Search

Your search keyword '"Stamberger, H."' showing total 19 results
Start Over Author "Stamberger, H." Database OAIster
19 results on '"Stamberger, H."'

1. Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition.

Author

Palmer, E.E., Pusch, M., Picollo, A., Forwood, C., Nguyen, M.H., Suckow, V., Gibbons, J., Hoff, A., Sigfrid, L., Megarbane, A., Nizon, M., Cogné, B., Beneteau, C., Alkuraya, F.S., Chedrawi, A., Hashem, M.O., Stamberger, H., Weckhuysen, S., Vanlander, A., Ceulemans, B., Rajagopalan, S., Nunn, K., Arpin, S., Raynaud, M., Motter, C.S., Ward-Melver, C., Janssens, K., Meuwissen, M., Beysen, D., Dikow, N., Grimmel, M., Haack, T.B., Clement, E., McTague, A., Hunt, D., Townshend, S., Ward, M., Richards, L.J., Simons, C., Costain, G., Dupuis, L., Mendoza-Londono, R., Dudding-Byth, T., Boyle, J., Saunders, C., Fleming, E., Chehadeh, S. El, Spitz, M.A., Piton, A., Gerard, B., bi Warde, M.T. A, Rea, G., McKenna, C., Douzgou, S., Banka, S., Akman, C., Bain, J.M., Sands, T.T., Wilson, G.N., Silvertooth, E.J., Miller, L., Lederer, D., Sachdev, R., Macintosh, R., Monestier, O., Karadurmus, D., Collins, F., Carter, M., Rohena, L., Willemsen, M.H., Ockeloen, C.W., Pfundt, R.P., Kroft, S.D., Field, M., Laranjeira, F.E.R., Fortuna, A.M., Soares, A.R., Michaud, V., Naudion, S., Golla, S., Weaver, D.D., Bird, L.M., Friedman, J., Clowes, V., Joss, S., Pölsler, L., Campeau, P.M., Blazo, M., Bijlsma, E.K., Rosenfeld, J.A., Beetz, C., Powis, Z., McWalter, K., Brandt, T., Torti, E., Mathot, M., Mohammad, S.S., Armstrong, R., Kalscheuer, V.M., Palmer, E.E., Pusch, M., Picollo, A., Forwood, C., Nguyen, M.H., Suckow, V., Gibbons, J., Hoff, A., Sigfrid, L., Megarbane, A., Nizon, M., Cogné, B., Beneteau, C., Alkuraya, F.S., Chedrawi, A., Hashem, M.O., Stamberger, H., Weckhuysen, S., Vanlander, A., Ceulemans, B., Rajagopalan, S., Nunn, K., Arpin, S., Raynaud, M., Motter, C.S., Ward-Melver, C., Janssens, K., Meuwissen, M., Beysen, D., Dikow, N., Grimmel, M., Haack, T.B., Clement, E., McTague, A., Hunt, D., Townshend, S., Ward, M., Richards, L.J., Simons, C., Costain, G., Dupuis, L., Mendoza-Londono, R., Dudding-Byth, T., Boyle, J., Saunders, C., Fleming, E., Chehadeh, S. El, Spitz, M.A., Piton, A., Gerard, B., bi Warde, M.T. A, Rea, G., McKenna, C., Douzgou, S., Banka, S., Akman, C., Bain, J.M., Sands, T.T., Wilson, G.N., Silvertooth, E.J., Miller, L., Lederer, D., Sachdev, R., Macintosh, R., Monestier, O., Karadurmus, D., Collins, F., Carter, M., Rohena, L., Willemsen, M.H., Ockeloen, C.W., Pfundt, R.P., Kroft, S.D., Field, M., Laranjeira, F.E.R., Fortuna, A.M., Soares, A.R., Michaud, V., Naudion, S., Golla, S., Weaver, D.D., Bird, L.M., Friedman, J., Clowes, V., Joss, S., Pölsler, L., Campeau, P.M., Blazo, M., Bijlsma, E.K., Rosenfeld, J.A., Beetz, C., Powis, Z., McWalter, K., Brandt, T., Torti, E., Mathot, M., Mohammad, S.S., Armstrong, R., and Kalscheuer, V.M.

Abstract

01 februari 2023, Item does not contain fulltext, Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

Published
2023

2. Natural History Study of STXBP1-Developmental and Epileptic Encephalopathy Into Adulthood

Author

Stamberger, H, Crosiers, D, Balagura, G, Bonardi, CM, Basu, A, Cantalupo, G, Chiesa, V, Christensen, J, Dalla Bernardina, B, Ellis, CA, Furia, F, Gardiner, F, Giron, C, Guerrini, R, Klein, KM, Korff, C, Krijtova, H, Leffner, M, Lerche, H, Lesca, G, Lewis-Smith, D, Marini, C, Marjanovic, D, Mazzola, L, Ruggiero, SM, Mochel, F, Ramond, F, Reif, PS, Richard-Mornas, A, Rosenow, F, Schropp, C, Thomas, RH, Vignoli, A, Weber, Y, Palmer, E, Helbig, I, Scheffer, IE, Striano, P, Moller, RS, Gardella, E, Weckhuysen, S, Stamberger, H, Crosiers, D, Balagura, G, Bonardi, CM, Basu, A, Cantalupo, G, Chiesa, V, Christensen, J, Dalla Bernardina, B, Ellis, CA, Furia, F, Gardiner, F, Giron, C, Guerrini, R, Klein, KM, Korff, C, Krijtova, H, Leffner, M, Lerche, H, Lesca, G, Lewis-Smith, D, Marini, C, Marjanovic, D, Mazzola, L, Ruggiero, SM, Mochel, F, Ramond, F, Reif, PS, Richard-Mornas, A, Rosenow, F, Schropp, C, Thomas, RH, Vignoli, A, Weber, Y, Palmer, E, Helbig, I, Scheffer, IE, Striano, P, Moller, RS, Gardella, E, and Weckhuysen, S

Abstract

BACKGROUND AND OBJECTIVES: Pathogenic STXBP1 variants cause a severe early-onset developmental and epileptic encephalopathy (STXBP1-DEE). We aimed to investigate the natural history of STXBP1-DEE in adults focusing on seizure evolution, the presence of movement disorders, and the level of functional (in)dependence. METHODS: In this observational study, patients with a minimum age of 18 years carrying a (likely) pathogenic STXBP1 variant were recruited through medical genetics departments and epilepsy centers. Treating clinicians completed clinical questionnaires and performed semistructured video examinations while performing tasks from the (modified) Unified Parkinson Disease Rating Scale when possible. RESULTS: Thirty adult patients were included for summary statistics, with video recordings available for 19 patients. The median age at last follow-up was 24 years (range 18-58 years). All patients had epilepsy, with a median onset age of 3.5 months. At last follow-up, 80% of adults had treatment-resistant seizures despite long periods of seizure freedom in 37%. Tonic-clonic, focal, and tonic seizures were most frequent in adults. Epileptic spasms, an unusual feature beyond infancy, were present in 3 adults. All individuals had developmental impairment. Periods of regression were present in 59% and did not always correlate with flare-ups in seizure activity. Eighty-seven percent had severe or profound intellectual disability, 42% had autistic features, and 65% had significant behavioral problems. Video examinations showed gait disorders in all 12 patients able to walk, including postural abnormalities with external rotation of the feet, broad-based gait, and asymmetric posture/dystonia. Tremor, present in 56%, was predominantly of the intention/action type. Stereotypies were seen in 63%. Functional outcome concerning mobility was variable ranging from independent walking (50%) to wheelchair dependence (39%). Seventy-one percent of adults were nonverbal, and all were

