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1. A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Author: Denomme-Pichon A. -S., Bruel A. -L., Duffourd Y., Safraou H., Thauvin-Robinet C., Tran Mau-Them F., Philippe C., Vitobello A., Jean-Marcais N., Moutton S., Thevenon J., Faivre L., Matalonga L., de Boer E., Gilissen C., Hoischen A., Kleefstra T., Pfundt R., de Vries B. B. A., Willemsen M. H., Vissers L. E. L. M., Jackson A., Banka S., Clayton-Smith J., Benetti E., Fallerini C., Renieri A., Ciolfi A., Dallapiccola B., Pizzi S., Radio F. C., Tartaglia M., Ellwanger K., Graessner H., Haack T. B., Zurek B., Havlovicova M., Macek M., Ryba L., Schwarz M., Votypka P., Lopez-Martin E., Posada M., Mencarelli M. A., Rooryck C., Trimouille A., Verloes A., Abbott K. M., Kerstjens M., Martin E. L., Maystadt I., Morleo M., Nigro V., Pinelli M., Riess O., Agathe J. -M. D. S., Santen G. W. E., Thauvin C., Torella A., Vissers L., Zguro K., Boer E. D., Cohen E., Danis D., Gao F., Horvath R., Johari M., Johanson L., Li S., Morsy H., Nelson I., Paramonov I., te Paske I. B. A. W., Robinson P., Savarese M., Steyaert W., Topf A., van der Velde J. K., Vandrovcova J., Ossowski S., Demidov G., Sturm M., Schulze-Hentrich J. M., Schule R., Xu J., Kessler C., Wayand M., Synofzik M., Wilke C., Traschutz A., Schols L., Hengel H., Lerche H., Kegele J., Heutink P., Brunner H., Scheffer H., Hoogerbrugge N., 't Hoen P. A. C., Sablauskas K., de Voer R. M., Kamsteeg E. -J., van de Warrenburg B., van Os N., Paske I. T., Janssen E., Steehouwer M., Yaldiz B., Brookes A. J., Veal C., Gibson S., Maddi V., Mehtarizadeh M., Riaz U., Warren G., Dizjikan F. Y., Shorter T., Straub V., Bettolo C. M., Manera J. D., Hambleton S., Engelhardt K., Alexander E., Peyron C., Pelissier A., Beltran S., Gut I. G., Laurie S., Piscia D., Papakonstantinou A., Bullich G., Corvo A., Fernandez-Callejo M., Hernandez C., Pico D., Lochmuller H., Gumus G., Bros-Facer V., Rath A., Hanauer M., Lagorce D., Hongnat O., Chahdil M., Lebreton E., Stevanin G., Durr A., Davoine C. -S., Guillot-Noel L., Heinzmann A., Coarelli G., Bonne G., Evangelista T., Allamand V., Ben Yaou R., Metay C., Eymard B., Atalaia A., Stojkovic T., Turnovec M., Thomasova D., Kremlikova R. P., Frankova V., Liskova P., Dolezalova P., Parkinson H., Keane T., Freeberg M., Thomas C., Spalding D., Robert G., Costa A., Patch C., Hanna M., Houlden H., Reilly M., Efthymiou S., Cali E., Magrinelli F., Sisodiya S. M., Rohrer J., Muntoni F., Zaharieva I., Sarkozy A., Timmerman V., Baets J., de Vries G., De Winter J., Beijer D., de Jonghe P., Van de Vondel L., De Ridder W., Weckhuysen S., Mutarelli M., Varavallo A., Banfi S., Musacchia F., Piluso G., Ferlini A., Selvatici R., Gualandi F., Bigoni S., Rossi R., Neri M., Aretz S., Spier I., Sommer A. K., Peters S., Oliveira C., Pelaez J. G., Matos A. R., Jose C. S., Ferreira M., Gullo I., Fernandes S., Garrido L., Ferreira P., Carneiro F., Swertz M. A., Johansson L., van der Vries G., Neerincx P. B., Ruvolo D., Kerstjens Frederikse W. S., Zonneveld-Huijssoon E., Roelofs-Prins D., van Gijn M., Kohler S., Metcalfe A., Drunat S., Heron D., Mignot C., Keren B., Lacombe D., Capella G., Valle L., Holinski-Feder E., Laner A., Steinke-Lange V., Cilio M. -R., Carpancea E., Depondt C., Lederer D., Sznajer Y., Duerinckx S., Mary S., Macaya A., Cazurro-Gutierrez A., Perez-Duenas B., Munell F., Jarava C. F., Maso L. B., Marce-Grau A., Colobran R., Hackman P., Udd B., Hemelsoet D., Dermaut B., Schuermans N., Poppe B., Verdin H., Osorio A. N., Depienne C., Roos A., Cordts I., Deschauer M., Striano P., Zara F., Riva A., Iacomino M., Uva P., Scala M., Scudieri P., Basak A. N., Claeys K., Boztug K., Haimel M., W. E G., Ruivenkamp C. A. L., Natera de Benito D., Thompson R., Polavarapu K., Grimbacher B., Zaganas I., Kokosali E., Lambros M., Evangeliou A., Spilioti M., Kapaki E., Bourbouli M., Balicza P., Molnar M. J., De la Paz M. P., Sanchez E. B., Delgado B. M., Alonso Garcia de la Rosa F. J., Schrock E., Rump A., Mei D., Vetro A., Balestrini S., Guerrini R., Chinnery P. F., Ratnaike T., Schon K., Maver A., Peterlin B., Munchau A., Lohmann K., Herzog R., Pauly M., May P., Beeson D., Cossins J., Furini S., Afenjar A., Goldenberg A., Masurel A., Phan A., Dieux-Coeslier A., Fargeot A., Guerrot A. -M., Toutain A., Molin A., Sorlin A., Putoux A., Jouret B., Laudier B., Demeer B., Doray B., Bonniaud B., Isidor B., Gilbert-Dussardier B., Leheup B., Reversade B., Paul C., Vincent-Delorme C., Neiva C., Poirsier C., Quelin C., Chiaverini C., Coubes C., Francannet C., Colson C., Desplantes C., Wells C., Goizet C., Sanlaville D., Amram D., Lehalle D., Genevieve D., Gaillard D., Zivi E., Sarrazin E., Steichen E., Schaefer E., Lacaze E., Jacquemin E., Bongers E., Kilic E., Colin E., Giuliano F., Prieur F., Laffargue F., Morice-Picard F., Petit F., Cartault F., Feillet F., Baujat G., Morin G., Diene G., Journel H., Perthus I., Lespinasse J., Alessandri J. -L., Amiel J., Martinovic J., Delanne J., Albuisson J., Lambert L., Perrin L., Ousager L. B., Van Maldergem L., Pinson L., Ruaud L., Samimi M., Bournez M., Bonnet-Dupeyron M. N., Vincent M., Jacquemont M. -L., Cordier-Alex M. -P., Gerard-Blanluet M., Willems M., Spodenkiewicz M., Doco-Fenzy M., Rossi M., Renaud M., Fradin M., Mathieu M., Holder-Espinasse M. H., Houcinat N., Hanna N., Leperrier N., Chassaing N., Philip N., Boute O., Van Kien P. K., Parent P., Bitoun P., Sarda P., Vabres P., Jouk P. -S., Touraine R., El Chehadeh S., Whalen S., Marlin S., Passemard S., Grotto S., Bellanger S. A., Blesson S., Nambot S., Naudion S., Lyonnet S., Odent S., Attie-Bitach T., Busa T., Drouin-Garraud V., Layet V., Bizaoui V., Cusin V., Capri Y., Alembik Y., Unión Europea. Comisión Europea. H2020, Unión Europea. Comisión Europea. 7 Programa Marco, Instituto de Salud Carlos III, Instituto Nacional de Bioinformatica (España), Ministry of Health (República Checa), Ministry of Education, Youth and Sports (República Checa), Denomme-Pichon, A. -S., Bruel, A. -L., Duffourd, Y., Safraou, H., Thauvin-Robinet, C., Tran Mau-Them, F., Philippe, C., Vitobello, A., Jean-Marcais, N., Moutton, S., Thevenon, J., Faivre, L., Matalonga, L., de Boer, E., Gilissen, C., Hoischen, A., Kleefstra, T., Pfundt, R., de Vries, B. B. A., Willemsen, M. H., Vissers, L. E. L. M., Jackson, A., Banka, S., Clayton-Smith, J., Benetti, E., Fallerini, C., Renieri, A., Ciolfi, A., Dallapiccola, B., Pizzi, S., Radio, F. C., Tartaglia, M., Ellwanger, K., Graessner, H., Haack, T. B., Zurek, B., Havlovicova, M., Macek, M., Ryba, L., Schwarz, M., Votypka, P., Lopez-Martin, E., Posada, M., Mencarelli, M. A., Rooryck, C., Trimouille, A., Verloes, A., Abbott, K. M., Kerstjens, M., Martin, E. L., Maystadt, I., Morleo, M., Nigro, V., Pinelli, M., Riess, O., Agathe, J. -M. D. S., Santen, G. W. E., Thauvin, C., Torella, A., Vissers, L., Zguro, K., Boer, E. D., Cohen, E., Danis, D., Gao, F., Horvath, R., Johari, M., Johanson, L., Li, S., Morsy, H., Nelson, I., Paramonov, I., te Paske, I. B. A. W., Robinson, P., Savarese, M., Steyaert, W., Topf, A., van der Velde, J. K., Vandrovcova, J., Ossowski, S., Demidov, G., Sturm, M., Schulze-Hentrich, J. M., Schule, R., Xu, J., Kessler, C., Wayand, M., Synofzik, M., Wilke, C., Traschutz, A., Schols, L., Hengel, H., Lerche, H., Kegele, J., Heutink, P., Brunner, H., Scheffer, H., Hoogerbrugge, N., 't Hoen, P. A. C., Sablauskas, K., de Voer, R. M., Kamsteeg, E. -J., van de Warrenburg, B., van Os, N., Paske, I. T., Janssen, E., Steehouwer, M., Yaldiz, B., Brookes, A. J., Veal, C., Gibson, S., Maddi, V., Mehtarizadeh, M., Riaz, U., Warren, G., Dizjikan, F. Y., Shorter, T., Straub, V., Bettolo, C. M., Manera, J. D., Hambleton, S., Engelhardt, K., Alexander, E., Peyron, C., Pelissier, A., Beltran, S., Gut, I. G., Laurie, S., Piscia, D., Papakonstantinou, A., Bullich, G., Corvo, A., Fernandez-Callejo, M., Hernandez, C., Pico, D., Lochmuller, H., Gumus, G., Bros-Facer, V., Rath, A., Hanauer, M., Lagorce, D., Hongnat, O., Chahdil, M., Lebreton, E., Stevanin, G., Durr, A., Davoine, C. -S., Guillot-Noel, L., Heinzmann, A., Coarelli, G., Bonne, G., Evangelista, T., Allamand, V., Ben Yaou, R., Metay, C., Eymard, B., Atalaia, A., Stojkovic, T., Turnovec, M., Thomasova, D., Kremlikova, R. P., Frankova, V., Liskova, P., Dolezalova, P., Parkinson, H., Keane, T., Freeberg, M., Thomas, C., Spalding, D., Robert, G., Costa, A., Patch, C., Hanna, M., Houlden, H., Reilly, M., Efthymiou, S., Cali, E., Magrinelli, F., Sisodiya, S. M., Rohrer, J., Muntoni, F., Zaharieva, I., Sarkozy, A., Timmerman, V., Baets, J., de Vries, G., De Winter, J., Beijer, D., de Jonghe, P., Van de Vondel, L., De Ridder, W., Weckhuysen, S., Mutarelli, M., Varavallo, A., Banfi, S., Musacchia, F., Piluso, G., Ferlini, A., Selvatici, R., Gualandi, F., Bigoni, S., Rossi, R., Neri, M., Aretz, S., Spier, I., Sommer, A. K., Peters, S., Oliveira, C., Pelaez, J. G., Matos, A. R., Jose, C. S., Ferreira, M., Gullo, I., Fernandes, S., Garrido, L., Ferreira, P., Carneiro, F., Swertz, M. A., Johansson, L., van der Vries, G., Neerincx, P. B., Ruvolo, D., Kerstjens Frederikse, W. S., Zonneveld-Huijssoon, E., Roelofs-Prins, D., van Gijn, M., Kohler, S., Metcalfe, A., Drunat, S., Heron, D., Mignot, C., Keren, B., Lacombe, D., Capella, G., Valle, L., Holinski-Feder, E., Laner, A., Steinke-Lange, V., Cilio, M. -R., Carpancea, E., Depondt, C., Lederer, D., Sznajer, Y., Duerinckx, S., Mary, S., Macaya, A., Cazurro-Gutierrez, A., Perez-Duenas, B., Munell, F., Jarava, C. F., Maso, L. B., Marce-Grau, A., Colobran, R., Hackman, P., Udd, B., Hemelsoet, D., Dermaut, B., Schuermans, N., Poppe, B., Verdin, H., Osorio, A. N., Depienne, C., Roos, A., Cordts, I., Deschauer, M., Striano, P., Zara, F., Riva, A., Iacomino, M., Uva, P., Scala, M., Scudieri, P., Basak, A. N., Claeys, K., Boztug, K., Haimel, M., W. E, G., Ruivenkamp, C. A. L., Natera de Benito, D., Thompson, R., Polavarapu, K., Grimbacher, B., Zaganas, I., Kokosali, E., Lambros, M., Evangeliou, A., Spilioti, M., Kapaki, E., Bourbouli, M., Balicza, P., Molnar, M. J., De la Paz, M. P., Sanchez, E. B., Delgado, B. M., Alonso Garcia de la Rosa, F. J., Schrock, E., Rump, A., Mei, D., Vetro, A., Balestrini, S., Guerrini, R., Chinnery, P. F., Ratnaike, T., Schon, K., Maver, A., Peterlin, B., Munchau, A., Lohmann, K., Herzog, R., Pauly, M., May, P., Beeson, D., Cossins, J., Furini, S., Afenjar, A., Goldenberg, A., Masurel, A., Phan, A., Dieux-Coeslier, A., Fargeot, A., Guerrot, A. -M., Toutain, A., Molin, A., Sorlin, A., Putoux, A., Jouret, B., Laudier, B., Demeer, B., Doray, B., Bonniaud, B., Isidor, B., Gilbert-Dussardier, B., Leheup, B., Reversade, B., Paul, C., Vincent-Delorme, C., Neiva, C., Poirsier, C., Quelin, C., Chiaverini, C., Coubes, C., Francannet, C., Colson, C., Desplantes, C., Wells, C., Goizet, C., Sanlaville, D., Amram, D., Lehalle, D., Genevieve, D., Gaillard, D., Zivi, E., Sarrazin, E., Steichen, E., Schaefer, E., Lacaze, E., Jacquemin, E., Bongers, E., Kilic, E., Colin, E., Giuliano, F., Prieur, F., Laffargue, F., Morice-Picard, F., Petit, F., Cartault, F., Feillet, F., Baujat, G., Morin, G., Diene, G., Journel, H., Perthus, I., Lespinasse, J., Alessandri, J. -L., Amiel, J., Martinovic, J., Delanne, J., Albuisson, J., Lambert, L., Perrin, L., Ousager, L. B., Van Maldergem, L., Pinson, L., Ruaud, L., Samimi, M., Bournez, M., Bonnet-Dupeyron, M. N., Vincent, M., Jacquemont, M. -L., Cordier-Alex, M. -P., Gerard-Blanluet, M., Willems, M., Spodenkiewicz, M., Doco-Fenzy, M., Rossi, M., Renaud, M., Fradin, M., Mathieu, M., Holder-Espinasse, M. H., Houcinat, N., Hanna, N., Leperrier, N., Chassaing, N., Philip, N., Boute, O., Van Kien, P. K., Parent, P., Bitoun, P., Sarda, P., Vabres, P., Jouk, P. -S., Touraine, R., El Chehadeh, S., Whalen, S., Marlin, S., Passemard, S., Grotto, S., Bellanger, S. A., Blesson, S., Nambot, S., Naudion, S., Lyonnet, S., Odent, S., Attie-Bitach, T., Busa, T., Drouin-Garraud, V., Layet, V., Bizaoui, V., Cusin, V., Capri, Y., Alembik, Y., and Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center]
Subjects: Exome reanalysis, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Multidisciplinaire, généralités & autres [D99] [Sciences de la santé humaine], Developmental disorder, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Biology and Life Sciences, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], ClinVar, Rare diseases, All institutes and research themes of the Radboud University Medical Center, Medicine and Health Sciences, Genetics & genetic processes [F10] [Life sciences], Génétique & processus génétiques [F10] [Sciences du vivant], Multidisciplinary, general & others [D99] [Human health sciences], Exome reanalysi, Genetics (clinical)
Abstract: Purpose: Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the "ClinVar low-hanging fruit" reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods: Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results: We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion: The "ClinVar low-hanging fruit" analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement number 779257. Data were analyzed using the RD-Connect Genome-Phenome Analysis Platform, which received funding from the EU projects RD-Connect, Solve-RD, and European Joint Programme on Rare Diseases (grant numbers FP7 305444, H2020 779257, H2020 825575), Instituto de Salud Carlos III (grant numbers PT13/0001/0044, PT17/0009/0019; Instituto Nacional de Bioinformática), and ELIXIR Implementation Studies. The collaborations in this study were facilitated by the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies, one of the 24 European Reference Networks approved by the European Reference Network Board of Member States, cofunded by the European Commission. This project was supported by the Czech Ministry of Health (number 00064203) and by the Czech Ministry of Education, Youth and Sports (number - LM2018132) to M.M. Sí
Published: 2023

2. Biallelic PRMT7 pathogenic variants are associated with a recognizable syndromic neurodevelopmental disorder with short stature, obesity, and craniofacial and digital abnormalities.

Author: Cali, E., Suri, M., Scala, M., Ferla, M.P., Alavi, S., Faqeih, E.A., Bijlsma, E.K., Wigby, K.M., Baralle, D., Mehrjardi, M.Y.V., Schwab, J., Platzer, K., Steindl, K., Hashem, M., Jones, M., Niyazov, Dmitriy, Jacober, J., Littlejohn, R.O., Weis, D., Zadeh, N., Rodan, L., Goldenberg, A., Lecoquierre, F., Dutra-Clarke, M., Horvath, G., Young, D., Orenstein, N., Bawazeer, S., Vulto-van Silfhout, A.T., Herenger, Y., Dehghani, M., Seyedhassani, S.M., Bahreini, A., Nasab, M.E., Ercan-Sencicek, A.G., Firoozfar, Z., Movahedinia, M., Efthymiou, S., Striano, P., Karimiani, E.G., Salpietro, V., Taylor, J.C., Redman, M., Stegmann, A.P.A., Laner, A., Abdel-Salam, G., Li, M., Bengala, M., Müller, A.J., Digilio, M.C., Rauch, A., Gunel, M., Titheradge, H., Schweitzer, D.N., Kraus, A., Valenzuela, I., McLean, S.D., Phornphutkul, C., Salih, M., Begtrup, A., Schnur, R.E., Torti, E., Haack, T.B., Prada, C.E., Alkuraya, F.S., Houlden, H., Maroofian, R., Cali, E., Suri, M., Scala, M., Ferla, M.P., Alavi, S., Faqeih, E.A., Bijlsma, E.K., Wigby, K.M., Baralle, D., Mehrjardi, M.Y.V., Schwab, J., Platzer, K., Steindl, K., Hashem, M., Jones, M., Niyazov, Dmitriy, Jacober, J., Littlejohn, R.O., Weis, D., Zadeh, N., Rodan, L., Goldenberg, A., Lecoquierre, F., Dutra-Clarke, M., Horvath, G., Young, D., Orenstein, N., Bawazeer, S., Vulto-van Silfhout, A.T., Herenger, Y., Dehghani, M., Seyedhassani, S.M., Bahreini, A., Nasab, M.E., Ercan-Sencicek, A.G., Firoozfar, Z., Movahedinia, M., Efthymiou, S., Striano, P., Karimiani, E.G., Salpietro, V., Taylor, J.C., Redman, M., Stegmann, A.P.A., Laner, A., Abdel-Salam, G., Li, M., Bengala, M., Müller, A.J., Digilio, M.C., Rauch, A., Gunel, M., Titheradge, H., Schweitzer, D.N., Kraus, A., Valenzuela, I., McLean, S.D., Phornphutkul, C., Salih, M., Begtrup, A., Schnur, R.E., Torti, E., Haack, T.B., Prada, C.E., Alkuraya, F.S., Houlden, H., and Maroofian, R.
Abstract: 01 januari 2023, Item does not contain fulltext, PURPOSE: Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyzes the methylation of arginine residues on several protein substrates. Biallelic pathogenic PRMT7 variants have previously been associated with a syndromic neurodevelopmental disorder characterized by short stature, brachydactyly, intellectual developmental disability, and seizures. To our knowledge, no comprehensive study describes the detailed clinical characteristics of this syndrome. Thus, we aim to delineate the phenotypic spectrum of PRMT7-related disorder. METHODS: We assembled a cohort of 51 affected individuals from 39 different families, gathering clinical information from 36 newly described affected individuals and reviewing data of 15 individuals from the literature. RESULTS: The main clinical characteristics of the PRMT7-related syndrome are short stature, mild to severe developmental delay/intellectual disability, hypotonia, brachydactyly, and distinct facial morphology, including bifrontal narrowing, prominent supraorbital ridges, sparse eyebrows, short nose with full/broad nasal tip, thin upper lip, full and everted lower lip, and a prominent or squared-off jaw. Additional variable findings include seizures, obesity, nonspecific magnetic resonance imaging abnormalities, eye abnormalities (i.e., strabismus or nystagmus), and hearing loss. CONCLUSION: This study further delineates and expands the molecular, phenotypic spectrum and natural history of PRMT7-related syndrome characterized by a neurodevelopmental disorder with skeletal, growth, and endocrine abnormalities.
Published: 2023

