van Paesschen, Wim, Waters, Jonathan J, Weckhuysen, Sarah, Zara, Federico, Jonghe, Peter De, Sisodiya, Sanjay M., Marini, Carla, Lehesjioki, Anna-Elina, Craiu, Dana, Talvik, Tiina, Caglayan, Hande, Serratosa, Jose, Sterbova, Katalin, Møller, Rikke S., Hjalgrim, Helle, Lerche, Holger, Weber, Yvonne, Helbig, Ingo, von Spiczak, Sarah, Barba, Carmen, Bogaerts, Anneleen, Boni, Antonella, Galizia, Elisabeth Caruana, Chiari, Sara, Di Gacomo, Gianpiero, Ferrari, Annarita, Guarducci, Silvia, Giglio, Sabrina, Holmgren, Philip, Leu, Costin, Melani, Federico, Novara, Francesca, Pantaleo, Marilena, Peeters, Elke, Pisano, Tiziana, Rosati, Anna, Sander, Josemir, Schoeler, Natasha, Stankiewicz, Pawel, Striano, Salvatore, Suls, Arvid, Traverso, Monica, Vandeweyer, Geert, Van Dijck, Anke, and Zuffardi, Orsetta

Subjects
epilepsy gene, Epilepsy, DNA Copy Number Variations, Genotype, Comorbidity, array CGH, copy number variants, epilepsy genes, SNP array, Phenotype, Neurology, mental disorders, Full‐length Original Research, Humans, copy number variant, Genetic Predisposition to Disease, Neurology (clinical)
Abstract

Summary Objective Copy number variations (CNVs) represent a significant genetic risk for several neurodevelopmental disorders including epilepsy. As knowledge increases, reanalysis of existing data is essential. Reliable estimates of the contribution of CNVs to epilepsies from sizeable populations are not available. Methods We assembled a cohort of 1255 patients with preexisting array comparative genomic hybridization or single nucleotide polymorphism array based CNV data. All patients had “epilepsy plus,” defined as epilepsy with comorbid features, including intellectual disability, psychiatric symptoms, and other neurological and nonneurological features. CNV classification was conducted using a systematic filtering workflow adapted to epilepsy. Results Of 1097 patients remaining after genetic data quality control, 120 individuals (10.9%) carried at least one autosomal CNV classified as pathogenic; 19 individuals (1.7%) carried at least one autosomal CNV classified as possibly pathogenic. Eleven patients (1%) carried more than one (possibly) pathogenic CNV. We identified CNVs covering recently reported (HNRNPU) or emerging (RORB) epilepsy genes, and further delineated the phenotype associated with mutations of these genes. Additional novel epilepsy candidate genes emerge from our study. Comparing phenotypic features of pathogenic CNV carriers to those of noncarriers of pathogenic CNVs, we show that patients with nonneurological comorbidities, especially dysmorphism, were more likely to carry pathogenic CNVs (odds ratio = 4.09, confidence interval = 2.51‐6.68; P = 2.34 × 10−9). Meta‐analysis including data from published control groups showed that the presence or absence of epilepsy did not affect the detected frequency of CNVs. Significance The use of a specifically adapted workflow enabled identification of pathogenic autosomal CNVs in 10.9% of patients with epilepsy plus, which rose to 12.7% when we also considered possibly pathogenic CNVs. Our data indicate that epilepsy with comorbid features should be considered an indication for patients to be selected for a diagnostic algorithm including CNV detection. Collaborative large‐scale CNV reanalysis leads to novel declaration of pathogenicity in unexplained cases and can promote discovery of promising candidate epilepsy genes.

Published
2019

13. The power of the Mediator complex-Expanding the genetic architecture and phenotypic spectrum of MED12 -related disorders

Author

Charzewska, A., primary, Maiwald, R., additional, Kahrizi, K., additional, Oehl-Jaschkowitz, B., additional, Dufke, A., additional, Lemke, J.R., additional, Enders, H., additional, Najmabadi, H., additional, Tzschach, A., additional, Hachmann, W., additional, Jensen, C., additional, Bienek, M., additional, Poznański, J., additional, Nawara, M., additional, Chilarska, T., additional, Obersztyn, E., additional, Hoffman-Zacharska, D., additional, Gos, M., additional, Bal, J., additional, and Kalscheuer, V.M., additional

Published
2018
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16. DE NOVO LOSS- OR GAIN-OF-FUNCTION MUTATIONS IN KCNA2 CAUSE EPILEPTIC ENCEPHALOPATHY