Published
2022

3. NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns

Author

Stamberger, H., Hammer, T.B., Gardella, E., Vlaskamp, D.R.M., Bertelsen, B., Mandelstam, S., Lange, I. de, Zhang, J., Myers, C.T., Fenger, C., Afawi, Z., Fuerte, E.P. Almanza, Andrade, D.M., Balcik, Y., Zeev, B. Ben, Bennett, M.F., Berkovic, S.F., Isidor, B., Bouman, A., Brilstra, E., Ø, L. Busk, Cairns, A., Caumes, R., Chatron, N., Dale, R.C., Geus, C. de, Edery, P., Gill, D., Granild-Jensen, J.B., Gunderson, L., Gunning, B., Heimer, G., Helle, J.R., Hildebrand, M.S., Hollingsworth, G., Kharytonov, V., Klee, E.W., Koeleman, B.P.C., Koolen, D.A., Korff, C., Küry, S., Lesca, G., Lev, D., Leventer, R.J., Mackay, M.T., Macke, E.L., McEntagart, M., Mohammad, S.S., Monin, P., Montomoli, M., Morava, E., Moutton, S., Muir, A.M., Parrini, E., Procopis, P., Ranza, E., Reed, L., Reif, P.S., Rosenow, F., Rossi, M., Sadleir, L.G., Sadoway, T., Schelhaas, H.J., Schneider, A.L., Shah, K., Shalev, R., Sisodiya, S.M., Smol, T., Stumpel, C., Stuurman, K., Symonds, J.D., Mau-Them, F.T., Verbeek, N., Verhoeven, J.S., Wallace, G., Yosovich, K., Zarate, Y.A., Zerem, A., Zuberi, S.M., Guerrini, R., Mefford, H.C., Patel, C., Zhang, Y.H., Møller, R.S., Scheffer, I.E., Stamberger, H., Hammer, T.B., Gardella, E., Vlaskamp, D.R.M., Bertelsen, B., Mandelstam, S., Lange, I. de, Zhang, J., Myers, C.T., Fenger, C., Afawi, Z., Fuerte, E.P. Almanza, Andrade, D.M., Balcik, Y., Zeev, B. Ben, Bennett, M.F., Berkovic, S.F., Isidor, B., Bouman, A., Brilstra, E., Ø, L. Busk, Cairns, A., Caumes, R., Chatron, N., Dale, R.C., Geus, C. de, Edery, P., Gill, D., Granild-Jensen, J.B., Gunderson, L., Gunning, B., Heimer, G., Helle, J.R., Hildebrand, M.S., Hollingsworth, G., Kharytonov, V., Klee, E.W., Koeleman, B.P.C., Koolen, D.A., Korff, C., Küry, S., Lesca, G., Lev, D., Leventer, R.J., Mackay, M.T., Macke, E.L., McEntagart, M., Mohammad, S.S., Monin, P., Montomoli, M., Morava, E., Moutton, S., Muir, A.M., Parrini, E., Procopis, P., Ranza, E., Reed, L., Reif, P.S., Rosenow, F., Rossi, M., Sadleir, L.G., Sadoway, T., Schelhaas, H.J., Schneider, A.L., Shah, K., Shalev, R., Sisodiya, S.M., Smol, T., Stumpel, C., Stuurman, K., Symonds, J.D., Mau-Them, F.T., Verbeek, N., Verhoeven, J.S., Wallace, G., Yosovich, K., Zarate, Y.A., Zerem, A., Zuberi, S.M., Guerrini, R., Mefford, H.C., Patel, C., Zhang, Y.H., Møller, R.S., and Scheffer, I.E.

Abstract

Contains fulltext : 231688.pdf (Publisher’s version ) (Closed access), PURPOSE: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy. METHODS: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy. RESULTS: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism. CONCLUSION: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants.

Published
2021

4. NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns

Author

Stamberger, H., Hammer, T.B., Gardella, E., Vlaskamp, D.R.M., Bertelsen, B., Mandelstam, S., Lange, I. de, Zhang, J., Myers, C.T., Fenger, C., Afawi, Z., Fuerte, E.P. Almanza, Andrade, D.M., Balcik, Y., Zeev, B. Ben, Bennett, M.F., Berkovic, S.F., Isidor, B., Bouman, A., Brilstra, E., Ø, L. Busk, Cairns, A., Caumes, R., Chatron, N., Dale, R.C., Geus, C. de, Edery, P., Gill, D., Granild-Jensen, J.B., Gunderson, L., Gunning, B., Heimer, G., Helle, J.R., Hildebrand, M.S., Hollingsworth, G., Kharytonov, V., Klee, E.W., Koeleman, B.P.C., Koolen, D.A., Korff, C., Küry, S., Lesca, G., Lev, D., Leventer, R.J., Mackay, M.T., Macke, E.L., McEntagart, M., Mohammad, S.S., Monin, P., Montomoli, M., Morava, E., Moutton, S., Muir, A.M., Parrini, E., Procopis, P., Ranza, E., Reed, L., Reif, P.S., Rosenow, F., Rossi, M., Sadleir, L.G., Sadoway, T., Schelhaas, H.J., Schneider, A.L., Shah, K., Shalev, R., Sisodiya, S.M., Smol, T., Stumpel, C., Stuurman, K., Symonds, J.D., Mau-Them, F.T., Verbeek, N., Verhoeven, J.S., Wallace, G., Yosovich, K., Zarate, Y.A., Zerem, A., Zuberi, S.M., Guerrini, R., Mefford, H.C., Patel, C., Zhang, Y.H., Møller, R.S., Scheffer, I.E., Stamberger, H., Hammer, T.B., Gardella, E., Vlaskamp, D.R.M., Bertelsen, B., Mandelstam, S., Lange, I. de, Zhang, J., Myers, C.T., Fenger, C., Afawi, Z., Fuerte, E.P. Almanza, Andrade, D.M., Balcik, Y., Zeev, B. Ben, Bennett, M.F., Berkovic, S.F., Isidor, B., Bouman, A., Brilstra, E., Ø, L. Busk, Cairns, A., Caumes, R., Chatron, N., Dale, R.C., Geus, C. de, Edery, P., Gill, D., Granild-Jensen, J.B., Gunderson, L., Gunning, B., Heimer, G., Helle, J.R., Hildebrand, M.S., Hollingsworth, G., Kharytonov, V., Klee, E.W., Koeleman, B.P.C., Koolen, D.A., Korff, C., Küry, S., Lesca, G., Lev, D., Leventer, R.J., Mackay, M.T., Macke, E.L., McEntagart, M., Mohammad, S.S., Monin, P., Montomoli, M., Morava, E., Moutton, S., Muir, A.M., Parrini, E., Procopis, P., Ranza, E., Reed, L., Reif, P.S., Rosenow, F., Rossi, M., Sadleir, L.G., Sadoway, T., Schelhaas, H.J., Schneider, A.L., Shah, K., Shalev, R., Sisodiya, S.M., Smol, T., Stumpel, C., Stuurman, K., Symonds, J.D., Mau-Them, F.T., Verbeek, N., Verhoeven, J.S., Wallace, G., Yosovich, K., Zarate, Y.A., Zerem, A., Zuberi, S.M., Guerrini, R., Mefford, H.C., Patel, C., Zhang, Y.H., Møller, R.S., and Scheffer, I.E.

Abstract

Contains fulltext : 231688.pdf (Publisher’s version ) (Closed access), PURPOSE: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy. METHODS: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy. RESULTS: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism. CONCLUSION: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants.