3. Expanding SNX14-Associated Movement Disorders in a Genotype–Phenotype Spectrum.

Author: Toepffer, E. M., Ojeda, N. Meave, Bakhtiari, S., Efthymiou, S., Horvath, R., Lochmüller, H., Zaki, M. S., Azam, M., Ben-Omran, T., Karagoz, I., Kaiyrzhanov, R., Guliyeva, U., Gulieva, S., Salayev, K., Hiz, S., Hiatt, S. M., Kunstmann, E., Miryounesi, M., Hashemi-Gorji, F., and Cooper, G. M.
Subjects: MOVEMENT disorders, GENETIC counseling, SKELETAL abnormalities, PATIENTS' families, DIAGNOSTIC imaging, ATAXIA
Abstract: This article, published in the journal Neuropediatrics, explores the genotype-phenotype spectrum of SNX14-associated movement disorders. SNX14 is a protein involved in vesicular tethering and trafficking in cells. The study collected clinical and imaging data from 62 patients with biallelic SNX14 variants, including 22 previously unreported cases. The findings reveal a wide clinical spectrum of symptoms, including ataxia, global neurodevelopmental delay, and skeletal abnormalities. The study also identifies novel phenotypes with movement disorders and provides important information for genetic counseling and support for patients and families. [Extracted from the article]
Published: 2023
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4. An open-source modular framework for quantum computing

Author: Carrazza, S., primary, Efthymiou, S., additional, Lazzarin, M., additional, and Pasquale, A., additional
Published: 2023
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5. P.139 A cross sectional study of genetically confirmed cohort of facioscapulohumeral muscular dystrophy (FSHD) in the Indian population

Author: Vishnu, V., primary, Lemmers, R., additional, Bugiardini, E., additional, Reyaz, A., additional, Efthymiou, S., additional, van der Maarel, S., additional, Bhatia, R., additional, Pitceathly, R., additional, Srivastava, P., additional, and Hanna, M., additional
Published: 2022
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6. Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement

Author: Kaiyrzhanov, R., Mohammed, S.E.M., Maroofian, R., Husain, R.A., Catania, A., Torraco, A., Alahmad, A., Dutra-Clarke, M., Grønborg, S., Sudarsanam, A., Vogt, J., Arrigoni, F., Baptista, J., Haider, S., Feichtinger, R.G., Bernardi, P., Zulian, A., Gusic, M., Efthymiou, S., Bai, R., Bibi, F., Horga, A., Martinez-Agosto, J.A., Lam, A., Manole, A, Rodriguez, D.P., Durigon, R., Pyle, A., Albash, B., Dionisi-Vici, C., Murphy, D., Martinelli, D., Bugiardini, E., Allis, K., Lamperti, C., Reipert, S., Risom, L., Laugwitz, L., Nottia, M. Di, McFarland, R., Vilarinho, L., Hanna, M., Prokisch, H., Mayr, J.A., Bertini, E.S., Ghezzi, D., Østergaard, E., Wortmann, S.B., Carrozzo, R., Haack, T.B., Taylor, R.W., Spinazzola, A., Nowikovsky, K., Houlden, H., Kaiyrzhanov, R., Mohammed, S.E.M., Maroofian, R., Husain, R.A., Catania, A., Torraco, A., Alahmad, A., Dutra-Clarke, M., Grønborg, S., Sudarsanam, A., Vogt, J., Arrigoni, F., Baptista, J., Haider, S., Feichtinger, R.G., Bernardi, P., Zulian, A., Gusic, M., Efthymiou, S., Bai, R., Bibi, F., Horga, A., Martinez-Agosto, J.A., Lam, A., Manole, A, Rodriguez, D.P., Durigon, R., Pyle, A., Albash, B., Dionisi-Vici, C., Murphy, D., Martinelli, D., Bugiardini, E., Allis, K., Lamperti, C., Reipert, S., Risom, L., Laugwitz, L., Nottia, M. Di, McFarland, R., Vilarinho, L., Hanna, M., Prokisch, H., Mayr, J.A., Bertini, E.S., Ghezzi, D., Østergaard, E., Wortmann, S.B., Carrozzo, R., Haack, T.B., Taylor, R.W., Spinazzola, A., Nowikovsky, K., and Houlden, H.
Abstract: Contains fulltext : 283148.pdf (Publisher’s version ) (Open Access), Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) encodes an inner mitochondrial membrane protein with an osmoregulatory function controlling mitochondrial volume and ion homeostasis. The putative association of LETM1 with a human disease was initially suggested in Wolf-Hirschhorn syndrome, a disorder that results from de novo monoallelic deletion of chromosome 4p16.3, a region encompassing LETM1. Utilizing exome sequencing and international gene-matching efforts, we have identified 18 affected individuals from 11 unrelated families harboring ultra-rare bi-allelic missense and loss-of-function LETM1 variants and clinical presentations highly suggestive of mitochondrial disease. These manifested as a spectrum of predominantly infantile-onset (14/18, 78%) and variably progressive neurological, metabolic, and dysmorphic symptoms, plus multiple organ dysfunction associated with neurodegeneration. The common features included respiratory chain complex deficiencies (100%), global developmental delay (94%), optic atrophy (83%), sensorineural hearing loss (78%), and cerebellar ataxia (78%) followed by epilepsy (67%), spasticity (53%), and myopathy (50%). Other features included bilateral cataracts (42%), cardiomyopathy (36%), and diabetes (27%). To better understand the pathogenic mechanism of the identified LETM1 variants, we performed biochemical and morphological studies on mitochondrial K(+)/H(+) exchange activity, proteins, and shape in proband-derived fibroblasts and muscles and in Saccharomyces cerevisiae, which is an important model organism for mitochondrial osmotic regulation. Our results demonstrate that bi-allelic LETM1 variants are associated with defective mitochondrial K(+) efflux, swollen mitochondrial matrix structures, and loss of important mitochondrial oxidative phosphorylation protein components, thus highlighting the implication of perturbed mitochondrial osmoregulation caused by LETM1 variants in neurological and mitochondrial patholog
Published: 2022

7. Clinico-radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency

Author: Scala, M., Wortmann, S.B., Kaya, N., Stellingwerff, M.D., Pistorio, A., Glamuzina, E., Karnebeek, C.D. van, Skrypnyk, C., Iwanicka-Pronicka, K., Piekutowska-Abramczuk, D., Ciara, E., Tort, F., Sheidley, B., Poduri, A., Jayakar, P., Jayakar, A., Upadia, J., Walano, N., Haack, T.B., Prokisch, H., Aldhalaan, H., Karimiani, E.G., Yildiz, Y., Ceylan, A.C., Santiago-Sim, T., Dameron, A., Yang, H., Toosi, M.B., Ashrafzadeh, F., Akhondian, J., Imannezhad, S., Mirzadeh, H.S., Maqbool, S., Farid, A., Al-Muhaizea, M.A., Alshwameen, M.O., Aldowsari, L., Alsagob, M., Alyousef, A., Almass, R., AlHargan, A., Alwadei, A.H., AlRasheed, M.M., Colak, D., Alqudairy, H., Khan, S., Lines, M.A., Cazorla, M., Ribes, A., Morava, E., Bibi, F., Haider, S., Ferla, M.P., Taylor, J.C., Alsaif, H.S., Firdous, A., Hashem, M., Shashkin, C., Koneev, K., Kaiyrzhanov, R., Efthymiou, S., Genomics, Q.S., Schmitt-Mechelke, T., Ziegler, A., Issa, M.Y., Elbendary, H.M., Striano, P., Alkuraya, F.S., Zaki, M.S., Gleeson, J.G., Barakat, T.S., Bierau, J., Knaap, M.S. van der, Maroofian, R., Houlden, H., Scala, M., Wortmann, S.B., Kaya, N., Stellingwerff, M.D., Pistorio, A., Glamuzina, E., Karnebeek, C.D. van, Skrypnyk, C., Iwanicka-Pronicka, K., Piekutowska-Abramczuk, D., Ciara, E., Tort, F., Sheidley, B., Poduri, A., Jayakar, P., Jayakar, A., Upadia, J., Walano, N., Haack, T.B., Prokisch, H., Aldhalaan, H., Karimiani, E.G., Yildiz, Y., Ceylan, A.C., Santiago-Sim, T., Dameron, A., Yang, H., Toosi, M.B., Ashrafzadeh, F., Akhondian, J., Imannezhad, S., Mirzadeh, H.S., Maqbool, S., Farid, A., Al-Muhaizea, M.A., Alshwameen, M.O., Aldowsari, L., Alsagob, M., Alyousef, A., Almass, R., AlHargan, A., Alwadei, A.H., AlRasheed, M.M., Colak, D., Alqudairy, H., Khan, S., Lines, M.A., Cazorla, M., Ribes, A., Morava, E., Bibi, F., Haider, S., Ferla, M.P., Taylor, J.C., Alsaif, H.S., Firdous, A., Hashem, M., Shashkin, C., Koneev, K., Kaiyrzhanov, R., Efthymiou, S., Genomics, Q.S., Schmitt-Mechelke, T., Ziegler, A., Issa, M.Y., Elbendary, H.M., Striano, P., Alkuraya, F.S., Zaki, M.S., Gleeson, J.G., Barakat, T.S., Bierau, J., Knaap, M.S. van der, Maroofian, R., and Houlden, H.
Abstract: Contains fulltext : 283128.pdf (Publisher’s version ) (Open Access), Developmental and epileptic encephalopathy 35 (DEE 35) is a severe neurological condition caused by biallelic variants in ITPA, encoding inosine triphosphate pyrophosphatase, an essential enzyme in purine metabolism. We delineate the genotypic and phenotypic spectrum of DEE 35, analyzing possible predictors for adverse clinical outcomes. We investigated a cohort of 28 new patients and reviewed previously described cases, providing a comprehensive characterization of 40 subjects. Exome sequencing was performed to identify underlying ITPA pathogenic variants. Brain MRI (magnetic resonance imaging) scans were systematically analyzed to delineate the neuroradiological spectrum. Survival curves according to the Kaplan-Meier method and log-rank test were used to investigate outcome predictors in different subgroups of patients. We identified 18 distinct ITPA pathogenic variants, including 14 novel variants, and two deletions. All subjects showed profound developmental delay, microcephaly, and refractory epilepsy followed by neurodevelopmental regression. Brain MRI revision revealed a recurrent pattern of delayed myelination and restricted diffusion of early myelinating structures. Congenital microcephaly and cardiac involvement were statistically significant novel clinical predictors of adverse outcomes. We refined the molecular, clinical, and neuroradiological characterization of ITPase deficiency, and identified new clinical predictors which may have a potentially important impact on diagnosis, counseling, and follow-up of affected individuals.
Published: 2022

8. Inhibition of G-protein signalling in cardiac dysfunction of intellectual developmental disorder with cardiac arrhythmia (IDDCA) syndrome

Author: De Nittis P., Efthymiou S., Sarre A., Guex N., Chrast J., Putoux A., Sultan T., Raza Alvi J., Ur Rahman Z., Zafar F., Rana N., Rahman F., Anwar N., Maqbool S., Zaki M. S., Gleeson J. G., Murphy D., Galehdari H., Shariati G., Mazaheri N., Sedaghat A., Lesca G., Chatron N., Salpietro V., Christoforou M., Houlden H., Simonds W. F., Pedrazzini T., Maroofian R., Reymond A., SYNAPS STUDY GROUP: SYNAPS Study Group: Stanislav Groppa, Blagovesta Marinova Karashova, Wolfgang Nachbauer, Sylvia Boesch, Larissa Arning, Dagmar Timmann, Bru Cormand, Belen Pérez-Dueñas, Jatinder S Goraya, Tipu Sultan, Jun Mine, Daniela Avdjieva, Hadil Kathom, Radka Tincheva, Selina Banu, Mercedes Pineda-Marfa, Pierangelo Veggiotti, Michel D. Ferrari, Arn M. J. M. van den Maagdenberg, Alberto Verrotti, Giangluigi Marseglia, Salvatore Savasta, Mayte García-Silva, Alfons Macaya Ruiz, Barbara Garavaglia, Eugenia Borgione, Simona Portaro, Benigno Monteagudo Sanchez, Richard Boles, Savvas Papacostas, Michail Vikelis, Eleni Zamba Papanicolaou, Efthymios Dardiotis, Shazia Maqbool, Shahnaz Ibrahim, Salman Kirmani, Nuzhat Noureen Rana, Osama Atawneh, George Koutsis, Salvatore Mangano, Carmela Scuderi, Giovanna Morello, Tanya Stojkovic, Massimo Zollo, Gali Heimer, Yves A. Dauvilliers, Pasquale Striano, Issam Al-Khawaja, Fuad Al-Mutairi, Hamed Sherifa., University of Lausanne (UNIL), University College of London [London] (UCL), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Children's Hospital [Lahore], Institute of Child Health [Lahore], Children's Hospital [Multan], Institute of Child Health [Multan], National Research Centre - NRC (EGYPT), Howard Hughes Medical Institute (HHMI), Shahid Chamran University of Ahvaz (SCU), Ahvaz Jundishapur University of Medical Sciences (AJUMS), National Institutes of Health [Bethesda] (NIH), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lausanne = University of Lausanne (UNIL), Herrada, Anthony, P., De Nitti, S., Efthymiou, A., Sarre, N., Guex, J., Chrast, A., Putoux, T., Sultan, J., Raza Alvi, Z., Ur Rahman, F., Zafar, N., Rana, F., Rahman, N., Anwar, S., Maqbool, M. S., Zaki, J. G., Gleeson, D., Murphy, H., Galehdari, G., Shariati, N., Mazaheri, A., Sedaghat, G., Lesca, N., Chatron, V., Salpietro, M., Christoforou, H., Houlden, W. F., Simond, T., Pedrazzini, R., Maroofian, A., Reymond, STUDY GROUP: SYNAPS Study Group: Stanislav Groppa, Synap, Marinova Karashova, Blagovesta, Nachbauer, Wolfgang, Boesch, Sylvia, Arning, Larissa, Timmann, Dagmar, Cormand, Bru, Pérez-Dueñas, Belen, S Goraya, Jatinder, Sultan, Tipu, Mine, Jun, Avdjieva, Daniela, Kathom, Hadil, Tincheva, Radka, Banu, Selina, Pineda-Marfa, Mercede, Veggiotti, Pierangelo, Ferrari, Michel D., van den Maagdenberg, Arn M. J. M., Verrotti, Alberto, Marseglia, Giangluigi, Savasta, Salvatore, García-Silva, Mayte, Macaya Ruiz, Alfon, Garavaglia, Barbara, Borgione, Eugenia, Portaro, Simona, Monteagudo Sanchez, Benigno, Boles, Richard, Papacostas, Savva, Vikelis, Michail, Zamba Papanicolaou, Eleni, Dardiotis, Efthymio, Maqbool, Shazia, Ibrahim, Shahnaz, Kirmani, Salman, Noureen Rana, Nuzhat, Atawneh, Osama, Koutsis, George, Mangano, Salvatore, Scuderi, Carmela, Morello, Giovanna, Stojkovic, Tanya, Zollo, Massimo, Heimer, Gali, Dauvilliers, Yves A., Striano, Pasquale, Al-Khawaja, Issam, Al-Mutairi, Fuad, and Sherifa., Hamed
Subjects: Male, 0301 basic medicine, Developmental Disabilities, Batecs cardíacs, 0302 clinical medicine, Neurodevelopmental disorder, Heart Rate, Medicine, Child, Genetics (clinical), Mice, Knockout, Gnb5-null mouse models, GTP-Binding Protein beta Subunits, Cardiac muscle, Heart, Syndrome, IDDCA, Functional Genomics, Pedigree, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, cardiac conduction anomalies, Gnb5 -null mouse models, GNB5 variants, medicine.anatomical_structure, Child, Preschool, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, medicine.symptom, Signal Transduction, Bradycardia, Cardiac function curve, Gnb5 -null mouse model, medicine.medical_specialty, Adolescent, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Contractility, Young Adult, Brain damage, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, GNB5variants, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Internal medicine, Exome Sequencing, Heart rate, Genetics, Animals, Humans, business.industry, Gene Expression Profiling, Heart beat, Proteins, Cardiac arrhythmia, Arrhythmias, Cardiac, GNB5 variant, medicine.disease, Mice, Inbred C57BL, Autonomic nervous system, 030104 developmental biology, Endocrinology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Lesions cerebrals, cardiac conduction anomalie, business, Proteïnes, 030217 neurology & neurosurgery
Abstract: BackgroundPathogenic variants of GNB5 encoding the β5 subunit of the guanine nucleotide-binding protein cause IDDCA syndrome, an autosomal recessive neurodevelopmental disorder associated with cognitive disability and cardiac arrhythmia, particularly severe bradycardia.MethodsWe used echocardiography and telemetric ECG recordings to investigate consequences of Gnb5 loss in mouse.ResultsWe delineated a key role of Gnb5 in heart sinus conduction and showed that Gnb5-inhibitory signalling is essential for parasympathetic control of heart rate (HR) and maintenance of the sympathovagal balance. Gnb5−/− mice were smaller and had a smaller heart than Gnb5+/+ and Gnb5+/−, but exhibited better cardiac function. Lower autonomic nervous system modulation through diminished parasympathetic control and greater sympathetic regulation resulted in a higher baseline HR in Gnb5−/− mice. In contrast, Gnb5−/− mice exhibited profound bradycardia on treatment with carbachol, while sympathetic modulation of the cardiac stimulation was not altered. Concordantly, transcriptome study pinpointed altered expression of genes involved in cardiac muscle contractility in atria and ventricles of knocked-out mice. Homozygous Gnb5 loss resulted in significantly higher frequencies of sinus arrhythmias. Moreover, we described 13 affected individuals, increasing the IDDCA cohort to 44 patients.ConclusionsOur data demonstrate that loss of negative regulation of the inhibitory G-protein signalling causes HR perturbations in Gnb5−/− mice, an effect mainly driven by impaired parasympathetic activity. We anticipate that unravelling the mechanism of Gnb5 signalling in the autonomic control of the heart will pave the way for future drug screening.
Published: 2020

9. Erratum: Biallelic Mutations in ADPRHL2, Encoding ADP-Ribosylhydrolase 3, Lead to a Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome (The American Journal of Human Genetics (2018) 103(3) (431–439), (S0002929718302374), (10.1016/j.ajhg.2018.07.010))

Author: Ghosh, S. G., Becker, K., Huang, H., Salazar, T. D., Chai, G., Salpietro, V., Al-Gazali, L., Waisfisz, Q., Wang, H., Vaux, K. K., Stanley, V., Manole, A., Akpulat, U., Weiss, M. M., Efthymiou, S., Hanna, M. G., Minetti, C., Striano, P., Pisciotta, L., De Grandis, E., Altmuller, J., Weixler, L., Nurnberg, P., Thiele, H., Yis, U., Okur, T. D., Polat, A. I., Amiri, N., Doosti, M., Karimani, E. G., Toosi, M. B., Haddad, G., Karakaya, M., Wirth, B., van Hagen, J. M., Wolf, N. I., Maroofian, R., Houlden, H., Cirak, S., Gleeson, J. G., Human genetics, Pediatric surgery, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, and Amsterdam Reproduction & Development (AR&D)
Abstract: (The American Journal of Human Genetics 103, 431–439; September 6, 2018) Lisa Weixler has been added to the author list for her experimental and scientific contributions to the biophysical analysis of wild-type and mutant proteins. Her contributions were already mentioned in the acknowledgments. The authors apologize for initially only listing her in the acknowledgments and for the inconvenience. The author list has been corrected online and appears correctly here, and Lisa Weixler's affiliation is indicated as footnote 3: Center for Molecular Medicine Cologne, Cologne, Germany.
Published: 2021

10. Biallelic variants in PCDHGC4 cause a novel neurodevelopmental syndrome with progressive microcephaly, seizures, and joint anomalies

Author: Iqbal, M, Maroofian, R, Çavdarlı, B, Riccardi, F, Field, M, Banka, S, Bubshait, DK, Li, Y, Hertecant, J, Baig, SM, Dyment, D, Efthymiou, S, Abdullah, U, Makhdoom, EUH, Ali, Z, Scherf de Almeida, T, Molinari, F, Mignon-Ravix, C, Chabrol, B, Antony, J, Ades, L, Pagnamenta, AT, Jackson, A, Douzgou, S, Genomics England Research Consortium, Beetz, C, Karageorgou, V, Vona, B, Rad, A, Baig, JM, Sultan, T, Alvi, JR, Maqbool, S, Rahman, F, Toosi, MB, Ashrafzadeh, F, Imannezhad, S, Karimiani, EG, Sarwar, Y, Khan, S, Jameel, M, Noegel, AA, Budde, B, Altmüller, J, Motameny, S, Höhne, W, Houlden, H, Nürnberg, P, Wollnik, B, Villard, L, Alkuraya, FS, Osmond, M, Hussain, MS, and Yigit, G
Abstract: PURPOSE: We aimed to define a novel autosomal recessive neurodevelopmental disorder, characterize its clinical features, and identify the underlying genetic cause for this condition. METHODS: We performed a detailed clinical characterization of 19 individuals from nine unrelated, consanguineous families with a neurodevelopmental disorder. We used genome/exome sequencing approaches, linkage and cosegregation analyses to identify disease-causing variants, and we performed three-dimensional molecular in silico analysis to predict causality of variants where applicable. RESULTS: In all affected individuals who presented with a neurodevelopmental syndrome with progressive microcephaly, seizures, and intellectual disability we identified biallelic disease-causing variants in Protocadherin-gamma-C4 (PCDHGC4). Five variants were predicted to induce premature protein truncation leading to a loss of PCDHGC4 function. The three detected missense variants were located in extracellular cadherin (EC) domains EC5 and EC6 of PCDHGC4, and in silico analysis of the affected residues showed that two of these substitutions were predicted to influence the Ca2+-binding affinity, which is essential for multimerization of the protein, whereas the third missense variant directly influenced the cis-dimerization interface of PCDHGC4. CONCLUSION: We show that biallelic variants in PCDHGC4 are causing a novel autosomal recessive neurodevelopmental disorder and link PCDHGC4 as a member of the clustered PCDH family to a Mendelian disorder in humans.
Published: 2021

11. Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination

Author: Efthymiou, S., Salpietro, V., Malintan, N., Poncelet, M., Kriouile, Y., Fortuna, S., Zorzi, R. de, Payne, K., Henderson, L.B., Cortese, A., Maddirevula, S., Alhashmi, N., Wiethoff, S., Ryten, M., Botia, J.A., Provitera, V., Schuelke, M., Vandrovcova, J., Groppa, S., Karashova, B.M., Nachbauer, W., Boesch, S., Arning, L., Timmann, D., Cormand, B., Perez-Duenas, B., Goraya, J.S., Sultan, T., Mine, J., Avdjieva, D., Kathom, H., Tincheva, R., Banu, S., Pineda-Marfa, M., Veggiotti, P., Ferrari, M.D., Maagdenberg, A.M.J.M. van den, Verrotti, A., Marseglia, G., Savasta, S., Garcia-Silva, M., Ruiz, A.M., Garavaglia, B., Borgione, E., Portaro, S., Sanchez, B.M., Boles, R., Papacostas, S., Vikelis, M., Rothman, J., Kullmann, D., Papanicolaou, E.Z., Dardiotis, E., Maqbool, S., Ibrahim, S., Kirmani, S., Rana, N.N., Atawneh, O., Lim, S.Y., Shaikh, F., Koutsis, G., Breza, M., Mangano, S., Scuderi, C., Morello, G., Stojkovic, T., Zollo, M., Heimer, G., Dauvilliers, Y.A., Minetti, C., Al-Khawaja, I., Al-Mutairi, F., Hamed, S., Pipis, M., Bettencourt, C., Rinaldi, S., Walsh, L., Torti, E., Iodice, V., Najafi, M., Karimiani, E.G., Maroofian, R., Siquier-Pernet, K., Boddaert, N., Lonlay, P. de, Cantagrel, V., Aguennouz, M., Khorassani, M. el, Schmidts, M., Alkuraya, F.S., Edvardson, S., Nolano, M., Devaux, J., Houlden, H., SYNAPS Study Grp, Efthymiou, S., Salpietro, V., Malintan, N., Poncelet, M., Kriouile, Y., Fortuna, S., De Zorzi, R., Payne, K., Henderson, L. B., Cortese, A., Maddirevula, S., Alhashmi, N., Wiethoff, S., Ryten, M., Botia, J. A., Provitera, V., Schuelke, M., Vandrovcova, J., Walsh, L., Torti, E., Iodice, V., Najafi, M., Karimiani, E. G., Maroofian, R., Siquier-Pernet, K., Boddaert, N., De Lonlay, P., Cantagrel, V., Aguennouz, M., El Khorassani, M., Schmidts, M., Alkuraya, F. S., Edvardson, S., Nolano, M., Devaux, J., Houlden, H., Groppa, S., Karashova, B. M., Nachbauer, W., Boesch, S., Arning, L., Timmann, D., Cormand, B., Perez-Duenas, B., Goraya, J. S., Sultan, T., Mine, J., Avdjieva, D., Kathom, H., Tincheva, R., Banu, S., Pineda-Marfa, M., Veggiotti, P., Ferrari, M. D., Van Den Maagdenberg, A. M. J. M., Verrotti, A., Marseglia, G., Savasta, S., Garcia-Silva, M., Ruiz, A. M., Garavaglia, B., Borgione, E., Portaro, S., Sanchez, B. M., Boles, R., Papacostas, S., Vikelis, M., Rothman, J., Kullmann, D., Papanicolaou, E. Z., Dardiotis, E., Maqbool, S., Ibrahim, S., Kirmani, S., Rana, N. N., Atawneh, O., Lim, S. -Y., Shaikh, F., Koutsis, G., Breza, M., Mangano, S., Scuderi, C., Morello, G., Stojkovic, T., Zollo, M., Heimer, G., Dauvilliers, Y. A., Minetti, C., Al-Khawaja, I., Al-Mutairi, F., Hamed, S., Pipis, M., Bettencourt, C., Rinaldi, S., Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratory of Molecular Biophysics, Department of Biochemistry, Department of Biochemistry, Hertie Institute for Clinical Brain Research and Center for Neurology, University of Tübingen, Department of Medical and Molecular Genetics, King‘s College London, Department of Human Genetics, Ruhr University Bochum (RUB), Universitat de Barcelona (UB), Fondazione, Leiden University Medical Center (LUMC), Department of Physiology and Cellular Biophysics [New York, NY, USA], Columbia University College of Physicians and Surgeons, Department of Microbiology, Università degli studi di Catania [Catania], Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ceinge, centro di Ingegneria Genetica e Biotecnologie Avanzate, Unité des troubles du sommeil, Centre de référence national sur les maladies rares (narcolepsie, hypersomnie idiopathique, syndrome de Kleine-Levin)-Hôpital Gui-de-Chauliac, Muscular and Neurodegenerative Disease Unit, University of Genoa (UNIGE), Department of Molecular Neuroscience, University College of London [London] (UCL)-Institute of Neurology, Indiana University, Indiana University [Bloomington], Indiana University System-Indiana University System, Molecular and Clinical Sciences Institute - St George’s [London, UK] (Genetics Research Centre), University of London [London], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neuroimagerie en psychiatrie (U1000), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service métabolisme, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-CHU Necker - Enfants Malades [AP-HP], Department of Genetics and Metabolic Diseases and the Monique and Jacques Roboh Department of Genetic Research, Hadassah Hebrew University Medical Center [Jerusalem], Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Efthymiou S., Salpietro V., Malintan N., Poncelet M., Kriouile Y., Fortuna S., De Zorzi R., Payne K., Henderson L.B., Cortese A., Maddirevula S., Alhashmi N., Wiethoff S., Ryten M., Botia J.A., Provitera V., Schuelke M., Vandrovcova J., Walsh L., Torti E., Iodice V., Najafi M., Karimiani E.G., Maroofian R., Siquier-Pernet K., Boddaert N., De Lonlay P., Cantagrel V., Aguennouz M., El Khorassani M., Schmidts M., Alkuraya F.S., Edvardson S., Nolano M., Devaux J., Houlden H., Groppa S., Karashova B.M., Nachbauer W., Boesch S., Arning L., Timmann D., Cormand B., Perez-Duenas B., Goraya J.S., Sultan T., Mine J., Avdjieva D., Kathom H., Tincheva R., Banu S., Pineda-Marfa M., Veggiotti P., Ferrari M.D., Van Den Maagdenberg A.M.J.M., Verrotti A., Marseglia G., Savasta S., Garcia-Silva M., Ruiz A.M., Garavaglia B., Borgione E., Portaro S., Sanchez B.M., Boles R., Papacostas S., Vikelis M., Rothman J., Kullmann D., Papanicolaou E.Z., Dardiotis E., Maqbool S., Ibrahim S., Kirmani S., Rana N.N., Atawneh O., Lim S.-Y., Shaikh F., Koutsis G., Breza M., Mangano S., Scuderi C., Morello G., Stojkovic T., Zollo M., Heimer G., Dauvilliers Y.A., Minetti C., Al-Khawaja I., Al-Mutairi F., Hamed S., Pipis M., Bettencourt C., Rinaldi S., Efthymiou, Stephanie, Salpietro, Vincenzo, Malintan, Nancy, Poncelet, Mallory, Kriouile, Yamna, Fortuna, Sara, De Zorzi, Rita, Payne, Katelyn, Henderson, Lindsay B, Cortese, Andrea, Maddirevula, Sateesh, Alhashmi, Nadia, Wiethoff, Sarah, Ryten, Mina, Botia, Juan A, Provitera, Vincenzo, Schuelke, Marku, Vandrovcova, Jana, Walsh, Laurence, Torti, Erin, Iodice, Valeria, Najafi, Maryam, Karimiani, Ehsan Ghayoor, Maroofian, Reza, Siquier-Pernet, Karine, Boddaert, Nathalie, De Lonlay, Pascale, Cantagrel, Vincent, Aguennouz, Mhammed, El Khorassani, Mohamed, Schmidts, Miriam, Alkuraya, Fowzan S, Edvardson, Simon, Nolano, Maria, Devaux, Jérôme, Houlden, Henry, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-CHU Necker - Enfants Malades [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Sud - Paris 11 (UP11)
Subjects: Male, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Nerve Fibers, Myelinated, Gene Frequency, Neurodevelopmental Disorder, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Nerve Growth Factor, Protein Isoforms, Child, ComputingMilieux_MISCELLANEOUS, Myelin Sheath, neurofascin, neurodevelopment, peripheral demyelination, Allele, Demyelinating Disease, Genomics, neurodevelopment, neurofascin, peripheral demyelination, Settore MED/39 - Neuropsichiatria Infantile, Pedigree, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Child, Preschool, Peripheral Nerve, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, Neuroglia, Human, Adult, Adolescent, Nervous System Malformations, Guillain-Barre Syndrome, Axon, Nervous System Malformation, Ranvier's Nodes, Humans, Nerve Growth Factors, Peripheral Nerves, Alleles, Autoantibodies, Infant, Protein Isoform, Original Articles, Axons, nervous system, Neurodevelopmental Disorders, Cell Adhesion Molecule, Mutation, Cell Adhesion Molecules, Demyelinating Diseases
Abstract: See Karakaya and Wirth (doi:10.1093/brain/awz273) for a scientific commentary on this article. Neurofascin (NFASC) isoforms are immunoglobulin cell adhesion molecules involved in node of Ranvier assembly. Efthymiou et al. identify biallelic NFASC variants in ten unrelated patients with a neurodevelopmental disorder characterized by variable degrees of central and peripheral involvement. Abnormal expression of Nfasc155 is accompanied by severe loss of myelinated fibres., Axon pathfinding and synapse formation are essential processes for nervous system development and function. The assembly of myelinated fibres and nodes of Ranvier is mediated by a number of cell adhesion molecules of the immunoglobulin superfamily including neurofascin, encoded by the NFASC gene, and its alternative isoforms Nfasc186 and Nfasc140 (located in the axonal membrane at the node of Ranvier) and Nfasc155 (a glial component of the paranodal axoglial junction). We identified 10 individuals from six unrelated families, exhibiting a neurodevelopmental disorder characterized with a spectrum of central (intellectual disability, developmental delay, motor impairment, speech difficulties) and peripheral (early onset demyelinating neuropathy) neurological involvement, who were found by exome or genome sequencing to carry one frameshift and four different homozygous non-synonymous variants in NFASC. Expression studies using immunostaining-based techniques identified absent expression of the Nfasc155 isoform as a consequence of the frameshift variant and a significant reduction of expression was also observed in association with two non-synonymous variants affecting the fibronectin type III domain. Cell aggregation studies revealed a severely impaired Nfasc155-CNTN1/CASPR1 complex interaction as a result of the identified variants. Immunofluorescence staining of myelinated fibres from two affected individuals showed a severe loss of myelinated fibres and abnormalities in the paranodal junction morphology. Our results establish that recessive variants affecting the Nfasc155 isoform can affect the formation of paranodal axoglial junctions at the nodes of Ranvier. The genetic disease caused by biallelic NFASC variants includes neurodevelopmental impairment and a spectrum of central and peripheral demyelination as part of its core clinical phenotype. Our findings support possible overlapping molecular mechanisms of paranodal damage at peripheral nerves in both the immune-mediated and the genetic disease, but the observation of prominent central neurological involvement in NFASC biallelic variant carriers highlights the importance of this gene in human brain development and function.
Published: 2019

12. Age-dependent epileptic encephalopathy associated with an unusual co-occurrence of ZEB2 and SCN1A variants

Author: Nardello, R., Fontana, A., Donato Mangano, G., Efthymiou, S., SALPIETRO DAMIANO, Vincenzo, Houlden, H., Mangano, S., Nardello, R, Fontana, A, Mangano, GD, Efthymiou, S, Salpietro, V, Houlden, H, and Mangano, S
Subjects: ZEB2, genotype-phenotype correlation, Settore MED/38 - Pediatria Generale E Specialistica, Settore M-PSI/08 - Psicologia Clinica, Intellectual Disability, Humans, Mowat-Wilson syndrome, EEG, SCN1A, Hirschsprung Disease, Child, Genetic Association Studies, Zinc Finger E-box Binding Homeobox 2, Epilepsy, epilepsy, GABAergic interneurons, Facies, Electroencephalography, Settore MED/39 - Neuropsichiatria Infantile, NAV1.1 Voltage-Gated Sodium Channel, Microcephaly, Settore MED/26 - Neurologia, Female
Abstract: Mowat-Wilson syndrome is a genetic disorder associated with a variable phenotype including peculiar facial features associated with intellectual disability, epilepsy, language impairment, and multiple congenital anomalies caused by heterozygous mutation of the ZEB2 gene. The ZEB2 protein is a complex transcription factor that encompasses multiple functional domains that interact with the regulatory regions of target genes including those involved in brain development. Recently, it has been documented that ZEB2 regulates the differentiation of interneuron progenitors migrating from the medial ganglionic eminence to cortical layers by repression of the Nkx2-1 homeobox transcription factor. It has therefore been suggested that the deficit in ZEB2 may induce an imbalance of neuronal inhibition/excitation leading to epileptic seizures. Given the phenotypic variability of Mowat-Wilson syndrome, to date, a distinctive genotype-phenotype correlation has not been delineated. Here, we report a patient with a severe phenotype of Mowat-Wilson syndrome, associated with a novel heterozygous de novo frame-shift variant in the ZEB2 gene, as well as an additional novel heterozygous missense variant in the SCN1A gene, the mutation of which is known to affect NaV1.1-mediated sodium current in GABAergic interneurons. We hypothesize that the severe neurological phenotype of our patient may be influenced by the coexistence of both genetic mutations. [Published with video sequence].
Published: 2020

13. Early-infantile onset epilepsy and developmental delay caused by bi-allelic GAD1 variants

Author: Neuray, C., Maroofian, R., Scala, M., Sultan, T., Pai, G. S., Mojarrad, M., Khashab, H. E., Deholl, L., Yue, W., Alsaif, H. S., Zanetti, M. N., Bello, O., Person, R., Eslahi, A., Khazaei, Z., Feizabadi, M. H., Efthymiou, S., El-Bassyouni, H. T., Soliman, D. R., Tekes, S., Ozer, L., Baltaci, V., Khan, S., Beetz, C., Amr, K. S., Salpietro, V., Jamshidi, Y., Alkuraya, F. S., Houlden, H., Groppa, S., Karashova, B. M., Nachbauer, W., Boesch, S., Arning, L., Timmann, D., Cormand, B., Perez-Duenas, B., Synaps, Group, Di Rosa, G., Aguennouz, M., Goraya, J. S., Mine, J., Avdjieva, D., Kathom, H., Tincheva, R., Banu, S., Pineda-Marfa, M., Veggiotti, P., Ferrari, M. D., Verrotti, A., Marseglia, G., Savasta, S., Garcia-Silva, M., Ruiz, A. M., Garavaglia, B., Borgione, E., Portaro, S., Sanchez, B. M., Boles, R., Papacostas, S., Vikelis, M., Papanicolaou, E. Z., Dardiotis, E., Maqbool, S., Ibrahim, S., Kirmani, S., Rana, N. N., Atawneh, O., Koutsis, G., Breza, M., Mangano, S., Scuderi, C., Morello, G., Stojkovic, T., Zollo, M., Heimer, G., Dauvilliers, Y. A., Striano, P., Al-Khawaja, I., Al-Mutairi, F., Sherifa, H., Neuray C., Maroofian R., Scala M., Sultan T., Pai G.S., Mojarrad M., Khashab H.E., deHoll L., Yue W., Alsaif H.S., Zanetti M.N., Bello O., Person R., Eslahi A., Khazaei Z., Feizabadi M.H., Efthymiou S., El-Bassyouni H.T., Soliman D.R., Tekes S., Ozer L., Baltaci V., Khan S., Beetz C., Amr K.S., Salpietro V., Jamshidi Y., Alkuraya F.S., Houlden H., Mangano S., Dicle Üniversitesi, Tıp Fakültesi, Temel Tıp Bilimleri Bölümü, Tıbbi Biyoloji Ana Bilim Dalı, Tekeş, Selahattin, University College of London [London] (UCL), Paracelsus Medizinische Privatuniversität = Paracelsus Medical University (PMU), University of Genoa (UNIGE), IRCCS Istituto Giannina Gaslini [Genoa, Italy], Children's Hospital [Lahore], Institute of Child Health [Lahore], Medical University of South Carolina [Charleston] (MUSC), Mashhad University of Medical Sciences, Ain Shams University (ASU), University of Oxford [Oxford], GeneDx [Gaithersburg, MD, USA], Khorasan Razavi Agricultural and Natural Resources Research and Education Center, National Research Centre [Cairo, Egypt], Benha University (BU), Dicle University, CENTOGENE AG, University of London [London], King Faisal Specialist Hospital [Riyadh, Saudi Arabia] (Research Centre), and SYNaPS Study Group: Stanislav Groppa, Blagovesta Marinova Karashova, Wolfgang Nachbauer, Sylvia Boesch, Larissa Arning, Dagmar Timmann, Bru Cormand, Belen Pérez-Dueñas, Gabriella Di Rosa, Jatinder S Goraya, Tipu Sultan, Jun Mine, Daniela Avdjieva, Hadil Kathom, Radka Tincheva, Selina Banu, Mercedes Pineda-Marfa, Pierangelo Veggiotti, Michel D Ferrari, Alberto Verrotti, Giangluigi Marseglia, Salvatore Savasta, Mayte García-Silva, Alfons Macaya Ruiz, Barbara Garavaglia, Eugenia Borgione, Simona Portaro, Benigno Monteagudo Sanchez, Richard Boles, Savvas Papacostas, Michail Vikelis, Eleni Zamba Papanicolaou, Efthymios Dardiotis, Shazia Maqbool, Shahnaz Ibrahim, Salman Kirmani, Nuzhat Noureen Rana, Osama Atawneh, George Koutsis, Marianthi Breza, Salvatore Mangano, Carmela Scuderi, Eugenia Borgione, Giovanna Morello, Tanya Stojkovic, Massimi Zollo, Gali Heimer, Yves A Dauvilliers, Pasquale Striano, Issam Al-Khawaja, Fuad Al-Mutairi, Hamed Sherifa
Subjects: Male, 0301 basic medicine, Glutamate decarboxylase, Malalties cerebrals, Neurotransmissors, Neurodevelopmental delay, Epilepsy, 0302 clinical medicine, MESH: Child, Age of Onset, Child, cleft palate, GAD1, AcademicSubjects/SCI01870, Glutamate Decarboxylase, Glutamate receptor, Muscle weakness, purl.org/becyt/ford/3.1 [https], Neurotransmitters, MESH: Infant, Hypotonia, muscle weakne, Cleft palate, MESH: Epilepsy, Child, Preschool, Muscle Hypotonia, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], purl.org/becyt/ford/3 [https], Female, Brain diseases, Abnormalities, medicine.symptom, Multiple, medicine.drug, epilepsy, muscle weakness, neurodevelopmental delay, MESH: Glutamate Decarboxylase, medicine.medical_specialty, MESH: Abnormalities, Multiple, MESH: Mutation, MESH: Age of Onset, Biology, Inhibitory postsynaptic potential, GAD1, cleft palate, epilepsy, muscle weakness, neurodevelopmental delay, gamma-Aminobutyric acid, 03 medical and health sciences, Excitatory synapse, Internal medicine, medicine, Humans, Abnormalities, Multiple, Preschool, Alleles, MESH: Neurodevelopmental Disorders, MESH: Humans, MESH: Muscle Hypotonia, MESH: Alleles, MESH: Child, Preschool, Infant, medicine.disease, MESH: Male, Epilèpsia, Editor's Choice, 030104 developmental biology, Endocrinology, Neurodevelopmental Disorders, Mutation, AcademicSubjects/MED00310, Neurology (clinical), MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery, Reports
Abstract: Mice lacking GAD1 show neonatal mortality, but the human phenotype associated with GAD1 disruption is poorly characterized. Neuray et al. describe six patients with biallelic GAD1 mutations, presenting with early-infantile onset epilepsy, neurodevelopmental delay, muscle weakness and non-CNS manifestations., Gamma-aminobutyric acid (GABA) and glutamate are the most abundant amino acid neurotransmitters in the brain. GABA, an inhibitory neurotransmitter, is synthesized by glutamic acid decarboxylase (GAD). Its predominant isoform GAD67, contributes up to ∼90% of base-level GABA in the CNS, and is encoded by the GAD1 gene. Disruption of GAD1 results in an imbalance of inhibitory and excitatory neurotransmitters, and as Gad1−/− mice die neonatally of severe cleft palate, it has not been possible to determine any potential neurological dysfunction. Furthermore, little is known about the consequence of GAD1 disruption in humans. Here we present six affected individuals from six unrelated families, carrying bi-allelic GAD1 variants, presenting with developmental and epileptic encephalopathy, characterized by early-infantile onset epilepsy and hypotonia with additional variable non-CNS manifestations such as skeletal abnormalities, dysmorphic features and cleft palate. Our findings highlight an important role for GAD1 in seizure induction, neuronal and extraneuronal development, and introduce GAD1 as a new gene associated with developmental and epileptic encephalopathy.
Published: 2020

14. Genome-wide association study identifies risk loci for cluster headache

Author: O'Connor, E., Fourier, C., Ran, C., Sivakumar, P., Liesecke, F., Southgate, L., Harder, A.V.E., Vijfhuizen, L.S., Yip, J., Giffin, N., Silver, N., Ahmed, F., Hostettler, I.C., Davies, B., Cader, M.Z., Simpson, B.S., Sullivan, R., Efthymiou, S., Adebimpe, J., Quinn, O., Campbell, C., Cavalleri, G.L., Vikelis, M., Kelderman, T., Paemeleire, K., Kilbride, E., Grangeon, L., Lagrata, S., Danno, D., Trembath, R., Wood, N.W., Kockum, I., Winsvold, B.S., Steinberg, A., Sjostrand, C., Waldenlind, E., Vandrovcova, J., Houlden, H., Matharu, M., and Belin, A.C.
Abstract: Objective This study was undertaken to identify susceptibility loci for cluster headache and obtain insights into relevant disease pathways. Methods We carried out a genome-wide association study, where 852 UK and 591 Swedish cluster headache cases were compared with 5,614 and 1,134 controls, respectively. Following quality control and imputation, single variant association testing was conducted using a logistic mixed model for each cohort. The 2 cohorts were subsequently combined in a merged analysis. Downstream analyses, such as gene-set enrichment, functional variant annotation, prediction and pathway analyses, were performed. Results Initial independent analysis identified 2 replicable cluster headache susceptibility loci on chromosome 2. A merged analysis identified an additional locus on chromosome 1 and confirmed a locus significant in the UK analysis on chromosome 6, which overlaps with a previously known migraine locus. The lead single nucleotide polymorphisms were rs113658130 (p = 1.92 x 10(-17), odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.37-1.66) and rs4519530 (p = 6.98 x 10(-17), OR = 1.47, 95% CI = 1.34-1.61) on chromosome 2, rs12121134 on chromosome 1 (p = 1.66 x 10(-8), OR = 1.36, 95% CI = 1.22-1.52), and rs11153082 (p = 1.85 x 10(-8), OR = 1.30, 95% CI = 1.19-1.42) on chromosome 6. Downstream analyses implicated immunological processes in the pathogenesis of cluster headache. Interpretation We identified and replicated several genome-wide significant associations supporting a genetic predisposition in cluster headache in a genome-wide association study involving 1,443 cases. Replication in larger independent cohorts combined with comprehensive phenotyping, in relation to, for example, treatment response and cluster headache subtypes, could provide unprecedented insights into genotype-phenotype correlations and the pathophysiological pathways underlying cluster headache. ANN NEUROL 2021
Published: 2021