Author

Syrbe, S., Hedrich, U., Riesch, E., Djemie, T., Mueller, S., Moller, R. S., Maher, B., Hernandez-Hernandez, L., Synofzik, M., Caglayan, H., Arslan, M., Serratosa, J., Nothnagel, M., May, P., Krause, R., Loeffler, H., Detert, K., Dorn, T., Vogt, H., Kraemer, G., Schoels, L., Mullis, P., Linnankivi, T., Lehesjoki, A. -E., Sterbova, K., Craiu, D., Hoffman-Zacharska, D., Korff, C., Weber, Y., Steinlin, M., Gallati, S., Bertsche, A., Bernhard, M., Merkenschlager, A., Kiess, W., Gonzalez, M., Zuechner, S., Palotie, A., Suls, A., De Jonghe, P., Helbig, I., Biskup, S., Wolff, M., Maljevic, S., Schuele, R., Sisodiya, S., Weckhuysen, S., Lerche, H., Lemke, J., Syrbe, S., Hedrich, U., Riesch, E., Djemie, T., Mueller, S., Moller, R. S., Maher, B., Hernandez-Hernandez, L., Synofzik, M., Caglayan, H., Arslan, M., Serratosa, J., Nothnagel, M., May, P., Krause, R., Loeffler, H., Detert, K., Dorn, T., Vogt, H., Kraemer, G., Schoels, L., Mullis, P., Linnankivi, T., Lehesjoki, A. -E., Sterbova, K., Craiu, D., Hoffman-Zacharska, D., Korff, C., Weber, Y., Steinlin, M., Gallati, S., Bertsche, A., Bernhard, M., Merkenschlager, A., Kiess, W., Gonzalez, M., Zuechner, S., Palotie, A., Suls, A., De Jonghe, P., Helbig, I., Biskup, S., Wolff, M., Maljevic, S., Schuele, R., Sisodiya, S., Weckhuysen, S., Lerche, H., and Lemke, J.

Published
2015

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

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Chemical Biology (Crawford Group) [research center], ESF, European Science Foundation; WT089062, Wellcome Trust; 098051, Wellcome Trust; 261123, EC, European Commission; DFG, Deutsche Forschungsgemeinschaft [sponsor], Suls, A., Jaehn, J. A., Kecskés, A., Weber, Y., Weckhuysen, S., Craiu, D. C., Siekierska, A., Djémie, T., Afrikanova, T., Gormley, P., Von Spiczak, S., Kluger, G., Iliescu, C. M., Talvik, T., Talvik, I., Meral, C., Caglayan, H. S., Giraldez, B. G., Serratosa, J., Lemke, J. R., Hoffman-Zacharska, D., Szczepanik, E., Barisic, N., Komarek, V., Hjalgrim, H., Møller, R. S., Linnankivi, T., Dimova, P., Striano, P., Zara, F., Marini, C., Guerrini, R., Depienne, C., Baulac, S., Kuhlenbäumer, G., Crawford, Alexander Dettmar, Lehesjoki, A.-E., De Witte, P. A. M., Palotie, A., Lerche, H., Esguerra, C. V., De Jonghe, P., Helbig, I., Luxembourg Centre for Systems Biomedicine (LCSB): Chemical Biology (Crawford Group) [research center], ESF, European Science Foundation; WT089062, Wellcome Trust; 098051, Wellcome Trust; 261123, EC, European Commission; DFG, Deutsche Forschungsgemeinschaft [sponsor], Suls, A., Jaehn, J. A., Kecskés, A., Weber, Y., Weckhuysen, S., Craiu, D. C., Siekierska, A., Djémie, T., Afrikanova, T., Gormley, P., Von Spiczak, S., Kluger, G., Iliescu, C. M., Talvik, T., Talvik, I., Meral, C., Caglayan, H. S., Giraldez, B. G., Serratosa, J., Lemke, J. R., Hoffman-Zacharska, D., Szczepanik, E., Barisic, N., Komarek, V., Hjalgrim, H., Møller, R. S., Linnankivi, T., Dimova, P., Striano, P., Zara, F., Marini, C., Guerrini, R., Depienne, C., Baulac, S., Kuhlenbäumer, G., Crawford, Alexander Dettmar, Lehesjoki, A.-E., De Witte, P. A. M., Palotie, A., Lerche, H., Esguerra, C. V., De Jonghe, P., and Helbig, I.