Published
2021

5. Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Author

Motelow, JE, Povysil, G, Dhindsa, RS, Stanley, KE, Allen, AS, Feng, Y-CA, Howrigan, DP, Abbott, LE, Tashman, K, Cerrato, F, Cusick, C, Singh, T, Heyne, H, Byrnes, AE, Churchhouse, C, Watts, N, Solomonson, M, Lal, D, Gupta, N, Neale, BM, Cavalleri, GL, Cossette, P, Cotsapas, C, De Jonghe, P, Dixon-Salazar, T, Guerrini, R, Hakonarson, H, Heinzen, EL, Helbig, I, Kwan, P, Marson, AG, Petrovski, S, Kamalakaran, S, Sisodiya, SM, Stewart, R, Weckhuysen, S, Depondt, C, Dlugos, DJ, Scheffer, IE, Striano, P, Freyer, C, Krause, R, May, P, McKenna, K, Regan, BM, Bennett, CA, Leu, C, Leech, SL, O'Brien, TJ, Todaro, M, Stamberger, H, Andrade, DM, Ali, QZ, Sadoway, TR, Krestel, H, Schaller, A, Papacostas, SS, Kousiappa, I, Tanteles, GA, Christou, Y, Sterbova, K, Vlckova, M, Sedlackova, L, Lassuthova, P, Klein, KM, Rosenow, F, Reif, PS, Knake, S, Neubauer, BA, Zimprich, F, Feucht, M, Reinthaler, EM, Kunz, WS, Zsurka, G, Surges, R, Baumgartner, T, von Wrede, R, Pendziwiat, M, Muhle, H, Rademacher, A, van Baalen, A, von Spiczak, S, Stephani, U, Afawi, Z, Korczyn, AD, Kanaan, M, Canavati, C, Kurlemann, G, Muller-Schluter, K, Kluger, G, Haeusler, M, Blatt, I, Lemke, JR, Krey, I, Weber, YG, Wolking, S, Becker, F, Lauxmann, S, Bosselmann, C, Kegele, J, Hengsbach, C, Rau, S, Steinhoff, BJ, Schulze-Bonhage, A, Borggraefe, I, Schankin, CJ, Schubert-Bast, S, Schreiber, H, Mayer, T, Korinthenberg, R, Brockmann, K, Wolff, M, Dennig, D, Madeleyn, R, Kalviainen, R, Saarela, A, Timonen, O, Linnankivi, T, Lehesjoki, A-E, Rheims, S, Lesca, G, Ryvlin, P, Maillard, L, Valton, L, Derambure, P, Bartolomei, F, Hirsch, E, Michel, V, Chassoux, F, Rees, M, Chung, S-K, Pickrell, WO, Powell, R, Baker, MD, Fonferko-Shadrach, B, Lawthom, C, Anderson, J, Schneider, N, Balestrini, S, Zagaglia, S, Braatz, V, Johnson, MR, Auce, P, Sills, GJ, Baum, LW, Sham, PC, Cherny, SS, Lui, CHT, Delanty, N, Doherty, CP, Shukralla, A, El-Naggar, H, Widdess-Walsh, P, Barisi, N, Canafoglia, L, Franceschetti, S, Castellotti, B, Granata, T, Ragona, F, Zara, F, Iacomino, M, Riva, A, Madia, F, Vari, MS, Salpietro, V, Scala, M, Mancardi, MM, Nobili, L, Amadori, E, Giacomini, T, Bisulli, F, Pippucci, T, Licchetta, L, Minardi, R, Tinuper, P, Muccioli, L, Mostacci, B, Gambardella, A, Labate, A, Annesi, G, Manna, L, Gagliardi, M, Parrini, E, Mei, D, Vetro, A, Bianchini, C, Montomoli, M, Doccini, V, Barba, C, Hirose, S, Ishii, A, Suzuki, T, Inoue, Y, Yamakawa, K, Beydoun, A, Nasreddine, W, Zgheib, NK, Tumiene, B, Utkus, A, Sadleir, LG, King, C, Caglayan, SH, Arslan, M, Yapici, Z, Topaloglu, P, Kara, B, Yis, U, Turkdogan, D, Gundogdu-Eken, A, Bebek, N, Tsai, M-H, Ho, C-J, Lin, C-H, Lin, K-L, Chou, I-J, Poduri, A, Shiedley, BR, Shain, C, Noebels, JL, Goldman, A, Busch, RM, Jehi, L, Najm, IM, Ferguson, L, Khoury, J, Glauser, TA, Clark, PO, Buono, RJ, Ferraro, TN, Sperling, MR, Lo, W, Privitera, M, French, JA, Schachter, S, Kuzniecky, R, Devinsky, O, Hegde, M, Greenberg, DA, Ellis, CA, Goldberg, E, Helbig, KL, Cosico, M, Vaidiswaran, P, Fitch, E, Berkovic, SF, Lerche, H, Lowenstein, DH, Goldstein, DB, Motelow, JE, Povysil, G, Dhindsa, RS, Stanley, KE, Allen, AS, Feng, Y-CA, Howrigan, DP, Abbott, LE, Tashman, K, Cerrato, F, Cusick, C, Singh, T, Heyne, H, Byrnes, AE, Churchhouse, C, Watts, N, Solomonson, M, Lal, D, Gupta, N, Neale, BM, Cavalleri, GL, Cossette, P, Cotsapas, C, De Jonghe, P, Dixon-Salazar, T, Guerrini, R, Hakonarson, H, Heinzen, EL, Helbig, I, Kwan, P, Marson, AG, Petrovski, S, Kamalakaran, S, Sisodiya, SM, Stewart, R, Weckhuysen, S, Depondt, C, Dlugos, DJ, Scheffer, IE, Striano, P, Freyer, C, Krause, R, May, P, McKenna, K, Regan, BM, Bennett, CA, Leu, C, Leech, SL, O'Brien, TJ, Todaro, M, Stamberger, H, Andrade, DM, Ali, QZ, Sadoway, TR, Krestel, H, Schaller, A, Papacostas, SS, Kousiappa, I, Tanteles, GA, Christou, Y, Sterbova, K, Vlckova, M, Sedlackova, L, Lassuthova, P, Klein, KM, Rosenow, F, Reif, PS, Knake, S, Neubauer, BA, Zimprich, F, Feucht, M, Reinthaler, EM, Kunz, WS, Zsurka, G, Surges, R, Baumgartner, T, von Wrede, R, Pendziwiat, M, Muhle, H, Rademacher, A, van Baalen, A, von Spiczak, S, Stephani, U, Afawi, Z, Korczyn, AD, Kanaan, M, Canavati, C, Kurlemann, G, Muller-Schluter, K, Kluger, G, Haeusler, M, Blatt, I, Lemke, JR, Krey, I, Weber, YG, Wolking, S, Becker, F, Lauxmann, S, Bosselmann, C, Kegele, J, Hengsbach, C, Rau, S, Steinhoff, BJ, Schulze-Bonhage, A, Borggraefe, I, Schankin, CJ, Schubert-Bast, S, Schreiber, H, Mayer, T, Korinthenberg, R, Brockmann, K, Wolff, M, Dennig, D, Madeleyn, R, Kalviainen, R, Saarela, A, Timonen, O, Linnankivi, T, Lehesjoki, A-E, Rheims, S, Lesca, G, Ryvlin, P, Maillard, L, Valton, L, Derambure, P, Bartolomei, F, Hirsch, E, Michel, V, Chassoux, F, Rees, M, Chung, S-K, Pickrell, WO, Powell, R, Baker, MD, Fonferko-Shadrach, B, Lawthom, C, Anderson, J, Schneider, N, Balestrini, S, Zagaglia, S, Braatz, V, Johnson, MR, Auce, P, Sills, GJ, Baum, LW, Sham, PC, Cherny, SS, Lui, CHT, Delanty, N, Doherty, CP, Shukralla, A, El-Naggar, H, Widdess-Walsh, P, Barisi, N, Canafoglia, L, Franceschetti, S, Castellotti, B, Granata, T, Ragona, F, Zara, F, Iacomino, M, Riva, A, Madia, F, Vari, MS, Salpietro, V, Scala, M, Mancardi, MM, Nobili, L, Amadori, E, Giacomini, T, Bisulli, F, Pippucci, T, Licchetta, L, Minardi, R, Tinuper, P, Muccioli, L, Mostacci, B, Gambardella, A, Labate, A, Annesi, G, Manna, L, Gagliardi, M, Parrini, E, Mei, D, Vetro, A, Bianchini, C, Montomoli, M, Doccini, V, Barba, C, Hirose, S, Ishii, A, Suzuki, T, Inoue, Y, Yamakawa, K, Beydoun, A, Nasreddine, W, Zgheib, NK, Tumiene, B, Utkus, A, Sadleir, LG, King, C, Caglayan, SH, Arslan, M, Yapici, Z, Topaloglu, P, Kara, B, Yis, U, Turkdogan, D, Gundogdu-Eken, A, Bebek, N, Tsai, M-H, Ho, C-J, Lin, C-H, Lin, K-L, Chou, I-J, Poduri, A, Shiedley, BR, Shain, C, Noebels, JL, Goldman, A, Busch, RM, Jehi, L, Najm, IM, Ferguson, L, Khoury, J, Glauser, TA, Clark, PO, Buono, RJ, Ferraro, TN, Sperling, MR, Lo, W, Privitera, M, French, JA, Schachter, S, Kuzniecky, R, Devinsky, O, Hegde, M, Greenberg, DA, Ellis, CA, Goldberg, E, Helbig, KL, Cosico, M, Vaidiswaran, P, Fitch, E, Berkovic, SF, Lerche, H, Lowenstein, DH, and Goldstein, DB

Abstract

Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.