15. Expanding the Spectrum of AP5Z1-Related Hereditary Spastic Paraplegia (HSP-SPG48): A Multicenter Study on a Rare Disease

Author: Breza, M. Hirst, J. Chelban, V. Banneau, G. Tissier, L. Kol, B. Bourinaris, T. Said, S.A. Péréon, Y. Heinzmann, A. Debs, R. Juntas-Morales, R. Martinez, V.G. Camdessanche, J.P. Scherer-Gagou, C. Zola, J.-M. Athanasiou-Fragkouli, A. Efthymiou, S. Vavougios, G. Velonakis, G. Stamelou, M. Tzartos, J. Potagas, C. Zambelis, T. Mariotti, C. Blackstone, C. Vandrovcova, J. Mavridis, T. Kartanou, C. Stefanis, L. Wood, N. Karadima, G. LeGuern, E. Koutsis, G. Houlden, H. Stevanin, G.
Published: 2021

16. α-Synuclein (SNCA) A30G Mutation as a Cause of a Complex Phenotype Without Parkinsonism

Author: Sokratous, M. Breza, M. Senkevich, K. Gan-Or, Z. Kalampokini, S. Spanaki, C. Provatas, A. Zaunmuktane, Z. Valotassiou, V. Georgoulias, P. Efthymiou, S. Hadjigeorgiou, G.M. Houlden, H. Xiromerisiou, G.
Published: 2021

17. Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

Author: Weerts, M.J.A., Lanko, K., Guzmán-Vega, F.J., Jackson, A., Ramakrishnan, R., Cardona-Londoño, K.J., Peña-Guerra, K.A., Bever, Y. Van, Paassen, B.W. van, Kievit, A., Slegtenhorst, M. van, Allen, N.M., Kehoe, C.M., Robinson, H.K., Pang, L., Banu, S.H., Zaman, M., Efthymiou, S., Houlden, H., Järvelä, I., Lauronen, L., Määttä, T., Schrauwen, I., Leal, S.M., Ruivenkamp, C.A.L., Barge-Schaapveld, D., Peeters-Scholte, C., Galehdari, H., Mazaheri, N., Sisodiya, S.M., Harrison, V., Sun, A., Thies, J., Pedroza, L.A., Lara-Taranchenko, Y., Chinn, I.K., Lupski, J.R., Garza-Flores, A., McGlothlin, J., Yang, L., Huang, S., Wang, X, Jewett, T., Rosso, G., Lin, X., Mohammed, S, Merritt, J.L., 2nd, Mirzaa, G.M., Timms, A.E., Scheck, J., Elting, M.W., Polstra, A.M., Schenck, L., Ruzhnikov, M.R.Z., Vetro, A., Montomoli, M., Guerrini, R., Koboldt, D.C., Mosher, T.M., Pastore, M.T., McBride, K.L., Peng, J., Pan, Z., Willemsen, M.H., Koning, S. de, Turnpenny, P.D., Vries, B.B. de, Gilissen, C., Pfundt, R.P., Lees, M., Braddock, S.R., Klemp, K.C., Vansenne, F., Gijn, M.E. van, Quindipan, C., Deardorff, M.A., Hamm, J.A., Putnam, A.M., Baud, R., Walsh, L., Lynch, S.A., Baptista, J., Person, R.E., Monaghan, K.G., Crunk, A., Keller-Ramey, J., Reich, A., Elloumi, H.Z., Alders, M., Kerkhof, J., McConkey, H., Haghshenas, S., Maroofian, R., Sadikovic, B., Banka, S., Arold, Stefan T., Barakat, T.S., Weerts, M.J.A., Lanko, K., Guzmán-Vega, F.J., Jackson, A., Ramakrishnan, R., Cardona-Londoño, K.J., Peña-Guerra, K.A., Bever, Y. Van, Paassen, B.W. van, Kievit, A., Slegtenhorst, M. van, Allen, N.M., Kehoe, C.M., Robinson, H.K., Pang, L., Banu, S.H., Zaman, M., Efthymiou, S., Houlden, H., Järvelä, I., Lauronen, L., Määttä, T., Schrauwen, I., Leal, S.M., Ruivenkamp, C.A.L., Barge-Schaapveld, D., Peeters-Scholte, C., Galehdari, H., Mazaheri, N., Sisodiya, S.M., Harrison, V., Sun, A., Thies, J., Pedroza, L.A., Lara-Taranchenko, Y., Chinn, I.K., Lupski, J.R., Garza-Flores, A., McGlothlin, J., Yang, L., Huang, S., Wang, X, Jewett, T., Rosso, G., Lin, X., Mohammed, S, Merritt, J.L., 2nd, Mirzaa, G.M., Timms, A.E., Scheck, J., Elting, M.W., Polstra, A.M., Schenck, L., Ruzhnikov, M.R.Z., Vetro, A., Montomoli, M., Guerrini, R., Koboldt, D.C., Mosher, T.M., Pastore, M.T., McBride, K.L., Peng, J., Pan, Z., Willemsen, M.H., Koning, S. de, Turnpenny, P.D., Vries, B.B. de, Gilissen, C., Pfundt, R.P., Lees, M., Braddock, S.R., Klemp, K.C., Vansenne, F., Gijn, M.E. van, Quindipan, C., Deardorff, M.A., Hamm, J.A., Putnam, A.M., Baud, R., Walsh, L., Lynch, S.A., Baptista, J., Person, R.E., Monaghan, K.G., Crunk, A., Keller-Ramey, J., Reich, A., Elloumi, H.Z., Alders, M., Kerkhof, J., McConkey, H., Haghshenas, S., Maroofian, R., Sadikovic, B., Banka, S., Arold, Stefan T., and Barakat, T.S.
Abstract: Contains fulltext : 243955.pdf (Publisher’s version ) (Open Access), PURPOSE: Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort. METHODS: We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. RESULTS: Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. CONCLUSION: Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.
Published: 2021

18. Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia

Author: Wiessner, M., Maroofian, R., Ni, M.Y., Pedroni, A., Müller, J.S., Stucka, R., Beetz, C., Efthymiou, S., Santorelli, F.M., Alfares, A.A., Zhu, C., Meszarosova, A. Uhrova, Alehabib, E., Bakhtiari, S., Janecke, A.R., Otero, M.G., Chen, J.Y., Peterson, J.T., Strom, T.M., Jonghe, P. De, Deconinck, T., Ridder, W. De, Winter, J., Pasquariello, R., Ricca, I., Alfadhel, M., Warrenburg, B.P.C. van de, Portier, R., Bergmann, C., Firouzabadi, S. Ghasemi, Jin, S.C., Bilguvar, K., Hamed, S., Abdelhameed, M., Haridy, N.A., Maqbool, S., Rahman, F., Anwar, N., Carmichael, J., Pagnamenta, A., Wood, N.W., Mau-Them, F. Tran, Haack, T., Rocco, M. Di, Ceccherini, I., Iacomino, M., Zara, F., Salpietro, V., Scala, M., Rusmini, M., Xu, Y., Wang, Y., Suzuki, Y., Koh, K., Nan, H., Ishiura, H., Tsuji, S., Lambert, L., Schmitt, E., Lacaze, E., Küpper, H., Dredge, D., Skraban, C., Goldstein, A., Willis, M.J.H., Grand, K., Graham, J.M., Lewis, R.A., Millan, F., Duman, Ö., Dündar, N., Uyanik, G., Schöls, L., Nürnberg, P., Nürnberg, G., Bordes, A. Catala, Seeman, P., Kuchar, M., Darvish, H., Rebelo, A., Bouçanova, F., Medard, J.J., Chrast, R., Auer-Grumbach, M., Alkuraya, F.S., Shamseldin, H., Tala, S. Al, Varaghchi, J. Rezazadeh, Najafi, Maryam, Deschner, S., Gläser, D., Hüttel, W., Kruer, M.C., Kamsteeg, E.J., Takiyama, Y., Züchner, S., Baets, J., Synofzik, M., Schüle, R., Horvath, R., Pierson, T.M., Senderek, J., Wiessner, M., Maroofian, R., Ni, M.Y., Pedroni, A., Müller, J.S., Stucka, R., Beetz, C., Efthymiou, S., Santorelli, F.M., Alfares, A.A., Zhu, C., Meszarosova, A. Uhrova, Alehabib, E., Bakhtiari, S., Janecke, A.R., Otero, M.G., Chen, J.Y., Peterson, J.T., Strom, T.M., Jonghe, P. De, Deconinck, T., Ridder, W. De, Winter, J., Pasquariello, R., Ricca, I., Alfadhel, M., Warrenburg, B.P.C. van de, Portier, R., Bergmann, C., Firouzabadi, S. Ghasemi, Jin, S.C., Bilguvar, K., Hamed, S., Abdelhameed, M., Haridy, N.A., Maqbool, S., Rahman, F., Anwar, N., Carmichael, J., Pagnamenta, A., Wood, N.W., Mau-Them, F. Tran, Haack, T., Rocco, M. Di, Ceccherini, I., Iacomino, M., Zara, F., Salpietro, V., Scala, M., Rusmini, M., Xu, Y., Wang, Y., Suzuki, Y., Koh, K., Nan, H., Ishiura, H., Tsuji, S., Lambert, L., Schmitt, E., Lacaze, E., Küpper, H., Dredge, D., Skraban, C., Goldstein, A., Willis, M.J.H., Grand, K., Graham, J.M., Lewis, R.A., Millan, F., Duman, Ö., Dündar, N., Uyanik, G., Schöls, L., Nürnberg, P., Nürnberg, G., Bordes, A. Catala, Seeman, P., Kuchar, M., Darvish, H., Rebelo, A., Bouçanova, F., Medard, J.J., Chrast, R., Auer-Grumbach, M., Alkuraya, F.S., Shamseldin, H., Tala, S. Al, Varaghchi, J. Rezazadeh, Najafi, Maryam, Deschner, S., Gläser, D., Hüttel, W., Kruer, M.C., Kamsteeg, E.J., Takiyama, Y., Züchner, S., Baets, J., Synofzik, M., Schüle, R., Horvath, R., Pierson, T.M., and Senderek, J.
Abstract: Item does not contain fulltext, Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays.
Published: 2021

19. De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects

Author: Manole, A, Efthymiou, S, O'Connor, E, Mendes, MI, Jennings, M, Maroofian, R, Davagnanam, I, Mankad, K, Lopez, MR, Salpietro, V, Harripaul, R, Badalato, L, Walia, J, Francklyn, CS, Athanasiou-Fragkouli, A, Sullivan, R, Desai, S, Baranano, K, Zafar, F, Rana, N, Ilyas, M, Horga, A, Kara, M, Mattioli, F, Goldenberg, A, Griffin, H, Piton, A, Henderson, LB, Kara, B, Aslanger, AD, Raaphorst, J, Pfundt, R, Portier, R, Shinawi, M, Kirby, A, Christensen, KM, Wang, L, Rosti, RO, Paracha, SA, Sarwar, MT, Jenkins, D, SYNAPS Study Group, Ahmed, J, Santoni, FA, Ranza, E, Iwaszkiewicz, J, Cytrynbaum, C, Weksberg, R, Wentzensen, IM, Guillen Sacoto, MJ, Si, Y, Telegrafi, A, Andrews, MV, Baldridge, D, Gabriel, H, Mohr, J, Oehl-Jaschkowitz, B, Debard, S, Senger, B, Fischer, F, van Ravenwaaij, C, Fock, AJM, Stevens, SJC, Bähler, J, Nasar, A, Mantovani, JF, Manzur, A, Sarkozy, A, Smith, DEC, Salomons, GS, Ahmed, ZM, Riazuddin, S, Usmani, MA, Seibt, A, Ansar, M, Antonarakis, SE, Vincent, JB, Ayub, M, Grimmel, M, Jelsig, AM, Hjortshøj, TD, Karstensen, HG, Hummel, M, Haack, TB, Jamshidi, Y, Distelmaier, F, Horvath, R, Gleeson, JG, Becker, H, Mandel, J-L, Koolen, DA, and Houlden, H
Abstract: Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function.
Published: 2020

20. Bi-allelic JAM2 Variants Lead to Early-Onset Recessive Primary Familial Brain Calcification

Author: Schottlaender, LV, Abeti, R, Jaunmuktane, Z, Macmillan, C, Chelban, V, O'Callaghan, B, McKinley, J, Maroofian, R, Efthymiou, S, Athanasiou-Fragkouli, A, Forbes, R, Soutar, MPM, Livingston, JH, Kalmar, B, Swayne, O, Hotton, G, SYNAPS Study Group, Pittman, A, Mendes de Oliveira, JR, de Grandis, M, Richard-Loendt, A, Launchbury, F, Althonayan, J, McDonnell, G, Carr, A, Khan, S, Beetz, C, Bisgin, A, Tug Bozdogan, S, Begtrup, A, Torti, E, Greensmith, L, Giunti, P, Morrison, PJ, Brandner, S, Aurrand-Lions, M, and Houlden, H
Abstract: Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by a combination of neurological, psychiatric, and cognitive decline associated with calcium deposition on brain imaging. To date, mutations in five genes have been linked to PFBC. However, more than 50% of individuals affected by PFBC have no molecular diagnosis. We report four unrelated families presenting with initial learning difficulties and seizures and later psychiatric symptoms, cerebellar ataxia, extrapyramidal signs, and extensive calcifications on brain imaging. Through a combination of homozygosity mapping and exome sequencing, we mapped this phenotype to chromosome 21q21.3 and identified bi-allelic variants in JAM2. JAM2 encodes for the junctional-adhesion-molecule-2, a key tight-junction protein in blood-brain-barrier permeability. We show that JAM2 variants lead to reduction of JAM2 mRNA expression and absence of JAM2 protein in patient's fibroblasts, consistent with a loss-of-function mechanism. We show that the human phenotype is replicated in the jam2 complete knockout mouse (jam2 KO). Furthermore, neuropathology of jam2 KO mouse showed prominent vacuolation in the cerebral cortex, thalamus, and cerebellum and particularly widespread vacuolation in the midbrain with reactive astrogliosis and neuronal density reduction. The regions of the human brain affected on neuroimaging are similar to the affected brain areas in the myorg PFBC null mouse. Along with JAM3 and OCLN, JAM2 is the third tight-junction gene in which bi-allelic variants are associated with brain calcification, suggesting that defective cell-to-cell adhesion and dysfunction of the movement of solutes through the paracellular spaces in the neurovascular unit is a key mechanism in CNS calcification.
Published: 2020

21. A homozygous GDAP2 loss-of-function variant in a patient with adult-onset cerebellar ataxia

Author: Breza, M. Bourinaris, T. Efthymiou, S. Maroofian, R. Athanasiou-Fragkouli, A. Tzartos, J. Velonakis, G. Karavasilis, E. Angelopoulou, G. Kasselimis, D. Potagas, C. Stefanis, L. Karadima, G. Koutsis, G. Houlden, H.
Published: 2020

22. Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases

Author: Perenthaler, E., Nikoncuk, A., Yousefi, S., Berdowski, W.M., Alsagob, M., Capo, I., Linde, H.C. van der, Berg, P. van den, Jacobs, E.H., Putar, D., Ghazvini, M., Aronica, E., van, I.W.F., Valk, W.G. de, Herik, E. Medici-van den, Slegtenhorst, M. van, Brick, L., Kozenko, M., Kohler, J.N., Bernstein, J.A., Monaghan, K.G., Begtrup, A., Torene, R., Futaisi, A. Al, Murshedi, F. Al, Mani, R., Azri, F. Al, Kamsteeg, E.J., Mojarrad, M., Eslahi, A., Khazaei, Z., Darmiyan, F.M., Doosti, M., Karimiani, E.G., Vandrovcova, J., Zafar, F., Rana, N., Kandaswamy, K.K., Hertecant, J., Bauer, P., AlMuhaizea, M.A., Salih, M.A., Aldosary, M., Almass, R., Al-Quait, L., Qubbaj, W., Coskun, S., Alahmadi, K.O., Hamad, M.H.A., Alwadaee, S., Awartani, K., Dababo, A.M., Almohanna, F., Colak, D., Dehghani, M., Mehrjardi, M.Y.V., Gunel, M., Ercan-Sencicek, A.G., Passi, G.R., Cheema, H.A., Efthymiou, S., Houlden, H., Bertoli-Avella, A.M., Brooks, A.S., Retterer, K., Maroofian, R., Kaya, N., Ham, T.J. van, Barakat, T.S., Perenthaler, E., Nikoncuk, A., Yousefi, S., Berdowski, W.M., Alsagob, M., Capo, I., Linde, H.C. van der, Berg, P. van den, Jacobs, E.H., Putar, D., Ghazvini, M., Aronica, E., van, I.W.F., Valk, W.G. de, Herik, E. Medici-van den, Slegtenhorst, M. van, Brick, L., Kozenko, M., Kohler, J.N., Bernstein, J.A., Monaghan, K.G., Begtrup, A., Torene, R., Futaisi, A. Al, Murshedi, F. Al, Mani, R., Azri, F. Al, Kamsteeg, E.J., Mojarrad, M., Eslahi, A., Khazaei, Z., Darmiyan, F.M., Doosti, M., Karimiani, E.G., Vandrovcova, J., Zafar, F., Rana, N., Kandaswamy, K.K., Hertecant, J., Bauer, P., AlMuhaizea, M.A., Salih, M.A., Aldosary, M., Almass, R., Al-Quait, L., Qubbaj, W., Coskun, S., Alahmadi, K.O., Hamad, M.H.A., Alwadaee, S., Awartani, K., Dababo, A.M., Almohanna, F., Colak, D., Dehghani, M., Mehrjardi, M.Y.V., Gunel, M., Ercan-Sencicek, A.G., Passi, G.R., Cheema, H.A., Efthymiou, S., Houlden, H., Bertoli-Avella, A.M., Brooks, A.S., Retterer, K., Maroofian, R., Kaya, N., Ham, T.J. van, and Barakat, T.S.
Abstract: Contains fulltext : 218287.pdf (Publisher’s version ) (Open Access), Developmental and/or epileptic encephalopathies (DEEs) are a group of devastating genetic disorders, resulting in early-onset, therapy-resistant seizures and developmental delay. Here we report on 22 individuals from 15 families presenting with a severe form of intractable epilepsy, severe developmental delay, progressive microcephaly, visual disturbance and similar minor dysmorphisms. Whole exome sequencing identified a recurrent, homozygous variant (chr2:64083454A > G) in the essential UDP-glucose pyrophosphorylase (UGP2) gene in all probands. This rare variant results in a tolerable Met12Val missense change of the longer UGP2 protein isoform but causes a disruption of the start codon of the shorter isoform, which is predominant in brain. We show that the absence of the shorter isoform leads to a reduction of functional UGP2 enzyme in neural stem cells, leading to altered glycogen metabolism, upregulated unfolded protein response and premature neuronal differentiation, as modeled during pluripotent stem cell differentiation in vitro. In contrast, the complete lack of all UGP2 isoforms leads to differentiation defects in multiple lineages in human cells. Reduced expression of Ugp2a/Ugp2b in vivo in zebrafish mimics visual disturbance and mutant animals show a behavioral phenotype. Our study identifies a recurrent start codon mutation in UGP2 as a cause of a novel autosomal recessive DEE syndrome. Importantly, it also shows that isoform-specific start-loss mutations causing expression loss of a tissue-relevant isoform of an essential protein can cause a genetic disease, even when an organism-wide protein absence is incompatible with life. We provide additional examples where a similar disease mechanism applies.
Published: 2020

23. Biallelic and monoallelic variants in PLXNA1 cause a syndromic disorder with neurodevelopmental and oculo-cerebral anomalies

Author: Dworschak, G. C., Punetha, J., Kalanithy, J. C., Mingardo, E., Erdem, H. B., Akdemir, Z. C., Karaca, E., Mitani, T., Marafi, D., Fatih, J. M., Jhangiani, S. N., Hunter, J. V., Dakal, T., Dhabhai, B., Dabbagh, O., Alsaif, H. S., Alkuraya, F. S., Maroofian, R., Houlden, H., Efthymiou, S., Dominik, N., Salpietro, V., Sultan, T., Haider, S., Bibi, F., Thiele, H., Hoefele, J., Riedhammer, K. M., Wagner, M., Guella, I., Demos, M., Keren, B., Buratti, J., Charles, P., Nava, C., Valkanas, E., Waddell, L. B., Jones, K. J., Oates, E. C., Cooper, S. T., MacArthur, D., Schnur, R. E., Hoganson, G. E., Burton, J. E., McEntagart, M., Pehlivan, D., Posey, J. E., Lupski, J. R., Reutter, H., Dworschak, G. C., Punetha, J., Kalanithy, J. C., Mingardo, E., Erdem, H. B., Akdemir, Z. C., Karaca, E., Mitani, T., Marafi, D., Fatih, J. M., Jhangiani, S. N., Hunter, J. V., Dakal, T., Dhabhai, B., Dabbagh, O., Alsaif, H. S., Alkuraya, F. S., Maroofian, R., Houlden, H., Efthymiou, S., Dominik, N., Salpietro, V., Sultan, T., Haider, S., Bibi, F., Thiele, H., Hoefele, J., Riedhammer, K. M., Wagner, M., Guella, I., Demos, M., Keren, B., Buratti, J., Charles, P., Nava, C., Valkanas, E., Waddell, L. B., Jones, K. J., Oates, E. C., Cooper, S. T., MacArthur, D., Schnur, R. E., Hoganson, G. E., Burton, J. E., McEntagart, M., Pehlivan, D., Posey, J. E., Lupski, J. R., and Reutter, H.
Published: 2020

