Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia–associated epilepsy
Open accessAbstract
DEP domain-containing 5 protein (DEPDC5) is a repressor of the recently recognized amino acid-sensing branch of the mTORC1 pathway. So far, its function in the brain remains largely unknown. Germline loss-of-function mutations in DEPDC5 have emerged as a major cause of familial refractory focal epilepsies, with case reports of sudden unexpected death in epilepsy (SUDEP). Remarkably, a fraction of patients also develop focal cortical dysplasia (FCD), a neurodevelopmental cortical malformation. We therefore hypothesized that a somatic second-hit mutation arising during brain development may support the focal nature of the dysplasia. Here, using postoperative human tissue, we provide the proof of concept that a biallelic 2-hit - brain somatic and germline - mutational mechanism in DEPDC5 causes focal epilepsy with FCD. We discovered a mutation gradient with a higher rate of mosaicism in the seizure-onset zone than in the surrounding epileptogenic zone. Furthermore, we demonstrate the causality of a Depdc5 brain mosaic inactivation using CRISPR-Cas9 editing and in utero electroporation in a mouse model recapitulating focal epilepsy with FCD and SUDEP-like events. We further unveil a key role of Depdc5 in shaping dendrite and spine morphology of excitatory neurons. This study reveals promising therapeutic avenues for treating drug-resistant focal epilepsies with mTORC1-targeting molecules.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In some individuals, a second genetic hit with a combination of both somatic and germline mutations in the same gene or genes in related pathways (eg mTOR pathway) is identified.
“In some individuals, a second genetic hit with a combination of both somatic and germline mutations in the same gene or genes in related pathways (eg.mTOR pathway) is identified 124 .”
From Developmental and epileptic encephalopathies (2024) · cites this paper as [124]
The Results and Discussion report a child with an inherited DEPDC5 variant and a second, somatic DEPDC5 variant in brain tissue, supporting a two-hit mechanism in the same mTORC1-pathway gene. The paper does not establish a two-hit combination across different genes in related pathways. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMCD, including FCD, may be associated with a pathogenic germline or somatic variant, which may show a mutation gradient in resected brain tissue.
“MCD, including FCD, may be associated with a pathogenic germline or somatic variant, which may show a mutation gradient in resected brain tissue.”
From Developmental and epileptic encephalopathies (2024) · cites this paper as [124]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
CRISPR-Cas9 Knockin Mice for Genome Editing and Cancer Modeling
Platt, R. J., Chen, S., Zhou, Y., Yim, M. J., Swiech, L., Kempton, H. R., Dahlman, J. E., Parnas, O., Eisenhaure, T. M., Jovanovic, M., et al. (2014) · Cell · doi:10.1016/j.cell.2014.09.014 · Cited by 2,001 · see citing works
Blümcke, I., Thom, M., Aronica, E., Armstrong, D. D., Vinters, H. V., Palmini, A., Jacques, T. S., AVANZINI, G., Barkovich, A. J., Battaglia, G. S., et al. (2010) · Epilepsia · doi:10.1111/j.1528-1167.2010.02777.x · Cited by 1,746 · see citing works
Dendritic spine pathology in neuropsychiatric disorders
Penzes, P., Cahill, M. E., Jones, K. A., VanLeeuwen, J.-E., & Woolfrey, K. M. (2011) · Nature Neuroscience · doi:10.1038/nn.2741 · Cited by 1,523 · see citing works