Published
2021

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

Author

Hengel, H. (Holger), Bosso-Lefèvre, C. (Célia), Grady, G. (George), Szenker-Ravi, E. (Emmanuelle), Li, H. (Hankun), Pierce, S. (Sarah), Lebigot, É. (Élise), Tan, T.-T. (Thong-Teck), Eio, M.Y. (Michelle Y.), Narayanan, G. (Gunaseelan), Utami, K.H. (Kagistia Hana), Yau, M. (Monica), Handal, N. (Nader), Deigendesch, W. (Werner), Keimer, R. (Reinhard), Marzouqa, H.M. (Hiyam M.), Gunay-Aygun, M. (Meral), Muriello, M.J. (Michael J.), Verhelst, H. (H.), Weckhuysen, S. (Sarah), Mahida, S. (Sonal), Naidu, S. (Sakkubai), Thomas, T.G. (Terrence G.), Lim, J.Y. (Jiin Ying), Tan, E.S. (Ee Shien), Haye, D. (Damien), Willemsen, M.A. (Michél), Oegema, R. (Renske), Mitchell, W.G. (Wendy G.), Pierson, T.M. (Tyler Mark), Andrews, M.V. (Marisa V.), Willing, M.C. (Marcia C.), Rodan, L.H. (Lance H.), Barakat, T.S. (Tahsin Stefan), Slegtenhorst, M.A. (Marjon) van, Gavrilova, R.H. (Ralitza H.), Martinelli, D. (Diego), Gilboa, T. (Tal), Tamim, A.M. (Abdullah M.), Hashem, M.O. (Mais O.), AlSayed, M.D. (Moeenaldeen D.), Abdulrahim, M.M. (Maha M.), Al-Owain, M. (Mohammed), Awaji, A. (Ali), Mahmoud, A.A.H. (Adel A. H.), Faqeih, E.A. (Eissa A.), Asmari, A.A. (Ali Al), Algain, S.M. (Sulwan M.), Jad, L.A. (Lamyaa A.), Aldhalaan, H.M. (Hesham M.), Helbig, I. (Ingo), Koolen, D.A. (David), Rieß, A. (Angelika), Kraegeloh-Mann, I. (Ingeborg), Bauer, P. (Peter), Gulsuner, S. (Suleyman), Stamberger, H. (Hannah), Ng, A.Y.J. (Alvin Yu Jin), Tang, S. (Sha), Tohari, S. (Sumanty), Keren, B. (Boris), Schultz-Rogers, L.E. (Laura E.), Klee, E.W. (Eric W.), Barresi, S. (Sabina), Tartaglia, M. (Marco), Mor-Shaked, H. (Hagar), Maddirevula, S. (Sateesh), Begtrup, A. (Amber), Telegrafi, A. (Aida), Pfundt, R. (Rolph), Schüle, R. (Rebecca), Ciruna, B. (Brian), Bonnard, C. (Carine), Pouladi, M.A. (Mahmoud A.), Stewart, J.C. (James C.), Claridge-Chang, A. (Adam), Lefeber, D.J. (Dirk J.), Alkuraya, F.S. (Fowzan S), Mathuru, A.S. (Ajay S.), Venkatesh, B. (Byrappa), Barycki, J.J. (Joseph J.), Simpson, M.A. (Melanie A.), Jamuar, S.S. (Saumya S.), Schöls, L. (Ludger), Reversade, B. (Bruno), Hengel, H. (Holger), Bosso-Lefèvre, C. (Célia), Grady, G. (George), Szenker-Ravi, E. (Emmanuelle), Li, H. (Hankun), Pierce, S. (Sarah), Lebigot, É. (Élise), Tan, T.-T. (Thong-Teck), Eio, M.Y. (Michelle Y.), Narayanan, G. (Gunaseelan), Utami, K.H. (Kagistia Hana), Yau, M. (Monica), Handal, N. (Nader), Deigendesch, W. (Werner), Keimer, R. (Reinhard), Marzouqa, H.M. (Hiyam M.), Gunay-Aygun, M. (Meral), Muriello, M.J. (Michael J.), Verhelst, H. (H.), Weckhuysen, S. (Sarah), Mahida, S. (Sonal), Naidu, S. (Sakkubai), Thomas, T.G. (Terrence G.), Lim, J.Y. (Jiin Ying), Tan, E.S. (Ee Shien), Haye, D. (Damien), Willemsen, M.A. (Michél), Oegema, R. (Renske), Mitchell, W.G. (Wendy G.), Pierson, T.M. (Tyler Mark), Andrews, M.V. (Marisa V.), Willing, M.C. (Marcia C.), Rodan, L.H. (Lance H.), Barakat, T.S. (Tahsin Stefan), Slegtenhorst, M.A. (Marjon) van, Gavrilova, R.H. (Ralitza H.), Martinelli, D. (Diego), Gilboa, T. (Tal), Tamim, A.M. (Abdullah M.), Hashem, M.O. (Mais O.), AlSayed, M.D. (Moeenaldeen D.), Abdulrahim, M.M. (Maha M.), Al-Owain, M. (Mohammed), Awaji, A. (Ali), Mahmoud, A.A.H. (Adel A. H.), Faqeih, E.A. (Eissa A.), Asmari, A.A. (Ali Al), Algain, S.M. (Sulwan M.), Jad, L.A. (Lamyaa A.), Aldhalaan, H.M. (Hesham M.), Helbig, I. (Ingo), Koolen, D.A. (David), Rieß, A. (Angelika), Kraegeloh-Mann, I. (Ingeborg), Bauer, P. (Peter), Gulsuner, S. (Suleyman), Stamberger, H. (Hannah), Ng, A.Y.J. (Alvin Yu Jin), Tang, S. (Sha), Tohari, S. (Sumanty), Keren, B. (Boris), Schultz-Rogers, L.E. (Laura E.), Klee, E.W. (Eric W.), Barresi, S. (Sabina), Tartaglia, M. (Marco), Mor-Shaked, H. (Hagar), Maddirevula, S. (Sateesh), Begtrup, A. (Amber), Telegrafi, A. (Aida), Pfundt, R. (Rolph), Schüle, R. (Rebecca), Ciruna, B. (Brian), Bonnard, C. (Carine), Pouladi, M.A. (Mahmoud A.), Stewart, J.C. (James C.), Claridge-Chang, A. (Adam), Lefeber, D.J. (Dirk J.), Alkuraya, F.S. (Fowzan S), Mathuru, A.S. (Ajay S.), Venkatesh, B. (Byrappa), Barycki, J.J. (Joseph J.), Simpson, M.A. (Melanie A.), Jamuar, S.S. (Saumya S.), Schöls, L. (Ludger), and Reversade, B. (Bruno)

Abstract

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

Published
2020
Full Text
View/download PDF

8. Epilepsy subtype-specific copy number burden observed in a genome-wide study of 17458 subjects

Author

Niestroj, LM, Perez-Palma, E, Howrigan, DP, Zhou, Y, Cheng, F, Saarentaus, E, Nürnberg, P, Stevelink, R, Daly, MJ, Palotie, A, Lal, D, Feng, YCA, Abbott, LE, Tashman, K, Cerrato, F, Churchhouse, C, Gupta, N, Neale, BM, Berkovic, SF, Lerche, H, Goldstein, DB, Lowenstein, DH, Cavalleri, GL, Cossette, P, Cotsapas, C, De Jonghe, P, Dixon-Salazar, T, Guerrini, R, Hakonarson, H, Heinzen, EL, Helbig, I, Kwan, P, Marson, AG, Petrovski, S, Kamalakaran, S, Sisodiya, SM, Stewart, R, Weckhuysen, S, Depondt, C, Dlugos, DJ, Scheffer, IE, Striano, P, Freyer, C, Krause, R, May, P, McKenna, K, Regan, BM, Leu, C, Bennett, CA, Bellows, Susannah, Johns, EMC, MacDonald, A, Shilling, H, Burgess, R, Weckhuysen, D, Bahlo, M, O'Brien, TJ, Todaro, M, Stamberger, H, Andrade, DM, Sadoway, TR, Mo, K, Krestel, H, Gallati, S, Papacostas, SS, Kousiappa, I, Tanteles, GA, Šterbová, K, Vlcková, M, Sedlácková, L, Laššuthová, P, Martin, K, Rosenow, F, Reif, PS, Knake, S, Kunz, WS, Zsurka, G, Elger, CE, Bauer, J, Rademacher, M, Pendziwiat, M, Muhle, H, Rademacher, A, Van Baalen, A, Von Spiczak, S, Stephani, U, Afawi, Z, Korczyn, AD, Kanaan, M, Canavati, C, Kurlemann, G, Müller-Schlüter, K, Kluger, G, Häusler, M, Blatt, I, Lemke, JR, Krey, I, Weber, YG, Wolking, S, Becker, F, Niestroj, LM, Perez-Palma, E, Howrigan, DP, Zhou, Y, Cheng, F, Saarentaus, E, Nürnberg, P, Stevelink, R, Daly, MJ, Palotie, A, Lal, D, Feng, YCA, Abbott, LE, Tashman, K, Cerrato, F, Churchhouse, C, Gupta, N, Neale, BM, Berkovic, SF, Lerche, H, Goldstein, DB, Lowenstein, DH, Cavalleri, GL, Cossette, P, Cotsapas, C, De Jonghe, P, Dixon-Salazar, T, Guerrini, R, Hakonarson, H, Heinzen, EL, Helbig, I, Kwan, P, Marson, AG, Petrovski, S, Kamalakaran, S, Sisodiya, SM, Stewart, R, Weckhuysen, S, Depondt, C, Dlugos, DJ, Scheffer, IE, Striano, P, Freyer, C, Krause, R, May, P, McKenna, K, Regan, BM, Leu, C, Bennett, CA, Bellows, Susannah, Johns, EMC, MacDonald, A, Shilling, H, Burgess, R, Weckhuysen, D, Bahlo, M, O'Brien, TJ, Todaro, M, Stamberger, H, Andrade, DM, Sadoway, TR, Mo, K, Krestel, H, Gallati, S, Papacostas, SS, Kousiappa, I, Tanteles, GA, Šterbová, K, Vlcková, M, Sedlácková, L, Laššuthová, P, Martin, K, Rosenow, F, Reif, PS, Knake, S, Kunz, WS, Zsurka, G, Elger, CE, Bauer, J, Rademacher, M, Pendziwiat, M, Muhle, H, Rademacher, A, Van Baalen, A, Von Spiczak, S, Stephani, U, Afawi, Z, Korczyn, AD, Kanaan, M, Canavati, C, Kurlemann, G, Müller-Schlüter, K, Kluger, G, Häusler, M, Blatt, I, Lemke, JR, Krey, I, Weber, YG, Wolking, S, and Becker, F