24. Bi-allelic Variants in the GPI Transamidase Subunit PIGK Cause a Neurodevelopmental Syndrome with Hypotonia, Cerebellar Atrophy, and Epilepsy

Author: Nguyen, T. T. M., Murakami, Y., Mobilio, S., Niceta, M., Zampino, Giuseppe, Philippe, C., Moutton, S., Zaki, M. S., James, K. N., Musaev, D., Mu, W., Baranano, K., Nance, J. R., Rosenfeld, J. A., Braverman, N., Ciolfi, A., Millan, F., Person, R. E., Bruel, A. -L., Thauvin-Robinet, C., Ververi, A., Devile, C., Male, A., Efthymiou, S., Maroofian, R., Houlden, H., Maqbool, S., Rahman, F., Baratang, N. V., Rousseau, J., St-Denis, A., Elrick, M. J., Anselm, I., Rodan, L. H., Tartaglia, M., Gleeson, J., Kinoshita, T., Campeau, P. M., Zampino G. (ORCID:0000-0003-3865-3253), Nguyen, T. T. M., Murakami, Y., Mobilio, S., Niceta, M., Zampino, Giuseppe, Philippe, C., Moutton, S., Zaki, M. S., James, K. N., Musaev, D., Mu, W., Baranano, K., Nance, J. R., Rosenfeld, J. A., Braverman, N., Ciolfi, A., Millan, F., Person, R. E., Bruel, A. -L., Thauvin-Robinet, C., Ververi, A., Devile, C., Male, A., Efthymiou, S., Maroofian, R., Houlden, H., Maqbool, S., Rahman, F., Baratang, N. V., Rousseau, J., St-Denis, A., Elrick, M. J., Anselm, I., Rodan, L. H., Tartaglia, M., Gleeson, J., Kinoshita, T., Campeau, P. M., and Zampino G. (ORCID:0000-0003-3865-3253)
Abstract: Glycosylphosphatidylinositol (GPI)-anchored proteins are critical for embryogenesis, neurogenesis, and cell signaling. Variants in several genes participating in GPI biosynthesis and processing lead to decreased cell surface presence of GPI-anchored proteins (GPI-APs) and cause inherited GPI deficiency disorders (IGDs). In this report, we describe 12 individuals from nine unrelated families with 10 different bi-allelic PIGK variants. PIGK encodes a component of the GPI transamidase complex, which attaches the GPI anchor to proteins. Clinical features found in most individuals include global developmental delay and/or intellectual disability, hypotonia, cerebellar ataxia, cerebellar atrophy, and facial dysmorphisms. The majority of the individuals have epilepsy. Two individuals have slightly decreased levels of serum alkaline phosphatase, while eight do not. Flow cytometric analysis of blood and fibroblasts from affected individuals showed decreased cell surface presence of GPI-APs. The overexpression of wild-type (WT) PIGK in fibroblasts rescued the levels of cell surface GPI-APs. In a knockout cell line, transfection with WT PIGK also rescued the GPI-AP levels, but transfection with the two tested mutant variants did not. Our study not only expands the clinical and known genetic spectrum of IGDs, but it also expands the genetic differential diagnosis for cerebellar atrophy. Given the fact that cerebellar atrophy is seen in other IGDs, flow cytometry for GPI-APs should be considered in the work-ups of individuals presenting this feature.
Published: 2020

25. Genotype-Phenotype Correlations in Charcot-Marie-Tooth Disease Due to MTMR2 Mutations and Implications in Membrane Trafficking

Author: Sprute, R, Bayram, N, Zeighami, J, Shariati, G, Azizi, Malamiri, Stumpfe, K, Mazaheri, N, Nedic, I, Efthymiou, S, Pergande, M, Cooper, E, Ozdemir, O, Kaçar, Bayram, Wang, H, Per, HÜSEYİN, Cirak, S, Jamshidi, Y, Shalbafan, B, Galehdari, H, Houlden, H, Salpietro, V, Sultan, T, Bibi, F, Sami, Güven, Yaşar, M, Tajik, M, and Naghibzadeh, SK
Published: 2019

26. Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia (vol 51, pg 649, 2019)

Author: Cortese, A, Simone, R, Sullivan, R, Vandrovcova, J, Tariq, H, Yau, Wy, Humphrey, J, Jaunmuktane, Z, Sivakumar, P, Polke, J, Ilyas, M, Tribollet, E, Tomaselli, Pj, Devigili, G, Callegari, I, Versino, M, Salpietro, V, Efthymiou, S, Kaski, D, Wood, Nw, Andrade, Ns, Buglo, E, Rebelo, A, Rossor, Am, Bronstein, A, Fratta, P, Marques, Wj, Zuchner, S, Reilly, Mm, and Houlden, H
Published: 2019

27. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Author: 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. Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment

Author: Salpietro V, Malintan NT, Llano-Rivas I, Spaeth CG, Efthymiou S, Striano P, Vandrovcova J, Cutrupi MC, Chimenz R, David E, Di Rosa G, Marce-Grau A, Raspall-Chaure M, Martin-Hernandez E, Zara F, Minetti C, Deciphering Developmental Disorders Study, SYNAPS Study Group, Bello OD, De Zorzi R, Fortuna S, Dauber A, Alkhawaja M, Sultan T, Mankad K, Vitobello A, Thomas Q, Mau-Them FT, Faivre L, Martinez-Azorin F, Prada CE, Alfons Macaya, Kullmann DM, Rothman JE, Krishnakumar SS, and Houlden H
Subjects: SNARE, VAMP2, autism, epilepsy, movement disorders, neurodevelopmental disorders, neuronal exocytosis, synaptobrevin, synaptopathy, vesicle fusion, sense organs
Abstract: VAMP2 encodes the vesicular SNARE protein VAMP2 (also called synaptobrevin-2). Together with its partners syntaxin-1A and synaptosomal-associated protein 25 (SNAP25), VAMP2 mediates fusion of synaptic vesicles to release neurotransmitters. VAMP2 is essential for vesicular exocytosis and activity-dependent neurotransmitter release. Here, we report five heterozygous de novo mutations in VAMP2 in unrelated individuals presenting with a neurodevelopmental disorder characterized by axial hypotonia (which had been present since birth), intellectual disability, and autistic features. In total, we identified two single-amino-acid deletions and three non-synonymous variants affecting conserved residues within the C terminus of the VAMP2 SNARE motif. Affected individuals carrying de novo non-synonymous variants involving the C-terminal region presented a more severe phenotype with additional neurological features, including central visual impairment, hyperkinetic movement disorder, and epilepsy or electroencephalography abnormalities. Reconstituted fusion involving a lipid-mixing assay indicated impairment in vesicle fusion as one of the possible associated disease mechanisms. The genetic synaptopathy caused by VAMP2 de novo mutations highlights the key roles of this gene in human brain development and function.
Published: 2019

29. Author Correction: Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia (Nature Genetics, (2019), 51, 4, (649-658), 10.1038/s41588-019-0372-4)

Author: Cortese, Alessandro, Simone, R., Sullivan, R., Vandrovcova, J., Tariq, H., Yau, W. Y., Humphrey, J., Jaunmuktane, Z., Sivakumar, P., Polke, J., Ilyas, M., Tribollet, E., Tomaselli, P. J., Devigili, G., Callegari, I., Versino, M., Salpietro, V., Efthymiou, S., Kaski, D., Wood, N. W., Andrade, N. S., Buglo, E., Rebelo, A., Rossor, A. M., Bronstein, A., Fratta, P., Marques, W. J., Zuchner, S., Reilly, M. M., and Houlden, H.
Published: 2019

30. SPASTIC PARAPLEGIA: CLINICAL AND GENETIC SPECTRUM IN A SELECTED ARGENTINEAN GROUP

Author: Heredia, Facundo, Berardo, Andres, Schottlaender, Lucia V, Marchesoni, Cintia, Luciana, Leon Cejas, Efthymiou S, Vandrovcova J, Rugiero Marcelo, Patrucco Liliana, Chaves Marcelo, Emmanuel, Silva, Rolle J, Gargiulo Gisella, Marta, Medina, C, Bas, Dubrovsky Alberto, Pirra Laura, Conti Eugenia, Albanese G, Esnaola Maria, Ihanota, Houlden Henry, and Reisin Ricardo
Published: 2019
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31. Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases

Author: Perenthaler, E. (Elena), Nikoncuk, A. (Anita), Yousefi, S. (Soheil), Berdowski, W.M. (Woutje M.), Alsagob, M. (Maysoon), Capo, I. (Ivan), Linde, H.C. (Herma) van der, van den Berg, P. (Paul), Jacobs, E.H. (Edwin H.), Putar, D. (Darija), Ghazvini, M. (Mehrnaz), Aronica, E.M.A. (Eleonora), IJcken, W.F.J. (Wilfred) van, de Valk, W.G. (Walter G.), Medici-van den Herik, E. (Evita), Slegtenhorst, M.A. (Marjon) van, Brick, L. (Lauren), Kozenko, M. (Mariya), Kohler, J.N. (Jennefer N.), Bernstein, J.A. (Jonathan A.), Monaghan, K.G. (Kristin G.), Begtrup, A. (Amber), Torene, R. (Rebecca), Al Futaisi, A. (Amna), Al Murshedi, F. (Fathiya), Mani, R. (Renjith), Al Azri, F. (Faisal), Kamsteeg, E.J. (Erik-Jan), Mojarrad, M. (Majid), Eslahi, A. (Atieh), Khazaei, Z. (Zaynab), Darmiyan, F.M. (Fateme Massinaei), Doosti, M. (Mohammad), Karimiani, E.G. (Ehsan Ghayoor), Vandrovcova, J. (Jana), Zafar, F. (Faisal), Rana, N. (Nuzhat), Kandaswamy, K.K. (Krishna K.), Hertecant, J. (Jozef), Bauer, P. (Peter), AlMuhaizea, M.A. (Mohammed A.), Salih, M.A. (Mustafa A.), Aldosary, M. (Mazhor), Almass, R. (Rawan), Al-Quait, L. (Laila), Qubbaj, W. (Wafa), Coskun, S. (Serdar), Alahmadi, K.O. (Khaled O.), Hamad, M.H.A. (Muddathir H. A.), Alwadaee, S. (Salem), Awartani, K. (Khalid), Dababo, A.M. (Anas M.), Almohanna, F. (Futwan), Colak, D. (Dilek), Dehghani, M. (Mohammadreza), Mehrjardi, M.Y.V. (Mohammad Yahya Vahidi), Günel, M. (Murat), Ercan-Sencicek, A.G. (A. Gulhan), Passi, G.R. (Gouri Rao), Cheema, H.A. (Huma Arshad), Efthymiou, S. (Stephanie), Houlden, H. (Henry), Bertoli Avella, A.M. (Aida), Brooks, A.S. (Alice), Retterer, K. (Kyle), Maroofian, R. (Reza), Kaya, N. (Namik), Ham, T.J. (Tjakko) van, Barakat, T.S. (Tahsin Stefan), Perenthaler, E. (Elena), Nikoncuk, A. (Anita), Yousefi, S. (Soheil), Berdowski, W.M. (Woutje M.), Alsagob, M. (Maysoon), Capo, I. (Ivan), Linde, H.C. (Herma) van der, van den Berg, P. (Paul), Jacobs, E.H. (Edwin H.), Putar, D. (Darija), Ghazvini, M. (Mehrnaz), Aronica, E.M.A. (Eleonora), IJcken, W.F.J. (Wilfred) van, de Valk, W.G. (Walter G.), Medici-van den Herik, E. (Evita), Slegtenhorst, M.A. (Marjon) van, Brick, L. (Lauren), Kozenko, M. (Mariya), Kohler, J.N. (Jennefer N.), Bernstein, J.A. (Jonathan A.), Monaghan, K.G. (Kristin G.), Begtrup, A. (Amber), Torene, R. (Rebecca), Al Futaisi, A. (Amna), Al Murshedi, F. (Fathiya), Mani, R. (Renjith), Al Azri, F. (Faisal), Kamsteeg, E.J. (Erik-Jan), Mojarrad, M. (Majid), Eslahi, A. (Atieh), Khazaei, Z. (Zaynab), Darmiyan, F.M. (Fateme Massinaei), Doosti, M. (Mohammad), Karimiani, E.G. (Ehsan Ghayoor), Vandrovcova, J. (Jana), Zafar, F. (Faisal), Rana, N. (Nuzhat), Kandaswamy, K.K. (Krishna K.), Hertecant, J. (Jozef), Bauer, P. (Peter), AlMuhaizea, M.A. (Mohammed A.), Salih, M.A. (Mustafa A.), Aldosary, M. (Mazhor), Almass, R. (Rawan), Al-Quait, L. (Laila), Qubbaj, W. (Wafa), Coskun, S. (Serdar), Alahmadi, K.O. (Khaled O.), Hamad, M.H.A. (Muddathir H. A.), Alwadaee, S. (Salem), Awartani, K. (Khalid), Dababo, A.M. (Anas M.), Almohanna, F. (Futwan), Colak, D. (Dilek), Dehghani, M. (Mohammadreza), Mehrjardi, M.Y.V. (Mohammad Yahya Vahidi), Günel, M. (Murat), Ercan-Sencicek, A.G. (A. Gulhan), Passi, G.R. (Gouri Rao), Cheema, H.A. (Huma Arshad), Efthymiou, S. (Stephanie), Houlden, H. (Henry), Bertoli Avella, A.M. (Aida), Brooks, A.S. (Alice), Retterer, K. (Kyle), Maroofian, R. (Reza), Kaya, N. (Namik), Ham, T.J. (Tjakko) van, and Barakat, T.S. (Tahsin Stefan)
Abstract: Developmental and/or epileptic encephalopathies (DEEs) are a group of devastating genetic disorders, resulting in early-onset, therapy-resistant seizures and developmental delay. Here we report on 22 individuals from 15 families presenting with a severe form of intractable epilepsy, severe developmental delay, progressive microcephaly, visual disturbance and similar minor dysmorphisms. Whole exome sequencing identified a recurrent, homozygous variant (chr2:64083454A > G) in the essential UDP-glucose pyrophosphorylase (UGP2) gene in all probands. This rare variant results in a tolerable Met12Val missense change of the longer UGP2 protein isoform but causes a disruption of the start codon of the shorter isoform, which is predominant in brain. We show that the absence of the shorter isoform leads to a reduction of functional UGP2 enzyme in neural stem cells, leading to altered glycogen metabolism, upregulated unfolded protein response and premature neuronal differentiation, as modeled during pluripotent stem cell differentiation in vitro. In contrast, the complete lack of all UGP2 isoforms leads to differentiation defects in multiple lineages in human cells. Reduced expression of Ugp2a/Ugp2b in vivo in zebrafish mimics visual disturbance and mutant animals show a behavioral phenotype. Our study identifies a recurrent start codon mutation in UGP2 as a cause of a novel autosomal recessive DEE syndrome. Importantly, it also shows that isoform-specific start-loss mutations causing expression loss of a tissue-relevant isoform of an essential protein can cause a genetic disease, even when an organism-wide protein absence is incompatible with
Published: 2019
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32. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Author: Salpietro, V, Dixon, CL, Guo, H, Bello, OD, 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, Mannikko, R, Manole, A, Brusco, A, Grosso, E, Ferrero, GB, Armstrong-Moron, J, Gueden, S, Bar-Yosef, O, Tzadok, M, Monaghan, KG, Santiago-Sim, T, Person, RE, Cho, MT, Willaert, R, Yoo, Y, Chae, J-H, Quan, Y, Wu, H, Wang, T, Bernier, RA, Xia, K, Blesson, A, Jain, M, Motazacker, MM, Jaeger, B, Schneider, AL, Boysen, K, Muir, AM, Myers, CT, Gavrilova, RH, Gunderson, L, Schultz-Rogers, L, Klee, EW, Dyment, D, Osmond, M, Parellada, M, Llorente, C, Gonzalez-Penas, J, Carracedo, A, Van Haeringen, A, Ruivenkamp, C, Nava, C, Heron, D, Nardello, R, Iacomino, M, Minetti, C, Skabar, A, Fabretto, A, Chez, M, Tsai, A, Fassi, E, Shinawi, M, Constantino, JN, De Zorzi, R, Fortuna, S, Kok, F, Keren, B, Bonneau, D, Choi, M, Benzeev, B, Zara, F, Mefford, HC, Scheffer, IE, Clayton-Smith, J, Macaya, A, Rothman, JE, Eichler, EE, Kullmann, DM, Houlden, H, Raspall-Chaure, M, Hanna, MG, Bugiardini, E, Hostettler, I, O'Callaghan, B, Khan, A, Cortese, A, O'Connor, E, Yau, WY, Bourinaris, T, Kaiyrzhanov, R, Chelban, V, Madej, M, Diana, MC, Vari, MS, Pedemonte, M, Bruno, C, Balagura, G, Scala, M, Fiorillo, C, Nobili, L, Malintan, NT, Zanetti, MN, Krishnakumar, SS, Lignani, G, Jepson, JEC, Broda, P, Baldassari, S, Rossi, P, Fruscione, F, Madia, F, Traverso, M, De-Marco, P, Perez-Duenas, 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, JS, Sultan, T, Kirmani, S, Ibrahim, S, Jan, F, Mine, J, Banu, S, Veggiotti, P, Zuccotti, G, Ferrari, MD, Van Den Maagdenberg, AMJ, Verrotti, A, Marseglia, GL, Savasta, S, Soler, MA, Scuderi, C, Borgione, E, Chimenz, R, Gitto, E, Dipasquale, V, Sallemi, A, Fusco, M, Cuppari, C, Cutrupi, MC, Ruggieri, M, Cama, A, Capra, V, Mencacci, NE, Boles, R, Gupta, N, Kabra, M, Papacostas, S, Zamba-Papanicolaou, E, Dardiotis, E, Maqbool, S, Rana, N, Atawneh, O, Lim, SY, Shaikh, F, Koutsis, G, Breza, M, Coviello, DA, Dauvilliers, YA, AlKhawaja, I, AlKhawaja, M, Al-Mutairi, F, Stojkovic, T, Ferrucci, V, Zollo, M, Alkuraya, FS, Kinali, M, Sherifa, H, Benrhouma, H, Turki, IBY, Tazir, M, Obeid, M, Bakhtadze, S, Saadi, NW, Zaki, MS, Triki, CC, Benfenati, F, Gustincich, S, Kara, M, Belcastro, V, Specchio, N, Capovilla, G, Karimiani, EG, Salih, AM, Okubadejo, NU, Ojo, OO, Oshinaike, OO, Oguntunde, O, Wahab, K, Bello, AH, 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, LA, Xiromerisiou, G, David, E, Aguennouz, M, Fidani, L, Spanaki, C, Tucci, A, Salpietro, V, Dixon, CL, Guo, H, Bello, OD, 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, Mannikko, R, Manole, A, Brusco, A, Grosso, E, Ferrero, GB, Armstrong-Moron, J, Gueden, S, Bar-Yosef, O, Tzadok, M, Monaghan, KG, Santiago-Sim, T, Person, RE, Cho, MT, Willaert, R, Yoo, Y, Chae, J-H, Quan, Y, Wu, H, Wang, T, Bernier, RA, Xia, K, Blesson, A, Jain, M, Motazacker, MM, Jaeger, B, Schneider, AL, Boysen, K, Muir, AM, Myers, CT, Gavrilova, RH, Gunderson, L, Schultz-Rogers, L, Klee, EW, Dyment, D, Osmond, M, Parellada, M, Llorente, C, Gonzalez-Penas, J, Carracedo, A, Van Haeringen, A, Ruivenkamp, C, Nava, C, Heron, D, Nardello, R, Iacomino, M, Minetti, C, Skabar, A, Fabretto, A, Chez, M, Tsai, A, Fassi, E, Shinawi, M, Constantino, JN, De Zorzi, R, Fortuna, S, Kok, F, Keren, B, Bonneau, D, Choi, M, Benzeev, B, Zara, F, Mefford, HC, Scheffer, IE, Clayton-Smith, J, Macaya, A, Rothman, JE, Eichler, EE, Kullmann, DM, Houlden, H, Raspall-Chaure, M, Hanna, MG, Bugiardini, E, Hostettler, I, O'Callaghan, B, Khan, A, Cortese, A, O'Connor, E, Yau, WY, Bourinaris, T, Kaiyrzhanov, R, Chelban, V, Madej, M, Diana, MC, Vari, MS, Pedemonte, M, Bruno, C, Balagura, G, Scala, M, Fiorillo, C, Nobili, L, Malintan, NT, Zanetti, MN, Krishnakumar, SS, Lignani, G, Jepson, JEC, Broda, P, Baldassari, S, Rossi, P, Fruscione, F, Madia, F, Traverso, M, De-Marco, P, Perez-Duenas, 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, JS, Sultan, T, Kirmani, S, Ibrahim, S, Jan, F, Mine, J, Banu, S, Veggiotti, P, Zuccotti, G, Ferrari, MD, Van Den Maagdenberg, AMJ, Verrotti, A, Marseglia, GL, Savasta, S, Soler, MA, Scuderi, C, Borgione, E, Chimenz, R, Gitto, E, Dipasquale, V, Sallemi, A, Fusco, M, Cuppari, C, Cutrupi, MC, Ruggieri, M, Cama, A, Capra, V, Mencacci, NE, Boles, R, Gupta, N, Kabra, M, Papacostas, S, Zamba-Papanicolaou, E, Dardiotis, E, Maqbool, S, Rana, N, Atawneh, O, Lim, SY, Shaikh, F, Koutsis, G, Breza, M, Coviello, DA, Dauvilliers, YA, AlKhawaja, I, AlKhawaja, M, Al-Mutairi, F, Stojkovic, T, Ferrucci, V, Zollo, M, Alkuraya, FS, Kinali, M, Sherifa, H, Benrhouma, H, Turki, IBY, Tazir, M, Obeid, M, Bakhtadze, S, Saadi, NW, Zaki, MS, Triki, CC, Benfenati, F, Gustincich, S, Kara, M, Belcastro, V, Specchio, N, Capovilla, G, Karimiani, EG, Salih, AM, Okubadejo, NU, Ojo, OO, Oshinaike, OO, Oguntunde, O, Wahab, K, Bello, AH, 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, LA, Xiromerisiou, G, David, E, Aguennouz, M, Fidani, L, Spanaki, C, and Tucci, A
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.
Published: 2019