Abstract

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

Published
2013

19. P228 – 2031 Preliminary results of the study of Rett syndrome phenotype in 27 patients from a Romanian pediatric neurology clinic

Author

Anghelescu, C, primary, Barca, D, additional, Burloiu, C, additional, Butoianu, N, additional, Darja, M, additional, Gherghiceanu, R, additional, Iliescu, C, additional, Gos, M, additional, Hoffman-Zacharska, D, additional, Iancu, D, additional, Minciu, I, additional, Motoescu, C, additional, Sandu, C, additional, Tarta-Arsene, O, additional, Todorova, A, additional, and Craiu, D, additional

Published
2013
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20. P25 – 2072 Diagnostic clues and difficulties in Dravet syndrome starting from 34 Dravet patients analysis within Romanian Research Group for Rare Genetic Epilepsies

Author

Craiu, D, primary, Barca, D, additional, Burloiu, C, additional, Butoianu, N, additional, Deconinck, T, additional, Gos, M, additional, Hoffman-Zacharska, D, additional, Iancu, D, additional, Minciu, I, additional, Motoescu, C, additional, Sandu, C, additional, Tarta-Arsene, O, additional, Weckhuysen, S, additional, and Iliescu, C, additional

Published
2013
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21. Erythrocyte glucose-6-phosphate dehydrogenase deficiency in Poland--a study on the 563 and 1311 mutations of the G6PD gene

Author

Jabłońska-Skwiecińska, E., Zimowski, J. G., Kłopocka, J., Bisko, M., Hoffman-Zacharska, D., and Jacek Zaremba

Subjects
Male, Erythrocytes, Glucosephosphate Dehydrogenase Deficiency, Mutation, Genetics, Humans, Favism, Female, DNA, Poland, Polymerase Chain Reaction, Genetics (clinical)
Abstract

Studies on the mutation 563T and silent mutation 1311T of the glucose-6-phosphate dehydrogenase (G6PD) gene in Poland were performed in 26 families affected with G6PD deficiency classified-according to WHO-as group 2 G6PD deficiency. Both mutations were found in 19 families, including 17 of Polish origin. Mutation 563T alone was found in 1 Greek female. The frequency of the silent mutation 1311T in Polish unaffected controls was 0.10. It is postulated that at least parts of the Polish (or Middle-Eastern European) and Mediterranean populations are of a common origin.

Published
1997

48. Case report: Early (molecular) diagnosis is the clue: report on ALDH7A1 deficiency in newborns.

Author

Lipiński P, Wójcicka-Kowalczyk K, Bogdańska A, Ehmke E, Pajdowska M, Skrzypek K, Charzewska A, and Hoffman-Zacharska D

Abstract

The first-tier genetic testing for developmental and epileptic encephalopathies (DEE) is now increasingly used in routine clinical practice. Antiquitin deficiency, also referred to as pyridoxine-dependent epilepsy (PDE-ALDH7A1), represents an inherited metabolic disorder with the phenotype of an early infantile DEE. In addition to the fact that biochemical biomarkers of PDE-ALDH7A1, including α-aminoadipic semialdehyde dehydrogenase, pipecolic acid (PA), Δ1-piperideine-6-carboxylate, and 6-oxopipecolate (6-oxo-PIP), are well-characterized, and their analysis and usefulness have some limitations. Here, we describe the case of a newborn presenting with seizures from the first hours of life, who was resistant to standard antiepileptic drugs and was found to be a biallelic compound heterozygote of two clearly pathogenic variants in the ALDH7A1 gene based on targeted next-generation sequencing (NGS). The diagnostic process of PDE-ALDH7A1 was limited by the possibility to determine only urinary PA and 6-oxo-PIP (urinary organic acid profile using the GC-MS method), and the exogenous peak of levetiracetam, due to the fact that it has a similar retention time as 6-oxo-PIP, masked the detection of 6-oxo-PIP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lipiński, Wójcicka-Kowalczyk, Bogdańska, Ehmke, Pajdowska, Skrzypek, Charzewska and Hoffman-Zacharska.)

Published
2024
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49. Differential diagnosis of Huntington's disease- neurological aspects of NKX2-1-related disorders.