Abstract

Cytogenic testing is routinely applied in most neurological centres for severe paediatric epilepsies. However, which characteristics of copy number variants (CNVs) confer most epilepsy risk and which epilepsy subtypes carry the most CNV burden, have not been explored on a genome-wide scale. Here, we present the largest CNV investigation in epilepsy to date with 10 712 European epilepsy cases and 6746 ancestry-matched controls. Patients with genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, and developmental and epileptic encephalopathy were included. All samples were processed with the same technology and analysis pipeline. All investigated epilepsy types, including lesional focal epilepsy patients, showed an increase in CNV burden in at least one tested category compared to controls. However, we observed striking differences in CNV burden across epilepsy types and investigated CNV categories. Genetic generalized epilepsy patients have the highest CNV burden in all categories tested, followed by developmental and epileptic encephalopathy patients. Both epilepsy types also show association for deletions covering genes intolerant for truncating variants. Genome-wide CNV breakpoint association showed not only significant loci for genetic generalized and developmental and epileptic encephalopathy patients but also for lesional focal epilepsy patients. With a 34-fold risk for developing genetic generalized epilepsy, we show for the first time that the established epilepsy-associated 15q13.3 deletion represents the strongest risk CNV for genetic generalized epilepsy across the whole genome. Using the human interactome, we examined the largest connected component of the genes overlapped by CNVs in the four epilepsy types. We observed that genetic generalized epilepsy and non-acquired focal epilepsy formed disease modules. In summary, we show that in all common epilepsy types, 1.5-3% of patients carry epilepsy-associated CNVs. The character

Published
2020

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

Author

Hengel, H., Bosso-Lefevre, C., Grady, G., Szenker-Ravi, E., Li, H., Pierce, S., Lebigot, E., Tan, T.T., Eio, M.Y., Narayanan, G., Utami, K.H., Yau, M., Handal, N., Deigendesch, W., Keimer, R., Marzouqa, H.M., Gunay-Aygun, M., Muriello, M.J., Verhelst, H., Weckhuysen, S., Mahida, S., Naidu, S., Thomas, T.G., Lim, J.Y., Tan, E.S., Haye, D., Willemsen, M.A.A.P., Oegema, R., Mitchell, W.G., Pierson, T.M., Andrews, M.V., Willing, M.C., Rodan, L.H., Barakat, T.S., Slegtenhorst, M. van, Gavrilova, R.H., Martinelli, D., Gilboa, T., Tamim, A.M., Hashem, M.O., AlSayed, M.D., Abdulrahim, M.M., Al-Owain, M., Awaji, A., Mahmoud, A.A.H., Faqeih, E.A., Asmari, A.A., Algain, S.M., Jad, L.A., Aldhalaan, H.M., Helbig, I., Koolen, D.A., Riess, A., Kraegeloh-Mann, I., Bauer, P., Gulsuner, S., Stamberger, H., Ng, A.Y., Tang, S., Tohari, S., Keren, B., Schultz-Rogers, L.E., Klee, E.W., Barresi, S., Tartaglia, M., Mor-Shaked, H., Maddirevula, S., Begtrup, A., Telegrafi, A., Pfundt, R.P., Schule, R., Ciruna, B., Bonnard, C., Pouladi, M.A., Stewart, J.C., Claridge-Chang, A., Lefeber, D.J., Alkuraya, F.S., Mathuru, A.S., Venkatesh, B., Barycki, J.J., Simpson, Malcolm, Jamuar, S.S., Schols, L., Reversade, B., Hengel, H., Bosso-Lefevre, C., Grady, G., Szenker-Ravi, E., Li, H., Pierce, S., Lebigot, E., Tan, T.T., Eio, M.Y., Narayanan, G., Utami, K.H., Yau, M., Handal, N., Deigendesch, W., Keimer, R., Marzouqa, H.M., Gunay-Aygun, M., Muriello, M.J., Verhelst, H., Weckhuysen, S., Mahida, S., Naidu, S., Thomas, T.G., Lim, J.Y., Tan, E.S., Haye, D., Willemsen, M.A.A.P., Oegema, R., Mitchell, W.G., Pierson, T.M., Andrews, M.V., Willing, M.C., Rodan, L.H., Barakat, T.S., Slegtenhorst, M. van, Gavrilova, R.H., Martinelli, D., Gilboa, T., Tamim, A.M., Hashem, M.O., AlSayed, M.D., Abdulrahim, M.M., Al-Owain, M., Awaji, A., Mahmoud, A.A.H., Faqeih, E.A., Asmari, A.A., Algain, S.M., Jad, L.A., Aldhalaan, H.M., Helbig, I., Koolen, D.A., Riess, A., Kraegeloh-Mann, I., Bauer, P., Gulsuner, S., Stamberger, H., Ng, A.Y., Tang, S., Tohari, S., Keren, B., Schultz-Rogers, L.E., Klee, E.W., Barresi, S., Tartaglia, M., Mor-Shaked, H., Maddirevula, S., Begtrup, A., Telegrafi, A., Pfundt, R.P., Schule, R., Ciruna, B., Bonnard, C., Pouladi, M.A., Stewart, J.C., Claridge-Chang, A., Lefeber, D.J., Alkuraya, F.S., Mathuru, A.S., Venkatesh, B., Barycki, J.J., Simpson, Malcolm, Jamuar, S.S., Schols, L., and Reversade, B.

Abstract

Contains fulltext : 218288.pdf (publisher's version ) (Open Access), Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients' primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy.

Published
2020

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

Author

Hengel, H., Bosso-Lefevre, C., Grady, G., Szenker-Ravi, E., Li, H., Pierce, S., Lebigot, E., Tan, T.T., Eio, M.Y., Narayanan, G., Utami, K.H., Yau, M., Handal, N., Deigendesch, W., Keimer, R., Marzouqa, H.M., Gunay-Aygun, M., Muriello, M.J., Verhelst, H., Weckhuysen, S., Mahida, S., Naidu, S., Thomas, T.G., Lim, J.Y., Tan, E.S., Haye, D., Willemsen, M.A.A.P., Oegema, R., Mitchell, W.G., Pierson, T.M., Andrews, M.V., Willing, M.C., Rodan, L.H., Barakat, T.S., Slegtenhorst, M. van, Gavrilova, R.H., Martinelli, D., Gilboa, T., Tamim, A.M., Hashem, M.O., AlSayed, M.D., Abdulrahim, M.M., Al-Owain, M., Awaji, A., Mahmoud, A.A.H., Faqeih, E.A., Asmari, A.A., Algain, S.M., Jad, L.A., Aldhalaan, H.M., Helbig, I., Koolen, D.A., Riess, A., Kraegeloh-Mann, I., Bauer, P., Gulsuner, S., Stamberger, H., Ng, A.Y., Tang, S., Tohari, S., Keren, B., Schultz-Rogers, L.E., Klee, E.W., Barresi, S., Tartaglia, M., Mor-Shaked, H., Maddirevula, S., Begtrup, A., Telegrafi, A., Pfundt, R.P., Schule, R., Ciruna, B., Bonnard, C., Pouladi, M.A., Stewart, J.C., Claridge-Chang, A., Lefeber, D.J., Alkuraya, F.S., Mathuru, A.S., Venkatesh, B., Barycki, J.J., Simpson, Malcolm, Jamuar, S.S., Schols, L., Reversade, B., Hengel, H., Bosso-Lefevre, C., Grady, G., Szenker-Ravi, E., Li, H., Pierce, S., Lebigot, E., Tan, T.T., Eio, M.Y., Narayanan, G., Utami, K.H., Yau, M., Handal, N., Deigendesch, W., Keimer, R., Marzouqa, H.M., Gunay-Aygun, M., Muriello, M.J., Verhelst, H., Weckhuysen, S., Mahida, S., Naidu, S., Thomas, T.G., Lim, J.Y., Tan, E.S., Haye, D., Willemsen, M.A.A.P., Oegema, R., Mitchell, W.G., Pierson, T.M., Andrews, M.V., Willing, M.C., Rodan, L.H., Barakat, T.S., Slegtenhorst, M. van, Gavrilova, R.H., Martinelli, D., Gilboa, T., Tamim, A.M., Hashem, M.O., AlSayed, M.D., Abdulrahim, M.M., Al-Owain, M., Awaji, A., Mahmoud, A.A.H., Faqeih, E.A., Asmari, A.A., Algain, S.M., Jad, L.A., Aldhalaan, H.M., Helbig, I., Koolen, D.A., Riess, A., Kraegeloh-Mann, I., Bauer, P., Gulsuner, S., Stamberger, H., Ng, A.Y., Tang, S., Tohari, S., Keren, B., Schultz-Rogers, L.E., Klee, E.W., Barresi, S., Tartaglia, M., Mor-Shaked, H., Maddirevula, S., Begtrup, A., Telegrafi, A., Pfundt, R.P., Schule, R., Ciruna, B., Bonnard, C., Pouladi, M.A., Stewart, J.C., Claridge-Chang, A., Lefeber, D.J., Alkuraya, F.S., Mathuru, A.S., Venkatesh, B., Barycki, J.J., Simpson, Malcolm, Jamuar, S.S., Schols, L., and Reversade, B.