33. PDXK mutations cause polyneuropathy responsive to pyridoxal 5'-phosphate supplementation

Author: Chelban, V., Wilson, M. P., Warman Chardon, J., Vandrovcova, J., Zanetti, M. N., Zamba-Papanicolaou, E., Efthymiou, S., Pope, S., Conte, M. R., Abis, G., Liu, Y. -T., Tribollet, E., Haridy, N. A., Botia, J. A., Ryten, M., Nicolaou, P., Minaidou, A., Christodoulou, K., Kernohan, K. D., Eaton, A., Osmond, M., Ito, Y., Bourque, P., Jepson, J. E. C., Bello, O., Bremner, F., Cordivari, C., Reilly, M. M., Foiani, M., Heslegrave, A., Zetterberg, H., Heales, S. J. R., Wood, N. W., Rothman, J. E., Boycott, K. M., Mills, P. B., Clayton, P. T., Houlden, H., Kriouile, Y., Khorassani, M. E., Aguennouz, M., Groppa, S., Marinova Karashova, B., Van Maldergem, L., Nachbauer, W., Boesch, S., Arning, L., Timmann, D., Cormand, B., Perez-Duenas, B., Di Rosa, G., Goraya, J. S., Sultan, T., Mine, J., Avdjieva, D., Kathom, H., Tincheva, R., Banu, S., Pineda-Marfa, M., Veggiotti, P., Ferrari, M. D., van den Maagdenberg, A. M. J. M., Verrotti, A., Marseglia, G., Savasta, S., Garcia-Silva, M., Ruiz, A. M., Garavaglia, B., Borgione, E., Portaro, S., Sanchez, B. M., Boles, R., Papacostas, S., Vikelis, M., Giunti, P., Salpietro, V., Oconnor, E., Kullmann, D., Kaiyrzhanov, R., Sullivan, R., Khan, A. M., Yau, W. Y., Hostettler, I., Papanicolaou, E. Z., Dardiotis, E., Maqbool, S., Ibrahim, S., Kirmani, S., Rana, N. N., Atawneh, O., Lim, S. -Y., Shaikh, F., Koutsis, G., Breza, M., Mangano, S., Scuderi, C., Morello, G., Stojkovic, T., Torti, E., Zollo, M., Heimer, G., Dauvilliers, Y. A., Striano, P., Al-Khawaja, I., Al-Mutairi, F., Alkuraya, F. S., Sherifa, H., Rizig, M., Okubadejo, N. U., Ojo, O. O., Oshinaike, O. O., Wahab, K., Bello, A. H., Abubakar, S., Obiabo, Y., Nwazor, E., Ekenze, O., Williams, U., Iyagba, A., Taiwo, L., Komolafe, M., Oguntunde, O., Pchelina, S., Senkevich, K., Shashkin, C., Zharkynbekova, N., Koneyev, K., Manizha, G., Isrofilov, M., Guliyeva, U., Salayev, K., Khachatryan, S., Rossi, S., Silvestri, Gabriella, Bourinaris, T., Xiromerisiou, G., Fidani, L., Spanaki, C., Tucci, A., Silvestri G. (ORCID:0000-0002-1950-1468), Chelban, V., Wilson, M. P., Warman Chardon, J., Vandrovcova, J., Zanetti, M. N., Zamba-Papanicolaou, E., Efthymiou, S., Pope, S., Conte, M. R., Abis, G., Liu, Y. -T., Tribollet, E., Haridy, N. A., Botia, J. A., Ryten, M., Nicolaou, P., Minaidou, A., Christodoulou, K., Kernohan, K. D., Eaton, A., Osmond, M., Ito, Y., Bourque, P., Jepson, J. E. C., Bello, O., Bremner, F., Cordivari, C., Reilly, M. M., Foiani, M., Heslegrave, A., Zetterberg, H., Heales, S. J. R., Wood, N. W., Rothman, J. E., Boycott, K. M., Mills, P. B., Clayton, P. T., Houlden, H., Kriouile, Y., Khorassani, M. E., Aguennouz, M., Groppa, S., Marinova Karashova, B., Van Maldergem, L., Nachbauer, W., Boesch, S., Arning, L., Timmann, D., Cormand, B., Perez-Duenas, B., Di Rosa, G., Goraya, J. S., Sultan, T., Mine, J., Avdjieva, D., Kathom, H., Tincheva, R., Banu, S., Pineda-Marfa, M., Veggiotti, P., Ferrari, M. D., van den Maagdenberg, A. M. J. M., Verrotti, A., Marseglia, G., Savasta, S., Garcia-Silva, M., Ruiz, A. M., Garavaglia, B., Borgione, E., Portaro, S., Sanchez, B. M., Boles, R., Papacostas, S., Vikelis, M., Giunti, P., Salpietro, V., Oconnor, E., Kullmann, D., Kaiyrzhanov, R., Sullivan, R., Khan, A. M., Yau, W. Y., Hostettler, I., Papanicolaou, E. Z., Dardiotis, E., Maqbool, S., Ibrahim, S., Kirmani, S., Rana, N. N., Atawneh, O., Lim, S. -Y., Shaikh, F., Koutsis, G., Breza, M., Mangano, S., Scuderi, C., Morello, G., Stojkovic, T., Torti, E., Zollo, M., Heimer, G., Dauvilliers, Y. A., Striano, P., Al-Khawaja, I., Al-Mutairi, F., Alkuraya, F. S., Sherifa, H., Rizig, M., Okubadejo, N. U., Ojo, O. O., Oshinaike, O. O., Wahab, K., Bello, A. H., Abubakar, S., Obiabo, Y., Nwazor, E., Ekenze, O., Williams, U., Iyagba, A., Taiwo, L., Komolafe, M., Oguntunde, O., Pchelina, S., Senkevich, K., Shashkin, C., Zharkynbekova, N., Koneyev, K., Manizha, G., Isrofilov, M., Guliyeva, U., Salayev, K., Khachatryan, S., Rossi, S., Silvestri, Gabriella, Bourinaris, T., Xiromerisiou, G., Fidani, L., Spanaki, C., Tucci, A., and Silvestri G. (ORCID:0000-0002-1950-1468)
Abstract: Objective: To identify disease-causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy. Methods: We performed genome-wide sequencing, homozygosity mapping, and segregation analysis for novel disease-causing gene discovery. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the impact of variants on adenosine triphosphate (ATP) binding. Pathogenicity was further supported by enzymatic assays and mass spectroscopy on recombinant protein, patient-derived fibroblasts, plasma, and erythrocytes. Response to supplementation was measured with clinical validated rating scales, electrophysiology, and biochemical quantification. Results: We identified biallelic mutations in PDXK in 5 individuals from 2 unrelated families with primary axonal polyneuropathy and optic atrophy. The natural history of this disorder suggests that untreated, affected individuals become wheelchair-bound and blind. We identified conformational rearrangement in the mutant enzyme around the ATP-binding pocket. Low PDXK ATP binding resulted in decreased erythrocyte PDXK activity and low pyridoxal 5′-phosphate (PLP) concentrations. We rescued the clinical and biochemical profile with PLP supplementation in 1 family, improvement in power, pain, and fatigue contributing to patients regaining their ability to walk independently during the first year of PLP normalization. Interpretation: We show that mutations in PDXK cause autosomal recessive axonal peripheral polyneuropathy leading to disease via reduced PDXK enzymatic activity and low PLP. We show that the biochemical profile can be rescued with PLP supplementation associated with clinical improvement. As B6 is a cofactor in diverse essential biological pathways, our findings may have direct implications for neuropathies of unknown etiology characterized by reduced PLP levels. ANN NEUROL 2019;86:225–240.
Published: 2019

34. PRUNE is crucial for normal brain development and mutated in microcephaly with neurodevelopmental impairment

Author: Zollo, M, Ahmed, M, Ferrucci, V, Salpietro, V, Asadzadeh, F, Carotenuto, M, Maroofian, R, Al-Amri, A, Singh, R, Scognamiglio, I, Mojarrad, M, Musella, L, Duilio, A, Di Somma, A, Karaca, E, Rajab, A, Al-Khayat, A, Mohan Mohapatra, T, Eslahi, A, Ashrafzadeh, F, Rawlins, LE, Prasad, R, Gupta, R, Kumari, P, Srivastava, M, Cozzolino, F, Kumar Rai, S, Monti, M, Harlalka, GV, Simpson, MA, Rich, P, Al-Salmi, F, Patton, MA, Chioza, BA, Efthymiou, S, Granata, F, Di Rosa, G, Wiethoff, S, Borgione, E, Scuderi, C, Mankad, K, Hanna, MG, Pucci, P, Houlden, H, Lupski, JR, Crosby, AH, Baple, EL, Zollo, Massimo, Ahmed, M., Ferrucci, Veronica, Salpietro, V., Asadzadeh, F., Carotenuto, Marianeve, Maroofian, R., Al Amri, A., Singh, R., Scognamiglio, I., Mojarrad, M., Musella, L., Duilio, Angela, Di Somma, Angela, Karaca, E., Rajab, A., Al Khayat, A., Mohapatra, T. M., Eslahi, A., Ashrafzadeh, F., Rawlins, L. E., Prasad, R., Gupta, R., Kumari, P., Srivastava, M, Cozzolino, Flora, Rai, S. K., Monti, Maria, Harlalka, G. V., Simpson, M. A., Rich, P., Al Salmi, F., Patton, M. A., Chioza, B. A., Efthymiou, S., Granata, F., Di Rosa, G., Wiethoff, S., Borgione, E., Scuderi, C., Mankad, K., Hanna, M. G., Pucci, Pietro, Houlden, H., Lupski, J. R., Crosby, A. H., and Baple, E. L.
Subjects: Male, Adolescent, Developmental delay, Developmental Disabilities, Nervous System, Microtubules, Normal brain development, Young Adult, Cell Movement, Recessive, Humans, microcephaly, Child, Preschool, Cytoskeleton, Cerebral Cortex, normal brain development, fungi, Brain, Infant, Cell Differentiation, Original Articles, Microtubule polymerization, PRUNE1, developmental delay, microcephaly, microtubule polymerization, tubulinopathy, normal brain development, Microcephaly, PRUNE1, Tubulinopathy, Carrier Proteins, Child, Preschool, Female, Genes, Recessive, Heredodegenerative Disorders, Nervous System, Mutation, Pedigree, microtubule polymerization, tubulinopathy, developmental delay, Genes, nervous system, Heredodegenerative Disorders
Abstract: Zollo et al. report that mutations in PRUNE1, a phosphoesterase superfamily molecule, underlie primary microcephaly and profound global developmental delay in four unrelated families from Oman, India, Iran and Italy. The study highlights a potential role for prune during microtubule polymerization, suggesting that prune syndrome may be a tubulinopathy., PRUNE is a member of the DHH (Asp-His-His) phosphoesterase protein superfamily of molecules important for cell motility, and implicated in cancer progression. Here we investigated multiple families from Oman, India, Iran and Italy with individuals affected by a new autosomal recessive neurodevelopmental and degenerative disorder in which the cardinal features include primary microcephaly and profound global developmental delay. Our genetic studies identified biallelic mutations of PRUNE1 as responsible. Our functional assays of disease-associated variant alleles revealed impaired microtubule polymerization, as well as cell migration and proliferation properties, of mutant PRUNE. Additionally, our studies also highlight a potential new role for PRUNE during microtubule polymerization, which is essential for the cytoskeletal rearrangements that occur during cellular division and proliferation. Together these studies define PRUNE as a molecule fundamental for normal human cortical development and define cellular and clinical consequences associated with PRUNE mutation.
Published: 2017

35. Genotype-phenotype correlations, dystonia and disease progression in spinocerebellar ataxia type 14

Author: Chelban, V, Wiethoff, S, Fabian-Jessing, B, Haridy, N, Khan, A, Efthymiou, S, Becker, E, O'Connor, E, Hersheson, J, Newland, K, Hojland, A, Gregersen, P, Lindquist, S, Petersen, M, Nielsen, J, Nielsen, M, Wood, N, Giunti, P, and Houlden, H
Subjects: Adult, Male, congenital, hereditary, and neonatal diseases and abnormalities, Mutation, Missense, Cohort Studies, Young Adult, Humans, Spinocerebellar Ataxias, genetics, Cysteine, Genetic Testing, Age of Onset, Research Articles, Genetic Association Studies, Protein Kinase C, Aged, Family Health, ataxia, Middle Aged, Magnetic Resonance Imaging, Dystonia, Phenotype, SCA14, Child, Preschool, Disease Progression, Female, dystonia, Peptides, Research Article, PRKCG
Abstract: BACKGROUND: Spinocerebellar ataxia type 14 is a rare form of autosomal dominant cerebellar ataxia caused by mutations in protein kinase Cγ gene. Clinically, it presents with a slowly progressive, mainly pure cerebellar ataxia.METHODS: Using next generation sequencing, we screened 194 families with autosomal dominant cerebellar ataxia and normal polyglutamine repeats. In-depth phenotyping was performed using validated clinical rating scales neuroimaging and electrophysiological investigations.RESULTS: We identified 25 individuals from 13 families carrying pathogenic mutations in protein kinase Cγ gene. A total of 10 unique protein kinase Cγ gene mutations have been confirmed of which 5 are novel and 5 were previously described. Our data suggest that the age at onset is highly variable; disease course is slowly progressive and rarely associated with severe disability. However, one third of patients presented with a complex ataxia comprising severe focal and/or task-induced dystonia, peripheral neuropathy, parkinsonism, myoclonus, and pyramidal syndrome. The most complex phenotype is related to a missense mutation in the catalytic domain in exon 11.CONCLUSION: We present one of the largest genetically confirmed spinocerebellar ataxia type 14 cohorts contributing novel variants and clinical characterisation. We show that although protein kinase Cγ gene mutations present mainly as slowly progressive pure ataxia, more than a third of cases had a complex phenotype. Overall, our case series extends the phenotype and suggests that protein kinase Cγ gene mutations should be considered in patients with slowly progressive autosomal dominant cerebellar ataxia, particularly when myoclonus, dystonia, or mild cognitive impairment are present in the absence of polyglutamine expansion. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
Published: 2018

36. Genetic and phenotypic characterization of NKX6‐2 ‐related spastic ataxia and hypomyelination

Author: Chelban, V., primary, Alsagob, M., additional, Kloth, K., additional, Chirita‐Emandi, A., additional, Vandrovcova, J., additional, Maroofian, R., additional, Davagnanam, I., additional, Bakhtiari, S., additional, AlSayed, M. D., additional, Rahbeeni, Z., additional, AlZaidan, H., additional, Malintan, N. T., additional, Johannsen, J., additional, Efthymiou, S., additional, Ghayoor Karimiani, E., additional, Mankad, K., additional, Al‐Shahrani, S. A., additional, Beiraghi Toosi, M., additional, AlShammari, M., additional, Groppa, S., additional, Haridy, N. A., additional, AlQuait, L., additional, Qari, A., additional, Huma, R., additional, Salih, M. A., additional, Almass, R., additional, Almutairi, F. B., additional, Hamad, M. H., additional, Alorainy, I. A., additional, Ramzan, K., additional, Imtiaz, F., additional, Puiu, M., additional, Kruer, M. C., additional, Bierhals, T., additional, Wood, N. W., additional, Colak, D., additional, Houlden, H., additional, and Kaya, N., additional
Published: 2019
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37. A homozygous loss-of-function mutation in PDE2A associated to early-onset hereditary chorea

Author: Salpietro V, Pérez-Dueñas B, Nakashima K, San Antonio-Arce V, Manole A, Efthymiou S, Vandrovcova J, Bettencourt C, Mencacci NE, Klein C, Kelly MP, Davies CH, Kimura H, Macaya A, and Houlden H
Subjects: Cyclic Nucleotide Phosphodiesterases, Male, striatum, PDE2A, Messenger, chorea, movement disorders, phosphodiesterase, Animals, Chorea, Cyclic AMP, Cyclic GMP, Cyclic Nucleotide Phosphodiesterases, Type 2, Family Health, Genetic Testing, Humans, Mutation, Phosphoric Diester Hydrolases, RNA, Messenger, Brief Report, RNA, Brief Reports, Type 2
Abstract: BACKGROUND: We investigated a family that presented with an infantile-onset chorea-predominant movement disorder, negative for NKX2-1, ADCY5, and PDE10A mutations. METHODS: Phenotypic characterization and trio whole-exome sequencing was carried out in the family. RESULTS: We identified a homozygous mutation affecting the GAF-B domain of the 3',5'-cyclic nucleotide phosphodiesterase PDE2A gene (c.1439A>G; p.Asp480Gly) as the candidate novel genetic cause of chorea in the proband. PDE2A hydrolyzes cyclic adenosine/guanosine monophosphate and is highly expressed in striatal medium spiny neurons. We functionally characterized the p.Asp480Gly mutation and found that it severely decreases the enzymatic activity of PDE2A. In addition, we showed equivalent expression in human and mouse striatum of PDE2A and its homolog gene, PDE10A. CONCLUSIONS: We identified a loss-of-function homozygous mutation in PDE2A associated to early-onset chorea. Our findings possibly strengthen the role of cyclic adenosine monophosphate and cyclic guanosine monophosphate metabolism in striatal medium spiny neurons as a crucial pathophysiological mechanism in hyperkinetic movement disorders. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
Published: 2017

38. Homozygous mutations in VAMP1 cause a presynaptic congenital myasthenic syndrome

Author: Salpietro, V., Lin, W., Vedove, A. D., Storbeck, M., Liu, Y., Efthymiou, S., Manole, A., Wiethoff, S., Ye, Q., Saggar, A., Mcelreavey, K., Krishnakumar, S. S., Pitt, M., Bello, O. D., Rothman, J. E., Basel-Vanagaite, L., Hubshman, M. W., Aharoni, S., Manzur, A. Y., Wirth, B., and Houlden, H.
Published: 2017

39. Genetic and phenotypic characterization of NKX6‐2‐related spastic ataxia and hypomyelination.

Author: Chelban, V., Alsagob, M., Kloth, K., Chirita‐Emandi, A., Vandrovcova, J., Maroofian, R., Davagnanam, I., Bakhtiari, S., AlSayed, M. D., Rahbeeni, Z., AlZaidan, H., Malintan, N. T., Johannsen, J., Efthymiou, S., Ghayoor Karimiani, E., Mankad, K., Al‐Shahrani, S. A., Beiraghi Toosi, M., AlShammari, M., and Groppa, S.
Subjects: LEUKODYSTROPHY, ATAXIA, GENETIC disorders, CEREBELLAR ataxia, SEIZURES (Medicine), RECESSIVE genes, HOMOZYGOSITY
Abstract: Background and purpose: Hypomyelinating leukodystrophies are a heterogeneous group of genetic disorders with a wide spectrum of phenotypes and a high rate of genetically unsolved cases. Bi‐allelic mutations in NKX6‐2 were recently linked to spastic ataxia 8 with hypomyelinating leukodystrophy. Methods: Using a combination of homozygosity mapping, exome sequencing, and detailed clinical and neuroimaging assessment a series of new NKX6‐2 mutations in a multicentre setting is described. Then, all reported NKX6‐2 mutations and those identified in this study were combined and an in‐depth analysis of NKX6‐2‐related disease spectrum was provided. Results: Eleven new cases from eight families of different ethnic backgrounds carrying compound heterozygous and homozygous pathogenic variants in NKX6‐2 were identified, evidencing a high NKX6‐2 mutation burden in the hypomyelinating leukodystrophy disease spectrum. Our data reveal a phenotype spectrum with neonatal onset, global psychomotor delay and worse prognosis at the severe end and a childhood onset with mainly motor phenotype at the milder end. The phenotypic and neuroimaging expression in NKX6‐2 is described and it is shown that phenotypes with epilepsy in the absence of overt hypomyelination and diffuse hypomyelination without seizures can occur. Conclusions: NKX6‐2 mutations should be considered in patients with autosomal recessive, very early onset of nystagmus, cerebellar ataxia with hypotonia that rapidly progresses to spasticity, particularly when associated with neuroimaging signs of hypomyelination. Therefore, it is recommended that NXK6‐2 should be included in hypomyelinating leukodystrophy and spastic ataxia diagnostic panels. [ABSTRACT FROM AUTHOR]
Published: 2020
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40. Clinical and Genetic analysis of Egyptian hereditary spastic paraplegia using next generation sequencing

Author: Haridy, N.A., primary, Chelban, V., additional, Vandrovcova, J., additional, Efthymiou, S., additional, Abd El-Hamed, M.A., additional, Hamed, S.A., additional, and Houlden, H., additional
Published: 2018
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41. Genetic investigation of inherited neuropathy in families from Middle East using next generation sequencing

Author: Khan, A.M., primary, Sultan, T., additional, Kriouile, Y., additional, Pipis, M., additional, Vandrovcova, J., additional, Tariq, H., additional, Efthymiou, S., additional, Salpietro, V., additional, Reilly, M.M., additional, and Houlden, H., additional
Published: 2018
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42. Pulsed performance of pyroelectric detectors

Author: Efthymiou, S, primary and Ozanyan, K B, additional
Published: 2009
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43. Advanced simulator of pyroelectric detector circuits and associated signal processing.

Author: Efthymiou, S. and Ozanyan, K.B.
Published: 2011
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44. Sensing of pulsed radiation with Pyroelectric Detectors.

Author: Efthymiou, S. and Ozanyan, K.B.
Published: 2010
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45. 630P Genetic diversity and clinical implications of facioscapulohumeral muscular dystrophy in the Indian population.