Author

Skwara J, Nowicki M, Sharif L, Milanowski Ł, Dulski J, Elert-Dobkowska E, Skrzypek K, Hoffman-Zacharska D, Koziorowski D, and Sławek J

Subjects
Humans, Female, Male, Diagnosis, Differential, Mutation, Adult, Pedigree, Congenital Hypothyroidism genetics, Congenital Hypothyroidism diagnosis, Respiratory Distress Syndrome, Newborn genetics, Respiratory Distress Syndrome, Newborn diagnosis, Thyroid Nuclear Factor 1 genetics, Huntington Disease genetics, Huntington Disease diagnosis, Chorea genetics, Chorea diagnosis
Abstract

Benign hereditary chorea (BHC) is an inherited neurological disorder consisting of childhood-onset, nonprogressive chorea, generally without any other manifestations. In most reported cases, the inheritance of BHC is autosomal dominant but both incomplete penetrance and variable expressivity are observed and can be caused by NKX2-1 mutations. The spectrum contains choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress syndrome. The neurological symptoms can be misdiagnosed as Huntington's disease (HD). The two Polish families were diagnosed with NKX2-1 gene mutations and a literature review concerning the NKX2-1-related disorders was conducted. All family members were examined by experienced movement disorders specialists. PubMed database was searched to obtain previously described NKX2-1 cases. Whole exome sequencing (WES) was performed in one proband (Family A) and direct NKX2-1 sequencing in the second (Family B). Two Polish families were diagnosed with NKX2-1 gene mutations (p.Trp208Leu and p.Cys117Alafs*8). In one family, the co-occurrence of HD was reported. Forty-nine publications were included in the literature review and symptoms of 195 patients with confirmed NKX2-1 mutation were analyzed. The most common symptoms were chorea and choreiform movements, and delayed motor milestones. The NKX2-1 mutation should always be considered as a potential diagnosis in families with chorea, even with a family history of HD. Lack of chorea does not exclude the NKX2-1-related disorders., (© 2024. The Author(s).)

Published
2024
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50. Genotype-phenotype correlations in Polish patients with SCN8A-related epilepsy: A multicentre observational study.

Author

Paprocka J, Steinborn B, Krygier M, Winczewska-Wiktor A, Przyslo L, Hutny M, Hoffman-Zacharska D, Mazurkiewicz H, Kochanowska I, Zebrowska J, Zawadzka M, Piasecki L, and Mazurkiewicz-Beldzinska M

Subjects
Humans, Male, Female, Poland, Child, Preschool, Infant, Child, Mutation, Electroencephalography, Phenotype, Adolescent, Magnetic Resonance Imaging, Neurodevelopmental Disorders genetics, Neurodevelopmental Disorders physiopathology, NAV1.6 Voltage-Gated Sodium Channel genetics, Epilepsy genetics, Epilepsy physiopathology, Genetic Association Studies
Abstract

Background: Voltage-gated sodium channels are involved in the initial depolarisation of neurones. As such, they play important roles in neurotransmission. Variants in the genes encoding these channels may lead to altered functionality and neurodevelopmental disorders. Pathogenic variants of SCN8A, which encodes the voltage-gated Na+ channel Nav1.6, have been associated with various encephalopathies characterised by developmental delay and epileptic seizures. Herein, we discuss the genotype-phenotype associations in a group of 17 novel Polish patients with SCN8A mutations, further expanding the molecular and phenotypic spectrum of SCN8A-related diseases., Methods: The participants were recruited from five clinical centres in Poland. Pathogenic and likely pathogenic SCN8A variants were identified using a next-generation sequencing (NGS) panel and exome sequencing, respectively. Magnetic resonance imaging (MRI) and electroencephalography (EEG) recordings were performed to obtain relevant clinical data on brain malformations and epileptic seizures., Results: Three phenotypes were observed in the study group: developmental and epileptic encephalopathy, early onset epileptic encephalopathy, and neurodevelopmental disorders without epilepsy. Patients in the first two phenotypic subgroups presented with epileptic seizures within the first few months of life. Their semiology evolved with age, comprising mostly tonic, clonic, and tonic-clonic seizures, with eyelid myoclonia, myoclonic seizures, and epileptic spasms. The most prevalent neurological feature was developmental delay. Alterations in muscle tone were more frequent than in previous reports., Conclusions: Seventeen patients with 11 novel mutations in SCN8A had alterations in muscular tone accompanied by typical features of SCN8A-related encephalopathies (i.e., developmental delay and a wide range of seizures)., Competing Interests: Declaration of competing interest The Authors declare no conflict of interests., (Copyright © 2024. Published by Elsevier Ltd.)

Published
2024
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