Abstract

Contains fulltext : 218288.pdf (publisher's version ) (Open Access), Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients' primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy.

Published
2020

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

Author

Reversade, Bruno, Hengel, H.; Bosso-Lefèvre, C.; Grady, G.; Szenker-Ravi, E.; Li, H.; Pierce, S.; Lebigot, É.; Tan, T.-T.; Eio, M.Y.; Narayanan, G.; Utami, K.H.; Yau, M.; Handal, N.; Deigendesch, W.; Keimer, R.; Marzouqa, H.M.; Gunay-Aygun, M.; Muriello, M.J.; Verhelst, H.; Weckhuysen, S.; Mahida, S.; Naidu, S.; Thomas, T.G.; Lim, J.Y.; Tan, E.S.; Haye, D.; Willemsen, M.A.A.P.; Oegema, R.; Mitchell, W.G.; Pierson, T.M.; Andrews, M.V.; Willing, M.C.; Rodan, L.H.; Barakat, T.S.; van Slegtenhorst, M.; Gavrilova, R.H.; Martinelli, D.; Gilboa, T.; Tamim, A.M.; Hashem, M.O.; AlSayed, M.D.; Abdulrahim, M.M.; Al-Owain, M.; Awaji, A.; Mahmoud, A.A.H.; Faqeih, E.A.; Asmari, A.A.; Algain, S.M.; Jad, L.A.; Aldhalaan, H.M.; Helbig, I.; Koolen, D.A.; Riess, A.; Kraegeloh-Mann, I.; Bauer, P.; Gulsuner, S.; Stamberger, H.; Ng, A.Y.J.; Tang, S.; Tohari, S.; Keren, B.; Schultz-Rogers, L.E.; Klee, E.W.; Barresi, S.; Tartaglia, M.; Mor-Shaked, H.; Maddirevula, S.; Begtrup, A.; Telegrafi, A.; Pfundt, R.; Schüle, R.; Ciruna, B.; Bonnard, C.; Pouladi, M.A.; Stewart, J.C.; Claridge-Chang, A.; Lefeber, D.J.; Alkuraya, F.S.; Mathuru, A.S.; Venkatesh, B.; Barycki, J.J.; Simpson, M.A.; Jamuar, S.S.; Schöls, L, School of Medicine, Reversade, Bruno, Hengel, H.; Bosso-Lefèvre, C.; Grady, G.; Szenker-Ravi, E.; Li, H.; Pierce, S.; Lebigot, É.; Tan, T.-T.; Eio, M.Y.; Narayanan, G.; Utami, K.H.; Yau, M.; Handal, N.; Deigendesch, W.; Keimer, R.; Marzouqa, H.M.; Gunay-Aygun, M.; Muriello, M.J.; Verhelst, H.; Weckhuysen, S.; Mahida, S.; Naidu, S.; Thomas, T.G.; Lim, J.Y.; Tan, E.S.; Haye, D.; Willemsen, M.A.A.P.; Oegema, R.; Mitchell, W.G.; Pierson, T.M.; Andrews, M.V.; Willing, M.C.; Rodan, L.H.; Barakat, T.S.; van Slegtenhorst, M.; Gavrilova, R.H.; Martinelli, D.; Gilboa, T.; Tamim, A.M.; Hashem, M.O.; AlSayed, M.D.; Abdulrahim, M.M.; Al-Owain, M.; Awaji, A.; Mahmoud, A.A.H.; Faqeih, E.A.; Asmari, A.A.; Algain, S.M.; Jad, L.A.; Aldhalaan, H.M.; Helbig, I.; Koolen, D.A.; Riess, A.; Kraegeloh-Mann, I.; Bauer, P.; Gulsuner, S.; Stamberger, H.; Ng, A.Y.J.; Tang, S.; Tohari, S.; Keren, B.; Schultz-Rogers, L.E.; Klee, E.W.; Barresi, S.; Tartaglia, M.; Mor-Shaked, H.; Maddirevula, S.; Begtrup, A.; Telegrafi, A.; Pfundt, R.; Schüle, R.; Ciruna, B.; Bonnard, C.; Pouladi, M.A.; Stewart, J.C.; Claridge-Chang, A.; Lefeber, D.J.; Alkuraya, F.S.; Mathuru, A.S.; Venkatesh, B.; Barycki, J.J.; Simpson, M.A.; Jamuar, S.S.; Schöls, L, and School of Medicine

Abstract

Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients’ primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy., German Research Foundation (DFG); European Union (European Union); NEUROMICS Network; International Coordination Action (ICA); Fund for Scientific Research Flanders (FWO); Netherlands Organization for Scientific Research (ZONMW VIDI); National Medical Research Council, Singapore; A Strategic Positioning Fund on Genetic Orphan Diseases (GODAFIT); Industry Alignment Fund on Singapore Childhood Undiagnosed Diseases Program (SUREKids); Biomedical Research Council, A*STAR; Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular Diseases; Fondazione Bambino Gesù (Vite Coraggiose); Canadian Institutes of Health Research; Natural Sciences and Engineering Research Council of Canada; Eurocores Program EuroEPINOMICS; University of Antwerp Research Fund; FRAXA Foundation; Brain & Behavior Research Foundation, NARSAD Young Investigator Grant

Published
2020

12. Re-annotation of 191 developmental and epileptic encephalopathy-associated genes unmasks de novo variants in SCN1A

Author

Steward, CA, Roovers, J, Suner, M-M, Gonzalez, JM, Uszczynska-Ratajczak, B, Pervouchine, D, Fitzgerald, S, Viola, M, Stamberger, H, Hamdan, FF, Ceulemans, B, Leroy, P, Nava, C, Lepine, A, Tapanari, E, Keiller, D, Abbs, S, Sanchis-Juan, A, Grozeva, D, Rogers, AS, Diekhans, M, Guigo, R, Petryszak, R, Minassian, BA, Cavalleri, G, Vitsios, D, Petrovski, S, Harrow, J, Flicek, P, Raymond, FL, Lench, NJ, De Jonghe, P, Mudge, JM, Weckhuysen, S, Sisodiya, SM, Frankish, A, Steward, CA, Roovers, J, Suner, M-M, Gonzalez, JM, Uszczynska-Ratajczak, B, Pervouchine, D, Fitzgerald, S, Viola, M, Stamberger, H, Hamdan, FF, Ceulemans, B, Leroy, P, Nava, C, Lepine, A, Tapanari, E, Keiller, D, Abbs, S, Sanchis-Juan, A, Grozeva, D, Rogers, AS, Diekhans, M, Guigo, R, Petryszak, R, Minassian, BA, Cavalleri, G, Vitsios, D, Petrovski, S, Harrow, J, Flicek, P, Raymond, FL, Lench, NJ, De Jonghe, P, Mudge, JM, Weckhuysen, S, Sisodiya, SM, and Frankish, A

Abstract

The developmental and epileptic encephalopathies (DEE) are a group of rare, severe neurodevelopmental disorders, where even the most thorough sequencing studies leave 60-65% of patients without a molecular diagnosis. Here, we explore the incompleteness of transcript models used for exome and genome analysis as one potential explanation for a lack of current diagnoses. Therefore, we have updated the GENCODE gene annotation for 191 epilepsy-associated genes, using human brain-derived transcriptomic libraries and other data to build 3,550 putative transcript models. Our annotations increase the transcriptional 'footprint' of these genes by over 674 kb. Using SCN1A as a case study, due to its close phenotype/genotype correlation with Dravet syndrome, we screened 122 people with Dravet syndrome or a similar phenotype with a panel of exon sequences representing eight established genes and identified two de novo SCN1A variants that now - through improved gene annotation - are ascribed to residing among our exons. These two (from 122 screened people, 1.6%) molecular diagnoses carry significant clinical implications. Furthermore, we identified a previously classified SCN1A intronic Dravet syndrome-associated variant that now lies within a deeply conserved exon. Our findings illustrate the potential gains of thorough gene annotation in improving diagnostic yields for genetic disorders.