Bar-Peled, L., Chantranupong, L., Cherniack, A. D., Chen, W. W., Ottina, K. A., Grabiner, B. C., Spear, E. D., Carter, S. L., Meyerson, M., & Sabatini, D. M. (2013) · Science · doi:10.1126/science.1232044 · Cited by 1,080 · see citing works
Histopathological Findings in Brain Tissue Obtained during Epilepsy Surgery
Blümcke, I., Spreafico, R., Haaker, G., Coras, R., Kobow, K., Bien, C. G., Pfäfflin, M., Elger, C. E., Widman, G., Schramm, J., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1703784 · Cited by 935 · see citing works
French, J. A., Lawson, J. A., Yapici, Z., Ikeda, H., Polster, T., Nabbout, R., Curatolo, P., de Vries, P. J., Dlugos, D. J., Berkowitz, N., et al. (2016) · The Lancet · doi:10.1016/s0140-6736(16)31419-2 · Cited by 764 · see citing works
Somatic mutation, genomic variation, and neurological disease
Poduri, A., Evrony, G. D., Cai, X., & Walsh, C. A. (2013) · Science · doi:10.1126/science.1237758 · Cited by 584 · see citing works
Lim, J. S., Kim, W.-I., Kang, H., Kim, S. H., Park, A. H., Park, E. K., Cho, Y., Kim, H. M., Kim, J. A., Kim, J. A., et al. (2015) · Nature Medicine · doi:10.1038/nm.3824 · Cited by 524 · see citing works
Aiba, I., & Noebels, J. L. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aaa4050 · Cited by 337 · see citing works
Bagnall, R. D., Crompton, D. E., Petrovski, S., Lam, L., Cutmore, C., Garry, S. I., Sadleir, L. G., Dibbens, L. M., Cairns, A. G., Kivity, S., et al. (2015) · Annals of Neurology · doi:10.1002/ana.24596 · Cited by 283 · see citing works
Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations
Baulac, S., Ishida, S., Marsan, E., Miquel, C., Biraben, A., Nguyen, D., Nordli, D., Cossette, P., Nguyen, S., Lambrecq, V., et al. (2015) · Annals of Neurology · doi:10.1002/ana.24368 · Cited by 279 · see citing works
Self-citationMirzaa, G., Campbell, C., Solovieff, N., Goold, C. P., Jansen, L., Menon, S., Timms, A., Conti, V., Biag, J., Adams, C., et al. (2016) · JAMA Neurology · doi:10.1001/jamaneurol.2016.0363 · Cited by 246 · see citing works
Hoang, M. L., Kinde, I., Tomasetti, C., McMahon, K. W., Rosenquist, T. A., Grollman, A. P., Kinzler, K. W., Vogelstein, B., & Papadopoulos, N. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1607794113 · Cited by 224 · see citing works
Somatic Mutations in the MTOR gene cause focal cortical dysplasia type IIb
Nakashima, M., Saitsu, H., Takei, N., Tohyama, J., Kato, M., Kitaura, H., Shiina, M., Shirozu, H., Masuda, H., Watanabe, K., et al. (2015) · Annals of Neurology · doi:10.1002/ana.24444 · Cited by 184 · see citing works
Review: Mechanistic target of rapamycin (mTOR) pathway, focal cortical dysplasia and epilepsy
Marsan, E., & Baulac, S. (2018) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12463 · Cited by 162 · see citing works
Self-citationGermline and somatic mutations in the MTOR gene in focal cortical dysplasia and epilepsy
Møller, R., Weckhuysen, S., Chipaux, M., Marsan, E., Taly, V., Bebin, E., Hiatt, S., Prokop, J., Bowling, K. M., Mei, D., et al. (2016) · Neurology: Genetics · doi:10.1212/nxg.0000000000000118 · Cited by 138 · see citing works
Self-citationNew and Improved Tools for In Utero Electroporation Studies of Developing Cerebral Cortex
LoTurco, J. J., Manent, J., & Siddiqi, F. (2009) · Cerebral Cortex · doi:10.1093/cercor/bhp033 · Cited by 129 · see citing works
Depdc5 knockout rat: A novel model of mTORopathy.