Author: Lemmers, R., Venugopalan, Y.V., van der Vliet, P., Reyaz, A., Mishra, R., Ahmad, T., Kretkiewicz, M., Macken, W., Efthymiou, S., Bhatia, R., Dominik, N., Houlden, H., Morrow, J., Wilson, L., Hanna, M., Bugiardini, E., van der Maarel, S., and Srivastava, M. Padma
Subjects: *ASIANS, *NEUROMUSCULAR diseases, *GENETIC testing, *GENETIC variation, *MIDDLE-income countries, *FACIOSCAPULOHUMERAL muscular dystrophy
Abstract: Facioscapulohumeral muscular dystrophy type 1 (FSHD1) is one of the most prevalent hereditary myopathies caused by D4Z4 repeat contraction. Its etiology involves derepression of the DUX4 gene within the D4Z4 repeat in skeletal muscle, with disease severity inversely correlating with D4Z4 repeat size. The genetic mechanism of FSHD is mainly studied in patients with a European or Northeast (NE) Asian background. These studies showed a difference in the FSHD1 allele repeat size distribution, ranging from 1-10 units in European to 1-7 units in NE Asian patients, suggesting that the likelihood of developing FSHD may vary between ethnic populations. Despite this difference, the global threshold for FSHD1 for genetic counsellors is still 1-10 units and the patient's genetic background is generally not taken into account. Until now, the diagnosis of FSHD in India, with over 1.4 billion people one of the biggest populations in the world, is based predominantly on clinical diagnosis only. Here, we present the first genetically confirmed FSHD cohort of Indian ancestry collected via the International Centre for Genomic Medicine in neuromuscular diseases consortium. The ICGNMD aims to perform clinical and genetic testing for neuromuscular diseases patients in low and middle-income countries such as India. Our study revealed 54/91 (59%) probands with FSHD1 suggesting a pathogenic FSHD1 allele size distribution intermediate between European and NE Asian populations. We also identified five FSHD2 patients with mutations in SMCHD1. The possible reduced penetrance of FSHD1 in NE Asian individuals is strengthened by the substantial proportion of asymptomatic carriers with a rather short FSHD1 allele in India. Our data provides important evidence of differences relevant to clinical diagnostics and reconsideration of FSHD1 repeat size thresholds. It also underscores the need for global FSHD participation in research and the establishment of trial-ready Indian FSHD cohorts. [ABSTRACT FROM AUTHOR]
Published: 2024
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46. Mutations in the Neuronal Vesicular SNARE VAMP2 Affect Synaptic Membrane Fusion and Impair Human Neurodevelopment

Author: Salpietro, Vincenzo, Malintan, Nancy T, Llano-Rivas, Isabel, Spaeth, Christine G, Efthymiou, Stephanie, Striano, Pasquale, Vandrovcova, Jana, Cutrupi, Maria C, Chimenz, Roberto, David, Emanuele, Di Rosa, Gabriella, Marce-Grau, Anna, Raspall-Chaure, Miquel, Martin-Hernandez, Elena, Zara, Federico, Minetti, Carlo, Bello, Oscar D, De Zorzi, Rita, Fortuna, Sara, Dauber, Andrew, Alkhawaja, Mariam, Sultan, Tipu, Mankad, Kshitij, Vitobello, Antonio, Thomas, Quentin, Mau-Them, Frederic Tran, Faivre, Laurence, Martinez-Azorin, Francisco, Prada, Carlos E, Macaya, Alfons, Kullmann, Dimitri M, Rothman, James E, Krishnakumar, Shyam S, Houlden, Henry, Kriouile, Yamna, El Khorassani, Mohamed, Aguennouz, Mhammed, Karashova, Blagovesta, Avdjieva, Daniela, Kathom, Hadil, Tincheva, Radka, Van Maldergem, Lionel, Nachbauer, Wolfgang, Boesch, Sylvia, Arning, Larissa, Timmann, Dagmar, Cormand, Bru, Pérez-Dueñas, Belen, Pironti, Erica, Goraya, Jatinder S, Kirmani, Salman, Ibrahim, Shahnaz, Jan, Farida, Mine, Jun, Banu, Selina, Veggiotti, Pierangelo, Ferrari, Michel D, Verrotti, Alberto, Marseglia, Gian Luigi, Savasta, Salvatore, Garavaglia, Barbara, Scuderi, Carmela, Borgione, Eugenia, Dipasquale, Valeria, Cutrupi, Maria Concetta, Portaro, Simona, Sanchez, Benigno Monteagudo, Pineda-Marfa’, Mercedes, Munell, Francina, Boles, Richard, Heimer, Gali, Papacostas, Savvas, Manole, Andreea, Malintan, Nancy, Zanetti, Maria Natalia, Hanna, Michael G, Houlden, Henry., Salpietro, V., Malintan, N. T., Llano-Rivas, I., Spaeth, C. G., Efthymiou, S., Striano, P., Vandrovcova, J., Cutrupi, M. C., Chimenz, R., David, E., Di Rosa, G., Marce-Grau, A., Raspall-Chaure, M., Martin-Hernandez, E., Zara, F., Minetti, C., Kriouile, Y., El Khorassani, M., Aguennouz, M., Karashova, B., Avdjieva, D., Kathom, H., Tincheva, R., Van Maldergem, L., Nachbauer, W., Boesch, S., Arning, L., Timmann, D., Cormand, B., Perez-Duenas, B., Pironti, E., Goraya, J. S., Sultan, T., Kirmani, S., Ibrahim, S., Jan, F., Mine, J., Banu, S., Veggiotti, P., Ferrari, M. D., Verrotti, A., Marseglia, G. L., Savasta, S., Garavaglia, B., Scuderi, C., Borgione, E., Dipasquale, V., Portaro, S., Sanchez, B. M., Pineda-Marfa, M., Munell, F., Macaya, A., Boles, R., Heimer, G., Papacostas, S., Manole, A., Malintan, N., Zanetti, M. N., Hanna, M. G., Rothman, J. E., Kullmann, D. M., Houlden, H., Bello, O. D., De Zorzi, R., Fortuna, S., Dauber, A., Alkhawaja, M., Mankad, K., Vitobello, A., Thomas, Q., Mau-Them, F. T., Faivre, L., Martinez-Azorin, F., Prada, C. E., and Krishnakumar, S. S.
Subjects: Male, Heterozygote, Adolescent, Vesicle-Associated Membrane Protein 2, neuronal exocytosi, synaptopathy, autism, synaptobrevin, Membrane Fusion, Exocytosis, R-SNARE Proteins, Protein Domains, Report, Intellectual Disability, Genetics, Humans, Autistic Disorder, Child, Genetics (clinical), Neurons, Neurotransmitter Agents, neurodevelopmental disorders, vesicle fusion, Brain, epilepsy, movement disorders, neuronal exocytosis, SNARE, VAMP2, Lipids, Magnetic Resonance Imaging, neurodevelopmental disorder, autism, epilepsy, movement disorders, neurodevelopmental disorders, neuronal exocytosis, SNARE, synaptobrevin, synaptopathy, VAMP2, vesicle fusion, Genetics, Genetics (clinical), Phenotype, Child, Preschool, Mutation, Synapses, Muscle Hypotonia, Female, sense organs, movement disorder
Abstract: VAMP2 encodes the vesicular SNARE protein VAMP2 (also called synaptobrevin-2). Together with its partners syntaxin-1A and synaptosomal-associated protein 25 (SNAP25), VAMP2 mediates fusion of synaptic vesicles to release neurotransmitters. VAMP2 is essential for vesicular exocytosis and activity-dependent neurotransmitter release. Here, we report five heterozygous de novo mutations in VAMP2 in unrelated individuals presenting with a neurodevelopmental disorder characterized by axial hypotonia (which had been present since birth), intellectual disability, and autistic features. In total, we identified two single-amino-acid deletions and three non-synonymous variants affecting conserved residues within the C terminus of the VAMP2 SNARE motif. Affected individuals carrying de novo non-synonymous variants involving the C-terminal region presented a more severe phenotype with additional neurological features, including central visual impairment, hyperkinetic movement disorder, and epilepsy or electroencephalography abnormalities. Reconstituted fusion involving a lipid-mixing assay indicated impairment in vesicle fusion as one of the possible associated disease mechanisms. The genetic synaptopathy caused by VAMP2 de novo mutations highlights the key roles of this gene in human brain development and function.
Published: 2019

47. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Author: Vincenzo Salpietro1, 2 3, 140, Christine L. Dixon4, Hui Guo5, 6 140, Oscar D. Bello Stephanie Efthymiou 1, 4, Reza Maroofian1, Gali Heimer7, Lydie Burglen 8, Stephanie Valence 9, Erin Torti 10, Moritz Hacke11, Julia Rankin12, Huma Tariq1, Estelle Colin13, Vincent Procaccio13, Pasquale Striano2, 3, Kshitij Mankad15, Andreas Lieb 4, Sharon Chen16, Laura Pisani16, Conceicao Bettencourt 17, Roope Männikkö 1, Andreea Manole1, Alfredo Brusco 18, Enrico Grosso18, Giovanni Battista Ferrero19, Judith Armstrong-Moron20, Sophie Gueden21, Omer Bar-Yosef7, Michal Tzadok7, Kristin G. Monaghan10, Teresa Santiago-Sim10, Richard E. Person10, Megan T. Cho10, Rebecca Willaert10, Yongjin Yoo22, Jong-Hee Chae23, Yingting Quan6, Huidan Wu6, Tianyun Wang5, 6, Raphael A. Bernier24, Kun Xia6, Alyssa Blesson25, Mahim Jain25, Mohammad M. Motazacker26, Bregje Jaeger27, Amy L. Schneider 28, Katja Boysen28, Alison M. Muir 29, Candace T. Myers30, Ralitza H. Gavrilova31, Lauren Gunderson31, Laura Schultz-Rogers 31, Eric W. Klee31, David Dyment32, Matthew Osmond32, 33 34, Mara Parellada35, Cloe Llorente36, Javier Gonzalez-Peñas37, Angel Carracedo38, Arie Van Haeringen40, Claudia Ruivenkamp40, Caroline Nava41, Delphine Heron41, Rosaria Nardello42, Michele Iacomino43, Carlo Minetti2, Aldo Skabar44, Antonella Fabretto44, SYNAPS Study GroupMiquel Raspall-Chaure45, Michael Chez46, Anne Tsai47, Emily Fassi48, Marwan Shinawi48, John N. Constantino49, Rita De Zorzi50, Sara Fortuna 50, Fernando Kok51, Boris Keren41, Dominique Bonneau13, Murim Choi 22, Bruria Benzeev7, Federico Zara43, Heather C. Mefford29, Ingrid E. Scheffer28, Jill Clayton-Smith53, Alfons Macaya45, James E. Rothman4, Evan E. Eichler 5, Dimitri M. Kullmann 4, Henry Houlden 1, SYNAPS Study Group Michael G. Hanna1, Enrico Bugiardini1, Isabel Hostettler1, Benjamin O’Callaghan1, Alaa Khan1, Andrea Cortese1, Emer O’Connor1, Wai Y. Yau1, Thomas Bourinaris1, Rauan Kaiyrzhanov1, Viorica Chelban1, Monika Madej1, Maria C. Diana2, Maria S. Vari2, Marina Pedemonte2, Claudio Bruno2, Ganna Balagura3, Marcello Scala3, Chiara Fiorillo3, Lino Nobili3, Nancy T. Malintan4, Maria N. Zanetti4, Shyam S. Krishnakumar4, Gabriele Lignani4, James E. C. Jepson4, Paolo Broda43, Simona Baldassari43, Pia Rossi43, Floriana Fruscione43, Francesca Madia43, Monica Traverso43, Patrizia De-Marco43, Belen Pérez-Dueñas45, Francina Munell45, Yamna Kriouile57, Mohamed El-Khorassani57, Blagovesta Karashova58, Daniela Avdjieva58, Hadil Kathom58, Radka Tincheva58, Lionel Van-Maldergem59, Wolfgang Nachbauer60, Sylvia Boesch60, Antonella Gagliano61, Elisabetta Amadori62, Jatinder S. Goraya63, Tipu Sultan64, Salman Kirmani65, Shahnaz Ibrahim66, Farida Jan66, Jun Mine67, Selina Banu68, Pierangelo Veggiotti69, Gian V. Zuccotti69, Michel D. Ferrari70, Arn M. J. Van Den Maagdenberg70, Alberto Verrotti71, Gian L. Marseglia72, Salvatore Savasta72, Miguel A. Soler73, Carmela Scuderi74, Eugenia Borgione74, Roberto Chimenz75, Eloisa Gitto75, Valeria Dipasquale75, Alessia Sallemi75, Monica Fusco75, Caterina Cuppari75, Maria C. Cutrupi75, Martino Ruggieri76, Armando Cama77, Valeria Capra77, Niccolò E. Mencacci78, Richard Boles79, Neerja Gupta80, Madhulika Kabra80, Savvas Papacostas81, Eleni Zamba-Papanicolaou81, Efthymios Dardiotis82, Shazia Maqbool83, Nuzhat Rana84, Osama Atawneh85, Shen Y. Lim86, Farooq Shaikh87, George Koutsis88, Marianthi Breza88, Domenico A. Coviello89, Yves A. Dauvilliers90, Issam AlKhawaja91, Mariam AlKhawaja92, Fuad Al-Mutairi93, Tanya Stojkovic94, Veronica Ferrucci, Massimo Zollo, Fowzan S. Alkuraya96, Maria Kinali97, Hamed Sherifa98, Hanene Benrhouma99, Ilhem B. Y. Turki99, Meriem Tazir100, Makram Obeid101, Sophia Bakhtadze102, Nebal W. Saadi103, Maha S. Zaki104, Chahnez C. Triki105, Fabio Benfenati106, Stefano Gustincich106, Majdi Kara107, Vincenzo Belcastro108, Nicola Specchio109, Giuseppe Capovilla110, Ehsan G. Karimiani111, Ahmed M. Salih112, Njideka U. Okubadejo113, Oluwadamilola O. Ojo113, Olajumoke O. Oshinaike113, Olapeju Oguntunde113, Kolawole Wahab114, Abiodun H. Bello114, Sanni Abubakar115, Yahaya Obiabo116, Ernest Nwazor117, Oluchi Ekenze118, Uduak Williams119, Alagoma Iyagba120, Lolade Taiwo121, Morenikeji Komolafe122, Konstantin Senkevich123, Chingiz Shashkin124, Nazira Zharkynbekova125, Kairgali Koneyev126, Ganieva Manizha127, Maksud Isrofilov127, Ulviyya Guliyeva128, Kamran Salayev129, Samson Khachatryan130, Salvatore Rossi131, Gabriella Silvestri131, Nourelhoda Haridy132, Luca A. Ramenghi133, Georgia Xiromerisiou134, Emanuele David135, Mhammed Aguennouz136, Liana Fidani137, Cleanthe Spanaki138, Arianna Tucci139, University College of London [London] (UCL), Instituto Giannina Gaslini, Genoa, University of Genoa (UNIGE), University of Washington [Seattle], Institute of Neurology, Queen Square, London, King‘s College London, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, Molecular and Clinical Sciences Institute - St George’s [London, UK] (Genetics Research Centre), University of London [London], Tel Aviv University Sackler School of Medicine [Tel Aviv, Israël], Service de génétique et embryologie médicales [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Neuropédiatrie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), GeneDx [Gaithersburg, MD, USA], Heidelberg University Hospital [Heidelberg], Royal Devon and Exeter NHS Foundation Trust [UK], Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Universita degli studi di Genova, Great Ormond Street Hospital for Children [London] (GOSH), The University of Sydney, Hofstra University [Hempstead], Università degli studi di Torino (UNITO), Hospital Sant Joan de Déu [Barcelona], Safra Children's Hospital, Seoul National University Hospital, Central South University [Changsha], Kennedy Krieger Institute [Baltimore], University of Amsterdam [Amsterdam] (UvA), University of Melbourne, Mayo Clinic [Rochester], Department of Health Sciences Research [Mayo Clinic] (HSR), Mayo Clinic, University of Ottawa [Ottawa], University of British Columbia (UBC), Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Universidade de Santiago de Compostela [Spain] (USC ), Universiteit Leiden [Leiden], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli studi di Palermo - University of Palermo, University of Trieste, Universitat Autònoma de Barcelona (UAB), Department of Neurology and Center for Neuroscience, University of California at Davis, Sacramento, University of California [Davis] (UC Davis), University of California-University of California, Children’s Hospital Colorado, University of Colorado Anschutz [Aurora], Washington University in Saint Louis (WUSTL), Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, Department of Psychiatry, Laboratory of Molecular Biophysics, Department of Biochemistry, University of Oxford, University of Oxford [Oxford], University of São Paulo (USP), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Service de Pédiatrie, CHUR Poitiers, Seoul National University [Seoul] (SNU), Pediatric Neurology and Neuromuscular Diseases Unit, University of Manchester [Manchester], Yale University School of Medicine, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Salvy-Córdoba, Nathalie, Università degli studi di Genova = University of Genoa (UniGe), Tel Aviv University (TAU), Università degli studi di Torino = University of Turin (UNITO), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Università degli studi di Trieste = University of Trieste, University of California (UC)-University of California (UC), University of Oxford, Universidade de São Paulo = University of São Paulo (USP), Yale School of Medicine [New Haven, Connecticut] (YSM), Salpietro V, Dixon CL, Guo H, Bello OD, 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 GB, Armstrong-Moron J, Gueden S, Bar-Yosef O, Tzadok M, Monaghan KG, Santiago-Sim T, Person RE, Cho MT, Willaert R, Yoo Y, Chae JH, Quan Y, Wu H, Wang T, Bernier RA, Xia K, Blesson A, Jain M, Motazacker MM, Jaeger B, Schneider AL, Boysen K, Muir AM, Myers CT, Gavrilova RH, Gunderson L, Schultz-Rogers L, Klee EW, 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, SYNAPS Study Group, Raspall-Chaure M, Chez M, Tsai A, Fassi E, Shinawi M, Constantino JN, De Zorzi R, Fortuna S, Kok F, Keren B, Bonneau D, Choi M, Benzeev B, Zara F, Mefford HC, Scheffer IE, Clayton-Smith J, Macaya A, Rothman JE, Eichler EE, Kullmann DM, Houlden H, Salpietro, Vincenzo, Dixon, Christine L, Guo, Hui, Bello, Oscar D, Vandrovcova, Jana, Efthymiou, Stephanie, Maroofian, Reza, Heimer, Gali, Burglen, Lydie, Valence, Stephanie, Torti, Erin, Hacke, Moritz, Rankin, Julia, Tariq, Huma, Colin, Estelle, Procaccio, Vincent, Striano, Pasquale, Mankad, Kshitij, Lieb, Andrea, Chen, Sharon, Pisani, Laura, Bettencourt, Conceicao, Männikkö, Roope, Manole, Andreea, Brusco, Alfredo, Grosso, Enrico, Ferrero, Giovanni Battista, Armstrong-Moron, Judith, Gueden, Sophie, Bar-Yosef, Omer, Tzadok, Michal, Monaghan, Kristin G, Santiago-Sim, Teresa, Person, Richard E, Cho, Megan T, Willaert, Rebecca, Yoo, Yongjin, Chae, Jong-Hee, Quan, Yingting, Wu, Huidan, Wang, Tianyun, Bernier, Raphael A, Xia, Kun, Blesson, Alyssa, Jain, Mahim, Motazacker, Mohammad M, Jaeger, Bregje, Schneider, Amy L, Boysen, Katja, Muir, Alison M, Myers, Candace T, Gavrilova, Ralitza H, Gunderson, Lauren, Schultz-Rogers, Laura, Klee, Eric W, Dyment, David, Osmond, Matthew, Parellada, Mara, Llorente, Cloe, Gonzalez-Peñas, Javier, Carracedo, Angel, Van Haeringen, Arie, Ruivenkamp, Claudia, Nava, Caroline, Heron, Delphine, Nardello, Rosaria, Iacomino, Michele, Minetti, Carlo, Skabar, Aldo, Fabretto, Antonella, Raspall-Chaure, Miquel, Chez, Michael, Tsai, Anne, Fassi, Emily, Shinawi, Marwan, Constantino, John N, De Zorzi, Rita, Fortuna, Sara, Kok, Fernando, Keren, Bori, Bonneau, Dominique, Choi, Murim, Benzeev, Bruria, Zara, Federico, Mefford, Heather C, Scheffer, Ingrid E, Clayton-Smith, Jill, Macaya, Alfon, Rothman, James E, Eichler, Evan E, Kullmann, Dimitri M, Houlden, Henry, Salpietro1, Vincenzo, 3, 2, Dixon4, Christine L., Guo5, Hui, 140, 6, Bello Stephanie Efthymiou 1, Oscar D., Maroofian1, Reza, Heimer7, Gali, 8, Lydie Burglen, 9, Stephanie Valence, Torti 10, Erin, Hacke11, Moritz, Rankin12, Julia, Tariq1, Huma, Colin13, Estelle, Procaccio13, Vincent, Striano2, Pasquale, Mankad15, Kshitij, 4, Andreas Lieb, Chen16, Sharon, Pisani16, Laura, Bettencourt 17, Conceicao, 1, Roope Männikkö, Manole1, Andreea, Brusco 18, Alfredo, Grosso18, Enrico, Battista Ferrero19, Giovanni, Armstrong-Moron20, Judith, Gueden21, Sophie, Bar-Yosef7, Omer, Tzadok7, Michal, Monaghan10, Kristin G., Santiago-Sim10, Teresa, Person10, Richard E., Cho10, Megan T., Willaert10, Rebecca, Yoo22, Yongjin, Chae23, Jong-Hee, Quan6, Yingting, Wu6, Huidan, Wang5, Tianyun, Bernier24, Raphael A., Xia6, Kun, Blesson25, Alyssa, Jain25, Mahim, Motazacker26, Mohammad M., Jaeger27, Bregje, Schneider 28, Amy L., Boysen28, Katja, Muir 29, Alison M., Myers30, Candace T., Gavrilova31, Ralitza H., Gunderson31, Lauren, Schultz-Rogers 31, Laura, Klee31, Eric W., Dyment32, David, Osmond32, Matthew, 34, 33, Parellada35, Mara, Llorente36, Cloe, Gonzalez-Peñas37, Javier, Carracedo38, Angel, Van Haeringen40, Arie, Ruivenkamp40, Claudia, Nava41, Caroline, Heron41, Delphine, Nardello42, Rosaria, Iacomino43, Michele, Minetti2, Carlo, Skabar44, Aldo, Fabretto44, Antonella, Study GroupMiquel Raspall-Chaure45, Synap, Chez46, Michael, Tsai47, Anne, Fassi48, Emily, Shinawi48, Marwan, Constantino49, John N., De Zorzi50, Rita, Fortuna 50, Sara, Kok51, Fernando, Keren41, Bori, Bonneau13, Dominique, Choi 22, Murim, Benzeev7, Bruria, Zara43, Federico, Mefford29, Heather C., Scheffer28, Ingrid E., Clayton-Smith53, Jill, Macaya45, Alfon, Rothman4, James E., Eichler 5, Evan E., Kullmann 4 &amp, Dimitri M., 1, Henry Houlden, Hanna1, SYNAPS Study Group Michael G., Bugiardini1, Enrico, Hostettler1, Isabel, O’Callaghan1, Benjamin, Khan1, Alaa, Cortese1, Andrea, O’Connor1, Emer, Yau1, Wai Y., Bourinaris1, Thoma, Kaiyrzhanov1, Rauan, Chelban1, Viorica, Madej1, Monika, Diana2, Maria C., Vari2, Maria S., Pedemonte2, Marina, Bruno2, Claudio, Balagura3, Ganna, Scala3, Marcello, Fiorillo3, Chiara, Nobili3, Lino, Malintan4, Nancy T., Zanetti4, Maria N., Krishnakumar4, Shyam S., Lignani4, Gabriele, Jepson4, James E. C., Broda43, Paolo, Baldassari43, Simona, Rossi43, Pia, Fruscione43, Floriana, Madia43, Francesca, Traverso43, Monica, De-Marco43, Patrizia, Pérez-Dueñas45, Belen, Munell45, Francina, Kriouile57, Yamna, El-Khorassani57, Mohamed, Karashova58, Blagovesta, Avdjieva58, Daniela, Kathom58, Hadil, Tincheva58, Radka, Van-Maldergem59, Lionel, Nachbauer60, Wolfgang, Boesch60, Sylvia, Gagliano61, Antonella, Amadori62, Elisabetta, Goraya63, Jatinder S., Sultan64, Tipu, Kirmani65, Salman, Ibrahim66, Shahnaz, Jan66, Farida, Mine67, Jun, Banu68, Selina, Veggiotti69, Pierangelo, Zuccotti69, Gian V., Ferrari70, Michel D., Van Den Maagdenberg70, Arn M. J., Verrotti71, Alberto, Marseglia72, Gian L., Savasta72, Salvatore, Soler73, Miguel A., Scuderi74, Carmela, Borgione74, Eugenia, Chimenz75, Roberto, Gitto75, Eloisa, Dipasquale75, Valeria, Sallemi75, Alessia, Fusco75, Monica, Cuppari75, Caterina, Cutrupi75, Maria C., Ruggieri76, Martino, Cama77, Armando, Capra77, Valeria, Mencacci78, Niccolò E., Boles79, Richard, Gupta80, Neerja, Kabra80, Madhulika, Papacostas81, Savva, Zamba-Papanicolaou81, Eleni, Dardiotis82, Efthymio, Maqbool83, Shazia, Rana84, Nuzhat, Atawneh85, Osama, Lim86, Shen Y., Shaikh87, Farooq, Koutsis88, George, Breza88, Marianthi, Coviello89, Domenico A., Dauvilliers90, Yves A., Alkhawaja91, Issam, Alkhawaja92, Mariam, Al-Mutairi93, Fuad, Stojkovic94, Tanya, Ferrucci, Veronica, Zollo, Massimo, Alkuraya96, Fowzan S., Kinali97, Maria, Sherifa98, Hamed, Benrhouma99, Hanene, Turki99, Ilhem B. Y., Tazir100, Meriem, Obeid101, Makram, Bakhtadze102, Sophia, Saadi103, Nebal W., Zaki104, Maha S., Triki105, Chahnez C., Benfenati106, Fabio, Gustincich106, Stefano, Kara107, Majdi, Belcastro108, Vincenzo, Specchio109, Nicola, Capovilla110, Giuseppe, Karimiani111, Ehsan G., Salih112, Ahmed M., Okubadejo113, Njideka U., Ojo113, Oluwadamilola O., Oshinaike113, Olajumoke O., Oguntunde113, Olapeju, Wahab114, Kolawole, Bello114, Abiodun H., Abubakar115, Sanni, Obiabo116, Yahaya, Nwazor117, Ernest, Ekenze118, Oluchi, Williams119, Uduak, Iyagba120, Alagoma, Taiwo121, Lolade, Komolafe122, Morenikeji, Senkevich123, Konstantin, Shashkin124, Chingiz, Zharkynbekova125, Nazira, Koneyev126, Kairgali, Manizha127, Ganieva, Isrofilov127, Maksud, Guliyeva128, Ulviyya, Salayev129, Kamran, Khachatryan130, Samson, Rossi131, Salvatore, Silvestri131, Gabriella, Haridy132, Nourelhoda, Ramenghi133, Luca A., Xiromerisiou134, Georgia, David135, Emanuele, Aguennouz136, Mhammed, Fidani137, Liana, Spanaki138 &amp, Cleanthe, and Tucci139, Arianna
Subjects: Male, [SDV.GEN] Life Sciences [q-bio]/Genetics, Ion channels in the nervous system, Cohort Studies, fluids and secretions, Loss of Function Mutation, Receptors, AMPA, AMPA receptor, lcsh:Science, Child, reproductive and urinary physiology, AMPA receptor, GluA2, neurodevelopmental disorders, autism spectrum disorder, glutamatergic synaptic transmission, GRIA2, neurodevelopmental disorders, Developmental disorders, Neurodevelopmental disorders, Brain, Magnetic Resonance Imaging, Settore MED/26 - NEUROLOGIA, GluA2, Child, Preschool, Female, Adult, Heterozygote, Adolescent, Science, autism spectrum disorder, Article, Young Adult, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, MESH: Intellectual Disability/genetics, Neurodevelopmental Disorders/genetics, Receptors AMPA/genetics, Intellectual Disability, mental disorders, Humans, Infant, Neurodevelopmental Disorders, Receptors, AMPA, GRIA2, Preschool, Ion channel in the nervous system, Developmental disorders, Synaptic development, NG sequencing, [SDV.GEN]Life Sciences [q-bio]/Genetics, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, glutamatergic synaptic transmission, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, NG sequencing, Synaptic development, Ion channel in the nervous system, Next-generation sequencing, lcsh:Q
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., Genetic variants in ionotropic glutamate receptors have been implicated in neurodevelopmental disorders. Here, the authors report heterozygous de novo mutations in the GRIA2 gene in 28 individuals with intellectual disability and neurodevelopmental abnormalities associated with reduced Ca2+ transport and AMPAR currents.”
Published: 2019