Published
2019

13. Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders

Author

Wolff, M. (Markus), Johannesen, K.M. (Katrine M.), Hedrich, U.B.S. (Ulrike B. S.), Masnada, S. (Silvia), Rubboli, G. (Guido), Gardella, E. (Elena), Lesca, G. (Gaetan), Ville, D. (Dorothée), Milh, M. (Mathieu), Villard, L. (Laurent), Afenjar, A. (Alexandra), Chantot-Bastaraud, S. (Sandra), Mignot, A., Lardennois, C. (Caroline), Nava, C. (Caroline), Schwarz, N. (Niklas), Gérard, M. (Marion), Perrin, L. (Laurence), Doummar, D. (Diane), Auvin, S. (Stéphane), Miranda, M.J. (Maria J.), Hempel, M. (Maja), Brilstra, E. (Eva), Knoers, N.V.A.M. (Nine), Verbeek, N.E. (Nienke), Kempen, M.J.A. (M. J A) van, Braun, K.P. (Kees P.), Mancini, G.M.S. (Grazia), Biskup, S. (Saskia), Hörtnagel, K. (Konstanze), Döcker, M. (Miriam), Bast, T. (Thomas), Loddenkemper, T. (Tobias), Wong-Kisiel, L. (Lily), Baumeister, F.M. (Friedrich M.), Fazeli, W. (Walid), Striano, P. (Pasquale), Dilena, R. (Robertino), Fontana, E. (Elena), Zara, F. (Federico), Kurlemann, G. (Gerhard), Klepper, J. (Joerg), Thoene, J.G. (Jess G.), Arndt, D.H. (Daniel H.), Deconinck, N. (Nicolas), Schmitt-Mechelke, T. (Thomas), Maier, O. (Oliver), Muhle, H. (Hiltrud), Wical, B. (Beverly), Finetti, C. (Claudio), Brückner, R. (Reinhard), Pietz, J. (Joachim), Golla, G. (Günther), Jillella, D. (Dinesh), Linnet, K.M. (Karen M.), Charles, P. (Perrine), Moog, U. (Ute), Õiglane-Shlik, E. (Eve), Mantovani, J.F. (John F.), Park, K. (Kristen), Deprez, M. (Marie), Lederer, D. (Damien), Mary, S. (Sandrine), Scalais, E. (Emmanuel), Selim, L. (Laila), Coster, R.N.A. (R. N A) van, Lagae, L. (Lieven), Nikanorova, M. (Marina), Hjalgrim, H. (Helle), Korenke, G.C. (Christoph), Trivisano, M. (Marina), Specchio, N. (Nicola), Ceulemans, B. (Berten), Dorn, T. (Thomas), Helbig, K.L. (Katherine L.), Hardies, K. (K.), Stamberger, H. (Hannah), Jonghe, P. (P.) de, Weckhuysen, S. (Sarah), Lemke, J.R. (Johannes R.), Krägeloh-Mann, I. (Ingeborg), Helbig, I. (Ingo), Kluger, G. (Gerhard), Lerche, H. (Holger), Møller, R.S. (Rikke), Wolff, M. (Markus), Johannesen, K.M. (Katrine M.), Hedrich, U.B.S. (Ulrike B. S.), Masnada, S. (Silvia), Rubboli, G. (Guido), Gardella, E. (Elena), Lesca, G. (Gaetan), Ville, D. (Dorothée), Milh, M. (Mathieu), Villard, L. (Laurent), Afenjar, A. (Alexandra), Chantot-Bastaraud, S. (Sandra), Mignot, A., Lardennois, C. (Caroline), Nava, C. (Caroline), Schwarz, N. (Niklas), Gérard, M. (Marion), Perrin, L. (Laurence), Doummar, D. (Diane), Auvin, S. (Stéphane), Miranda, M.J. (Maria J.), Hempel, M. (Maja), Brilstra, E. (Eva), Knoers, N.V.A.M. (Nine), Verbeek, N.E. (Nienke), Kempen, M.J.A. (M. J A) van, Braun, K.P. (Kees P.), Mancini, G.M.S. (Grazia), Biskup, S. (Saskia), Hörtnagel, K. (Konstanze), Döcker, M. (Miriam), Bast, T. (Thomas), Loddenkemper, T. (Tobias), Wong-Kisiel, L. (Lily), Baumeister, F.M. (Friedrich M.), Fazeli, W. (Walid), Striano, P. (Pasquale), Dilena, R. (Robertino), Fontana, E. (Elena), Zara, F. (Federico), Kurlemann, G. (Gerhard), Klepper, J. (Joerg), Thoene, J.G. (Jess G.), Arndt, D.H. (Daniel H.), Deconinck, N. (Nicolas), Schmitt-Mechelke, T. (Thomas), Maier, O. (Oliver), Muhle, H. (Hiltrud), Wical, B. (Beverly), Finetti, C. (Claudio), Brückner, R. (Reinhard), Pietz, J. (Joachim), Golla, G. (Günther), Jillella, D. (Dinesh), Linnet, K.M. (Karen M.), Charles, P. (Perrine), Moog, U. (Ute), Õiglane-Shlik, E. (Eve), Mantovani, J.F. (John F.), Park, K. (Kristen), Deprez, M. (Marie), Lederer, D. (Damien), Mary, S. (Sandrine), Scalais, E. (Emmanuel), Selim, L. (Laila), Coster, R.N.A. (R. N A) van, Lagae, L. (Lieven), Nikanorova, M. (Marina), Hjalgrim, H. (Helle), Korenke, G.C. (Christoph), Trivisano, M. (Marina), Specchio, N. (Nicola), Ceulemans, B. (Berten), Dorn, T. (Thomas), Helbig, K.L. (Katherine L.), Hardies, K. (K.), Stamberger, H. (Hannah), Jonghe, P. (P.) de, Weckhuysen, S. (Sarah), Lemke, J.R. (Johannes R.), Krägeloh-Mann, I. (Ingeborg), Helbig, I. (Ingo), Kluger, G. (Gerhard), Lerche, H. (Holger), and Møller, R.S. (Rikke)

Abstract

Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) occur almost as often as those with an early infantile onset (<3 months), and are thus more frequent than previously reported; (ii) distinct phenotypes can be seen within the late onset group, including myoclonic-atonic epilepsy (two patients), Lennox-Gastaut not emerging from West syndrome (two patients), and focal epilepsies with an electrical status epilepticus during slow sleep-like EEG pattern (six patients); and (iii) West syndrome constitutes a common phenotype with a major recurring mutation (p.Arg853Gln: two new and four previously reported children). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatme

Published
2017
Full Text
View/download PDF

14. STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy

Author

Stamberger, H., Nikanorova, M., Willemsen, M.H., Accorsi, P., Angriman, M., Baier, H., Benkel-Herrenbrueck, I., Benoit, V., Budetta, M., Caliebe, A., Cantalupo, G., Capovilla, G., Casara, G., Courage, C., Deprez, M., Destree, A., Dilena, R., Erasmus, C.E., Fannemel, M., Fjaer, R., Giordano, L., Helbig, K.L., Heyne, H.O., Klepper, J., Kluger, G.J., Lederer, D., Lodi, M., Maier, O., Merkenschlager, A., Michelberger, N., Minetti, C., Muhle, H., Phalin, J., Ramsey, K., Romeo, A., Schallner, J., Schanze, I., Shinawi, M., Sleegers, K., Sterbova, K., Syrbe, S., Traverso, M., Tzschach, A., Uldall, P., Coster, R. van, Verhelst, H., Viri, M., Winter, S., Wolff, M., Zenker, M., Zoccante, L., Jonghe, P. De, Helbig, I., Striano, P., Lemke, J.R., Moller, R.S., Weckhuysen, S., Stamberger, H., Nikanorova, M., Willemsen, M.H., Accorsi, P., Angriman, M., Baier, H., Benkel-Herrenbrueck, I., Benoit, V., Budetta, M., Caliebe, A., Cantalupo, G., Capovilla, G., Casara, G., Courage, C., Deprez, M., Destree, A., Dilena, R., Erasmus, C.E., Fannemel, M., Fjaer, R., Giordano, L., Helbig, K.L., Heyne, H.O., Klepper, J., Kluger, G.J., Lederer, D., Lodi, M., Maier, O., Merkenschlager, A., Michelberger, N., Minetti, C., Muhle, H., Phalin, J., Ramsey, K., Romeo, A., Schallner, J., Schanze, I., Shinawi, M., Sleegers, K., Sterbova, K., Syrbe, S., Traverso, M., Tzschach, A., Uldall, P., Coster, R. van, Verhelst, H., Viri, M., Winter, S., Wolff, M., Zenker, M., Zoccante, L., Jonghe, P. De, Helbig, I., Striano, P., Lemke, J.R., Moller, R.S., and Weckhuysen, S.