Marsan, E., Ishida, S., Schramm, A. E., Weckhuysen, S., Muraca, G., Lecas, S., Liang, N., Treins, C., Pende, M., Roussel, D., et al. (2016) · Neurobiology of Disease · doi:10.1016/j.nbd.2016.02.010 · Cited by 95 · see citing works
Self-citationmTOR signaling pathway genes in focal epilepsies
Baulac, S. (2016) · Progress in Brain Research · doi:10.1016/bs.pbr.2016.04.013 · Cited by 84 · see citing works
Self-citationUnderestimation of sudden deaths among patients with seizures and epilepsy
Devinsky, O., Friedman, D. J., Cheng, J. Y., Moffatt, E., Kim, A., & Tseng, Z. H. (2017) · Neurology · doi:10.1212/wnl.0000000000004292 · Cited by 83 · see citing works
Cardiac arrhythmia in a mouse model of sodium channel SCN8A epileptic encephalopathy
Frasier, C. R., Wagnon, J. L., Bao, Y. O., McVeigh, L. G., Lopez‐Santiago, L. F., Meisler, M. H., & Isom, L. L. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1612746113 · Cited by 80 · see citing works
Two definite cases of sudden unexpected death in epilepsy in a family with a DEPDC5 mutation
Nascimento, F. A., Borlot, F., Cossette, P., Minassian, B. A., & Andrade, D. M. (2015) · Neurology Genetics · doi:10.1212/nxg.0000000000000028 · Cited by 64 · see citing works
Leaky RyR2 channels unleash a brainstem spreading depolarization mechanism of sudden cardiac death
Aiba, I., Wehrens, X. H. T., & Noebels, J. L. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1605216113 · Cited by 64 · see citing works
In Utero Electroporation as a Tool For Genetic Manipulation In Vivo to Study Psychiatric Disorders
Taniguchi, Y., Young‐Pearse, T. L., Sawa, A., & Kamiya, A. (2011) · The Neuroscientist · doi:10.1177/1073858411399925 · Cited by 62 · see citing works
Hughes, J. N., Dawson, R. E., Tea, M. N., McAninch, D., Piltz, S. G., Jackson, D., Stewart, L. W., Ricos, M. G., Dibbens, L., Harvey, N. L., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-12574-2 · Cited by 53 · see citing works
DEPDC5 as a potential therapeutic target for epilepsy
Myers, K., & Scheffer, I. (2017) · Expert opinion on therapeutic targets · doi:10.1080/14728222.2017.1316715 · Cited by 40 · see citing works
Burger, B., Rose, S., Bennuri, S. C., Gill, P. S., Tippett, M., Delhey, L., Melnyk, S., & Frye, R. (2017) · Frontiers in Pediatrics · doi:10.3389/fped.2017.00219 · Cited by 32 · see citing works
The evolving landscape of epilepsy neuropathology
French, J. A., & Friedman, D. J. (2017) · The Lancet Neurology · doi:10.1016/s1474-4422(17)30429-5 · Cited by 7 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Goldman AM, Buchanan G, Aiba I, Noebels JL. SUDEP animal Models. In: Pitkänen A, Buck- master P, Galanopoulou A, Moshé S, eds. Models of Seizures and Epilepsy (Second edition). Amster- dam, Netherlands:Elsevier;2017:1007-1018.