48. The phenotypic and molecular spectrum of PEHO syndrome and PEHO-like disorders

Author: Vincenzo, Salpietro, Massimo, Zollo, Jana, Vandrovcova, Mina, Ryten, Botia, Juan A., Veronica, Ferrucci, Andreea, Manole, Stephanie, Efthymiou, Fuad Al Mutairi, Enrico, Bertini, Marco, Tartaglia, SYNAPS Study Group, Aguennouz, M'Hammed, and Henry Houlden, Salpietro, V, Zollo, M, Vandrovcova, J, Ryten, M, Botia, Ja, Ferrucci, V, Manole, A, Efthymiou, S, Al Mutairi, F, Bertini, E, Tartaglia, M, and SYNAPS Study Group, Houlden H.
Subjects: Humans, Neurodegenerative Diseases, Neurons, Brain Edema, Optic Atrophy, Spasms, Infantile, HYPSARRHYTHMIA, MOUSE-BRAIN, TBCD, PROGRESSIVE ENCEPHALOPATHY, MUTATIONS, EDEMA, Infantile, Spasms, CHILD, Letters to the Editor, PRUNE
Published: 2017

49. PDXK mutations cause polyneuropathy responsive to pyridoxal 5′‐phosphate supplementation

Author: Chelban, Viorica, Wilson, Matthew P., Warman Chardon, Jodi, Vandrovcova, Jana, Zanetti, M. Natalia, Zamba‐Papanicolaou, Eleni, Efthymiou, Stephanie, Pope, Simon, Conte, Maria R., Abis, Giancarlo, Liu, Yo‐Tsen, Tribollet, Eloise, Haridy, Nourelhoda A., Botía, Juan A., Ryten, Mina, Nicolaou, Paschalis, Minaidou, Anna, Christodoulou, Kyproula, Kernohan, Kristin D., Eaton, Alison, Osmond, Matthew, Ito, Yoko, Bourque, Pierre, Jepson, James E. C., Bello, Oscar, Bremner, Fion, Cordivari, Carla, Reilly, Mary M., Foiani, Martha, Heslegrave, Amanda, Zetterberg, Henrik, Heales, Simon J. R., Wood, Nicholas W., Rothman, James E., Boycott, Kym M., Mills, Philippa B., Clayton, Peter T., Houlden, Henry, Kriouile, Yamna, Khorassani, Mohamed El, Aguennouz, Mhammed, Groppa, Stanislav, Marinova Karashova, Blagovesta, Van Maldergem, Lionel, Nachbauer, Wolfgang, Boesch, Sylvia, Arning, Larissa, Timmann, Dagmar, Cormand, Bru, Pérez‐Dueñas, Belen, Di Rosa, Gabriella, Goraya, Jatinder S., Sultan, Tipu, Mine, Jun, Avdjieva, Daniela, Kathom, Hadil, Tincheva, Radka, Banu, Selina, Pineda‐Marfa, Mercedes, Veggiotti, Pierangelo, Ferrari, Michel D., van den Maagdenberg, Arn M J M, Verrotti, Alberto, Marseglia, Giangluigi, Savasta, Salvatore, García‐Silva, Mayte, Ruiz, Alfons Macaya, Garavaglia, Barbara, Borgione, Eugenia, Portaro, Simona, Sanchez, Benigno Monteagudo, Boles, Richard, Papacostas, Savvas, Vikelis, Michail, Rothman, James, Giunti, Paola, Salpietro, Vincenzo, Oconnor, Emer, Kullmann, Dimitri, Kaiyrzhanov, Rauan, Sullivan, Roisin, Khan, Alaa Matooq, Yau, Wai Yan, Hostettler, Isabel, Papanicolaou, Eleni Zamba, Dardiotis, Efthymios, Maqbool, Shazia, Ibrahim, Shahnaz, Kirmani, Salman, Rana, Nuzhat Noureen, Atawneh, Osama, Lim, Shen‐Yang, Shaikh, Farooq, Koutsis, George, Breza, Marianthi, Mangano, Salvatore, Scuderi, Carmela, Morello, Giovanna, Stojkovic, Tanya, Torti, Erin, Zollo, Massimi, Heimer, Gali, Dauvilliers, Yves A., Striano, Pasquale, Al‐Khawaja, Issam, Al‐Mutairi, Fuad, Alkuraya, Fowzan S, Sherifa, Hamed, Rizig, Mie, Okubadejo, Njideka U., Ojo, Oluwadamilola O., Oshinaike, Olajumoke O., Wahab, Kolawole, Bello, Abiodun H., Abubakar, Sanni, Obiabo, Yahaya, Nwazor, Ernest, Ekenze, Oluchi, Williams, Uduak, Iyagba, Alagoma, Taiwo, Lolade, Komolafe, Morenikeji, Oguntunde, Olapeju, Pchelina, Sofya, Senkevich, Konstantin, Haridy, Nourelhoda, Shashkin, Chingiz, Zharkynbekova, Nazira, Koneyev, Kairgali, Manizha, Ganieva, Isrofilov, Maksud, Guliyeva, Ulviyya, Salayev, Kamran, Khachatryan, Samson, Rossi, Salvatore, Silvestri, Gabriella, Bourinaris, Thomas, Xiromerisiou, Georgia, Fidani, Liana, Spanaki, Cleanthe, Tucci, Arianna, University College London Hospitals (UCLH), Université d'Ottawa [Ontario] (uOttawa), King‘s College London, University College of London [London] (UCL), University of Cyprus [Nicosia], UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, Institute of Psychiatry, Psychology & Neuroscience, King's College London, National Yang Ming University (NYMU), Department of Information and Communications Engineering [Murcia], Universidad de Murcia, Guy's Hospital [London], Cyprus Institute of Neurology and Genetics, University of Ottawa [Ottawa], The Ottawa Hospital, University of British Columbia (UBC), Ottawa Hospital Research Institute [Ottawa] (OHRI), Institute of Neurology, Queen Square, London, Sahlgrenska University Hospital, Biochemistry, Endocrinology and Metabolism Unit, Institute of Child Health, Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Department of Human Genetics, Ruhr University Bochum (RUB), Universitat de Barcelona (UB), Department of Medical and Surgical Pediatrics, University Hospital, Fondazione, Departments of Human Genetics & Neurology, Leiden University Medical Center (LUMC), University of Laquila, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Yale University School of Medicine, Department of Microbiology, Università degli studi di Catania [Catania], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Gene Dx, Partenaires INRAE, Tel Aviv University Sackler School of Medicine [Tel Aviv, Israël], Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Universita degli studi di Genova, Fondazione 'Policlinico Universitario A. Gemelli' [Rome], UCL Institute of neurology, UCL Institute of Neurology, Chelban V., Wilson M.P., Warman Chardon J., Vandrovcova J., Zanetti M.N., Zamba-Papanicolaou E., Efthymiou S., Pope S., Conte M.R., Abis G., Liu Y.-T., Tribollet E., Haridy N.A., Botia J.A., Ryten M., Nicolaou P., Minaidou A., Christodoulou K., Kernohan K.D., Eaton A., Osmond M., Ito Y., Bourque P., Jepson J.E.C., Bello O., Bremner F., Cordivari C., Reilly M.M., Foiani M., Heslegrave A., Zetterberg H., Heales S.J.R., Wood N.W., Rothman J.E., Boycott K.M., Mills P.B., Clayton P.T., Houlden H., Kriouile Y., Khorassani M.E., Aguennouz M., Groppa S., Marinova Karashova B., Van Maldergem L., Nachbauer W., Boesch S., Arning L., Timmann D., Cormand B., Perez-Duenas B., Di Rosa G., Goraya J.S., Sultan T., Mine J., Avdjieva D., Kathom H., Tincheva R., Banu S., Pineda-Marfa M., Veggiotti P., Ferrari M.D., van den Maagdenberg A.M.J.M., Verrotti A., Marseglia G., Savasta S., Garcia-Silva M., Ruiz A.M., Garavaglia B., Borgione E., Portaro S., Sanchez B.M., Boles R., Papacostas S., Vikelis M., Rothman J., Giunti P., Salpietro V., Oconnor E., Kullmann D., Kaiyrzhanov R., Sullivan R., Khan A.M., Yau W.Y., Hostettler I., Papanicolaou E.Z., Dardiotis E., Maqbool S., Ibrahim S., Kirmani S., Rana N.N., Atawneh O., Lim S.-Y., Shaikh F., Koutsis G., Breza M., Mangano S., Scuderi C., Morello G., Stojkovic T., Torti E., Zollo M., Heimer G., Dauvilliers Y.A., Striano P., Al-Khawaja I., Al-Mutairi F., Alkuraya F.S., Sherifa H., Rizig M., Okubadejo N.U., Ojo O.O., Oshinaike O.O., Wahab K., Bello A.H., Abubakar S., Obiabo Y., Nwazor E., Ekenze O., Williams U., Iyagba A., Taiwo L., Komolafe M., Oguntunde O., Pchelina S., Senkevich K., Haridy N., Shashkin C., Zharkynbekova N., Koneyev K., Manizha G., Isrofilov M., Guliyeva U., Salayev K., Khachatryan S., Rossi S., Silvestri G., Bourinaris T., Xiromerisiou G., Fidani L., Spanaki C., and Tucci A.
Subjects: 0301 basic medicine, Male, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, LOCAL TRANSLATION, Medizin, medicine.disease_cause, DISEASE, chemistry.chemical_compound, 0302 clinical medicine, polineuropathy, Cinètica enzimàtica, Gene Regulatory Networks, Pyridoxal phosphate, Child, Pyridoxal Kinase, Adenosine triphosphate (ATP), Research Articles, Aged, 80 and over, Mutation, Gene Regulatory Network, PLASMA, Autosomal recessive axonal polyneuropathy, Disease gene identification, Pyridoxal kinase, 3. Good health, Settore MED/26 - NEUROLOGIA, Neuropaties perifèriques, Treatment Outcome, Polyneuropathie, Neurology, Child, Preschool, Pyridoxal Phosphate, RELIABILITY, Vitamin B Complex, Female, Life Sciences & Biomedicine, Polyneuropathy, Human, Research Article, Adult, Adolescent, PDXK, Clinical Neurology, CHARCOT-MARIE-TOOTH, CHARCOT-MARIE-TOOTH, CMT NEUROPATHY SCORE, LOCAL TRANSLATION, DISEASE, RELIABILITY, MECHANISMS, DISCOVERY, FRAMEWORK, KINASE, PLASMA, MECHANISMS, 03 medical and health sciences, Polyneuropathies, Atrophy, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], KINASE, medicine, Humans, CMT NEUROPATHY SCORE, PDXK mutations, Pyridoxal, Dietary Supplement, Aged, Peripheral neuropathies, Science & Technology, [SCCO.NEUR]Cognitive science/Neuroscience, Enzyme kinetics, Neurosciences, FRAMEWORK, medicine.disease, Molecular biology, 030104 developmental biology, chemistry, DISCOVERY, Dietary Supplements, Neurosciences & Neurology, Neurology (clinical), Adenosine triphosphate, 030217 neurology & neurosurgery
Abstract: OBJECTIVE: To identify disease-causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy. METHODS: We performed genome-wide sequencing, homozygosity mapping, and segregation analysis for novel disease-causing gene discovery. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the impact of variants on adenosine triphosphate (ATP) binding. Pathogenicity was further supported by enzymatic assays and mass spectroscopy on recombinant protein, patient-derived fibroblasts, plasma, and erythrocytes. Response to supplementation was measured with clinical validated rating scales, electrophysiology, and biochemical quantification. RESULTS: We identified biallelic mutations in PDXK in 5 individuals from 2 unrelated families with primary axonal polyneuropathy and optic atrophy. The natural history of this disorder suggests that untreated, affected individuals become wheelchair-bound and blind. We identified conformational rearrangement in the mutant enzyme around the ATP-binding pocket. Low PDXK ATP binding resulted in decreased erythrocyte PDXK activity and low pyridoxal 5'-phosphate (PLP) concentrations. We rescued the clinical and biochemical profile with PLP supplementation in 1 family, improvement in power, pain, and fatigue contributing to patients regaining their ability to walk independently during the first year of PLP normalization. INTERPRETATION: We show that mutations in PDXK cause autosomal recessive axonal peripheral polyneuropathy leading to disease via reduced PDXK enzymatic activity and low PLP. We show that the biochemical profile can be rescued with PLP supplementation associated with clinical improvement. As B6 is a cofactor in diverse essential biological pathways, our findings may have direct implications for neuropathies of unknown etiology characterized by reduced PLP levels. ANN NEUROL 2019;86:225-240. ispartof: ANNALS OF NEUROLOGY vol:86 issue:2 pages:225-240 ispartof: location:United States status: published
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50. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Author: Salpietro, Vincenzo, Dixon, Christine L, Guo, Hui, Bello, Oscar D, Vandrovcova, Jana, Efthymiou, Stephanie, Raspall Chaure, Miquel, Macaya Ruíz, Alfons, Institut Català de la Salut, [Salpietro V] Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, UK. Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto 'Giannina Gaslini', Genoa, Italy. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy. [Dixon CL, Bello OD] Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK. [Guo H] Department of Genome Sciences, University of Washington School of Medicine, Seattle, USA. Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China. [Vandrovcova J] Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, UK. [Efthymiou S] Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, UK. Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK. [Raspall-Chaure M, Macaya A] Servei de Neurologia Pediatrica, Hospital Universitari Vall d'Hebron, Barcelona, Spain. Universitat Autònoma de Barcelona, Barcelona, Spain., Hospital Universitari Vall d'Hebron, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Trastornos Mentales::Trastornos del Neurodesarrollo [PSIQUIATRÍA Y PSICOLOGÍA], Otros calificadores::Otros calificadores::/genética [Otros calificadores], trastornos mentales::trastornos del desarrollo neurológico [PSIQUIATRÍA Y PSICOLOGÍA], Mutació (Biologia), Proteïnes de membrana, Other subheadings::Other subheadings::/genetics [Other subheadings], Genetic Phenomena::Genetic Variation::Mutation [PHENOMENA AND PROCESSES], Amino Acids, Peptides, and Proteins::Proteins::Carrier Proteins::Membrane Transport Proteins::Ion Channels::Ligand-Gated Ion Channels::Receptors, Ionotropic Glutamate::Receptors, AMPA [CHEMICALS AND DRUGS], Trastorns del desenvolupament - Aspectes genètics, Aminoácidos, Péptidos y Proteínas::Proteínas::Proteínas Portadoras::Proteínas de Transporte de Membrana::Canales Iónicos::Canales Iónicos Activados por Ligandos::Receptores Ionotrópicos de Glutamato::Receptores AMPA [COMPUESTOS QUÍMICOS Y DROGAS], fenómenos genéticos::variación genética::mutación [FENÓMENOS Y PROCESOS], aminoácidos, péptidos y proteínas::proteínas::proteínas transportadoras::proteínas de transporte de membrana::canales iónicos::canales iónicos de apertura por ligandos::receptores ionotrópicos de glutamato::receptores AMPA [COMPUESTOS QUÍMICOS Y DROGAS], Mental Disorders::Neurodevelopmental Disorders [PSYCHIATRY AND PSYCHOLOGY]
Abstract: Neurodevelopmental disorders; AMPA; GluA2 Trastorns del neurodesenvolupament; AMPA; GluA2 Trastornos del neurodesarrollo; AMPA; GluA2 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. Supported by the Wellcome Trust (WT093205MA and WT104033AIA), Medical Research Council (H.H. and D.M.K.), European Community’s Seventh Framework Programme (FP7/2007‐2013, under grant agreement No. 2012‐305121 to H.H.), Muscular Dystrophy Association (MDA), Muscular Dystrophy UK, The MSA Trust, Ataxia UK, The Sparkes Children’s Medical Research Charity, The Great Ormond Street Hospital Charity, Rosetrees Trust, Brain Research UK, The UK HSP Society, The European Union’s Horizon 2020 research and innovation programme Solve-RD project (No 779257), The Pakistan Council (Scholarship to HT), The National Natural Science Foundation of China (31671114, 81871079, 81330027, and 81525007 to H.G. and K.X.), the US National Institutes of Health (NIH grant R01MH101221 to E.E.E), the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) and the Biomedical Research Centre (BRC)

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