Abstract

Contains fulltext : 168130.pdf (publisher's version ) (Closed access), OBJECTIVE: To give a comprehensive overview of the phenotypic and genetic spectrum of STXBP1 encephalopathy (STXBP1-E) by systematically reviewing newly diagnosed and previously reported patients. METHODS: We recruited newly diagnosed patients with STXBP1 mutations through an international network of clinicians and geneticists. Furthermore, we performed a systematic literature search to review the phenotypes of all previously reported patients. RESULTS: We describe the phenotypic features of 147 patients with STXBP1-E including 45 previously unreported patients with 33 novel STXBP1 mutations. All patients have intellectual disability (ID), which is mostly severe to profound (88%). Ninety-five percent of patients have epilepsy. While one-third of patients presented with Ohtahara syndrome (21%) or West syndrome (9.5%), the majority has a nonsyndromic early-onset epilepsy and encephalopathy (53%) with epileptic spasms or tonic seizures as main seizure type. We found no correlation between severity of seizures and severity of ID or between mutation type and seizure characteristics or cognitive outcome. Neurologic comorbidities including autistic features and movement disorders are frequent. We also report 2 previously unreported adult patients with prominent extrapyramidal features. CONCLUSION: De novo STXBP1 mutations are among the most frequent causes of epilepsy and encephalopathy. Most patients have severe to profound ID with little correlation among seizure onset, seizure severity, and the degree of ID. Accordingly, we hypothesize that seizure severity and ID present 2 independent dimensions of the STXBP1-E phenotype. STXBP1-E may be conceptualized as a complex neurodevelopmental disorder rather than a primary epileptic encephalopathy.

Published
2016

16. STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy

Author

Stamberger, H., Nikanorova, M., Willemsen, M.H., Accorsi, P., Angriman, M., Baier, H., Benkel-Herrenbrueck, I., Benoit, V., Budetta, M., Caliebe, A., Cantalupo, G., Capovilla, G., Casara, G., Courage, C., Deprez, M., Destree, A., Dilena, R., Erasmus, C.E., Fannemel, M., Fjaer, R., Giordano, L., Helbig, K.L., Heyne, H.O., Klepper, J., Kluger, G.J., Lederer, D., Lodi, M., Maier, O., Merkenschlager, A., Michelberger, N., Minetti, C., Muhle, H., Phalin, J., Ramsey, K., Romeo, A., Schallner, J., Schanze, I., Shinawi, M., Sleegers, K., Sterbova, K., Syrbe, S., Traverso, M., Tzschach, A., Uldall, P., Coster, R. van, Verhelst, H., Viri, M., Winter, S., Wolff, M., Zenker, M., Zoccante, L., Jonghe, P. De, Helbig, I., Striano, P., Lemke, J.R., Moller, R.S., Weckhuysen, S., Stamberger, H., Nikanorova, M., Willemsen, M.H., Accorsi, P., Angriman, M., Baier, H., Benkel-Herrenbrueck, I., Benoit, V., Budetta, M., Caliebe, A., Cantalupo, G., Capovilla, G., Casara, G., Courage, C., Deprez, M., Destree, A., Dilena, R., Erasmus, C.E., Fannemel, M., Fjaer, R., Giordano, L., Helbig, K.L., Heyne, H.O., Klepper, J., Kluger, G.J., Lederer, D., Lodi, M., Maier, O., Merkenschlager, A., Michelberger, N., Minetti, C., Muhle, H., Phalin, J., Ramsey, K., Romeo, A., Schallner, J., Schanze, I., Shinawi, M., Sleegers, K., Sterbova, K., Syrbe, S., Traverso, M., Tzschach, A., Uldall, P., Coster, R. van, Verhelst, H., Viri, M., Winter, S., Wolff, M., Zenker, M., Zoccante, L., Jonghe, P. De, Helbig, I., Striano, P., Lemke, J.R., Moller, R.S., and Weckhuysen, S.

Abstract

Contains fulltext : 168130.pdf (publisher's version ) (Closed access), OBJECTIVE: To give a comprehensive overview of the phenotypic and genetic spectrum of STXBP1 encephalopathy (STXBP1-E) by systematically reviewing newly diagnosed and previously reported patients. METHODS: We recruited newly diagnosed patients with STXBP1 mutations through an international network of clinicians and geneticists. Furthermore, we performed a systematic literature search to review the phenotypes of all previously reported patients. RESULTS: We describe the phenotypic features of 147 patients with STXBP1-E including 45 previously unreported patients with 33 novel STXBP1 mutations. All patients have intellectual disability (ID), which is mostly severe to profound (88%). Ninety-five percent of patients have epilepsy. While one-third of patients presented with Ohtahara syndrome (21%) or West syndrome (9.5%), the majority has a nonsyndromic early-onset epilepsy and encephalopathy (53%) with epileptic spasms or tonic seizures as main seizure type. We found no correlation between severity of seizures and severity of ID or between mutation type and seizure characteristics or cognitive outcome. Neurologic comorbidities including autistic features and movement disorders are frequent. We also report 2 previously unreported adult patients with prominent extrapyramidal features. CONCLUSION: De novo STXBP1 mutations are among the most frequent causes of epilepsy and encephalopathy. Most patients have severe to profound ID with little correlation among seizure onset, seizure severity, and the degree of ID. Accordingly, we hypothesize that seizure severity and ID present 2 independent dimensions of the STXBP1-E phenotype. STXBP1-E may be conceptualized as a complex neurodevelopmental disorder rather than a primary epileptic encephalopathy.

Published
2016

17. STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy

Author

Stamberger, H., Nikanorova, M., Willemsen, M.H., Accorsi, P., Angriman, M., Baier, H., Benkel-Herrenbrueck, I., Benoit, V., Budetta, M., Caliebe, A., Cantalupo, G., Capovilla, G., Casara, G., Courage, C., Deprez, M., Destree, A., Dilena, R., Erasmus, C.E., Fannemel, M., Fjaer, R., Giordano, L., Helbig, K.L., Heyne, H.O., Klepper, J., Kluger, G.J., Lederer, D., Lodi, M., Maier, O., Merkenschlager, A., Michelberger, N., Minetti, C., Muhle, H., Phalin, J., Ramsey, K., Romeo, A., Schallner, J., Schanze, I., Shinawi, M., Sleegers, K., Sterbova, K., Syrbe, S., Traverso, M., Tzschach, A., Uldall, P., Coster, R. van, Verhelst, H., Viri, M., Winter, S., Wolff, M., Zenker, M., Zoccante, L., Jonghe, P. De, Helbig, I., Striano, P., Lemke, J.R., Moller, R.S., Weckhuysen, S., Stamberger, H., Nikanorova, M., Willemsen, M.H., Accorsi, P., Angriman, M., Baier, H., Benkel-Herrenbrueck, I., Benoit, V., Budetta, M., Caliebe, A., Cantalupo, G., Capovilla, G., Casara, G., Courage, C., Deprez, M., Destree, A., Dilena, R., Erasmus, C.E., Fannemel, M., Fjaer, R., Giordano, L., Helbig, K.L., Heyne, H.O., Klepper, J., Kluger, G.J., Lederer, D., Lodi, M., Maier, O., Merkenschlager, A., Michelberger, N., Minetti, C., Muhle, H., Phalin, J., Ramsey, K., Romeo, A., Schallner, J., Schanze, I., Shinawi, M., Sleegers, K., Sterbova, K., Syrbe, S., Traverso, M., Tzschach, A., Uldall, P., Coster, R. van, Verhelst, H., Viri, M., Winter, S., Wolff, M., Zenker, M., Zoccante, L., Jonghe, P. De, Helbig, I., Striano, P., Lemke, J.R., Moller, R.S., and Weckhuysen, S.

Abstract

Contains fulltext : 168130.pdf (publisher's version ) (Closed access), OBJECTIVE: To give a comprehensive overview of the phenotypic and genetic spectrum of STXBP1 encephalopathy (STXBP1-E) by systematically reviewing newly diagnosed and previously reported patients. METHODS: We recruited newly diagnosed patients with STXBP1 mutations through an international network of clinicians and geneticists. Furthermore, we performed a systematic literature search to review the phenotypes of all previously reported patients. RESULTS: We describe the phenotypic features of 147 patients with STXBP1-E including 45 previously unreported patients with 33 novel STXBP1 mutations. All patients have intellectual disability (ID), which is mostly severe to profound (88%). Ninety-five percent of patients have epilepsy. While one-third of patients presented with Ohtahara syndrome (21%) or West syndrome (9.5%), the majority has a nonsyndromic early-onset epilepsy and encephalopathy (53%) with epileptic spasms or tonic seizures as main seizure type. We found no correlation between severity of seizures and severity of ID or between mutation type and seizure characteristics or cognitive outcome. Neurologic comorbidities including autistic features and movement disorders are frequent. We also report 2 previously unreported adult patients with prominent extrapyramidal features. CONCLUSION: De novo STXBP1 mutations are among the most frequent causes of epilepsy and encephalopathy. Most patients have severe to profound ID with little correlation among seizure onset, seizure severity, and the degree of ID. Accordingly, we hypothesize that seizure severity and ID present 2 independent dimensions of the STXBP1-E phenotype. STXBP1-E may be conceptualized as a complex neurodevelopmental disorder rather than a primary epileptic encephalopathy.

Published
2016

Catalog

Books, media, physical & digital resources
See catalog results