Cited by
Sorted by citations
Neurodevelopmental Disorders: From Genetics to Functional Pathways
Parenti, I., Rabaneda, L. G., Schoen, H., & Novarino, G. (2020) · Trends in Neurosciences · doi:10.1016/j.tins.2020.05.004 · Cited by 634 · see citing works
Najm, I., Lal, D., Alonso‐Vanegas, M., Cendes, F., Lopes‐Cendes, Í., Palmini, A., Paglioli, E., Sarnat, H. B., Walsh, C. A., Wiebe, S., et al. (2022) · Epilepsia · doi:10.1111/epi.17301 · Cited by 368 · see citing works
Self-citationDissecting the genetic basis of focal cortical dysplasia: a large cohort study
Baldassari, S., Ribierre, T., Marsan, E., Adle-Biassette, H., Ferrand-Sorbets, S., Bulteau, C., Dorison, N., Fohlen, M., Polivka, M., Weckhuysen, S., et al. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-02061-5 · Cited by 356 · see citing works
Self-citationDefinitions and classification of malformations of cortical development: practical guidelines
Severino, M., Geraldo, A. F., Utz, N., Tortora, D., Pogledić, I., Klonowski, W., Triulzi, F. M., Arrigoni, F., Mankad, K., Leventer, R. J., et al. (2020) · Brain · doi:10.1093/brain/awaa174 · Cited by 312 · see citing works
The landscape of epilepsy-related GATOR1 variants
Baldassari, S., Picard, F., Verbeek, N., van Kempen, M., Brilstra, E., Lesca, G., Conti, V., Guerrini, R., Bisulli, F., Licchetta, L., et al. (2018) · Genetics in Medicine · doi:10.1038/s41436-018-0060-2 · Cited by 216 · see citing works
Self-citationPerucca, P., Bahlo, M., & Berkovic, S. F. (2020) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-120219-074937 · Cited by 235 · see citing works
Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum
Guerrini, R., Conti, V., Mantegazza, M., Balestrini, S., Galanopoulou, A. S., & Benfenati, F. (2023) · Physiological Reviews · doi:10.1152/physrev.00063.2021 · Cited by 196 · see citing works
Precision medicine and therapies of the future
Sisodiya, S. (2020) · Epilepsia · doi:10.1111/epi.16539 · Cited by 139 · see citing works
Oegema, R., Barakat, T. S., Wilke, M., Stouffs, K., Amrom, D., Aronica, E., Bahi‐Buisson, N., Conti, V., Fry, A. E., Geis, T., et al. (2020) · Nature Reviews Neurology · doi:10.1038/s41582-020-0395-6 · Cited by 147 · see citing works
Precise detection of low-level somatic mutation in resected epilepsy brain tissue
Sim, N. S., Ko, A., Kim, W. K., Kim, S. H., Kim, J. S., Shim, K.-W., Aronica, E., Mijnsbergen, C., Spliet, W. G. M., Koh, H. Y., et al. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-02052-6 · Cited by 137 · see citing works
Cortical Malformations: Lessons in Human Brain Development
Subramanian, L., Calcagnotto, M. E., & Paredes, M. F. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00576 · Cited by 131 · see citing works
Developmental and epileptic encephalopathies
Scheffer, I. E., Zuberi, S., Mefford, H. C., Guerrini, R., & McTague, A. (2024) · Nature Reviews Disease Primers · doi:10.1038/s41572-024-00546-6 · Cited by 128 · see citing works
Epilepsy in the mTORopathies: opportunities for precision medicine
Moloney, P. B., Cavalleri, G. L., & Delanty, N. (2021) · Brain Communications · doi:10.1093/braincomms/fcab222 · Cited by 126 · see citing works
Epilepsy genetics: Current knowledge, applications, and future directions
Myers, K. A., Johnstone, D. L., & Dyment, D. A. (2018) · Clinical Genetics · doi:10.1111/cge.13414 · Cited by 118 · see citing works
Monogenic Epilepsies: Disease Mechanisms, Clinical Phenotypes, and Targeted Therapies
Guerrini, R., Balestrini, S., Wirrell, E. C., & Walker, M. C. (2021) · Neurology · doi:10.1212/wnl.0000000000012744 · Cited by 108 · see citing works
Mühlebner, A., Bongaarts, A., Sarnat, H. B., Scholl, T. O., & Aronica, E. (2019) · Journal of Anatomy · doi:10.1111/joa.12956 · Cited by 96 · see citing works
Neocortical development and epilepsy: insights from focal cortical dysplasia and brain tumours.
Blümcke, I., Budday, S., Poduri, A., Lal, D., Kobow, K., & Baulac, S. (2021) · Lancet Neurology · doi:10.1016/s1474-4422(21)00265-9 · Cited by 83 · see citing works
Self-citationBlümcke, I., Coras, R., Busch, R. M., Morita, M. E., Lal, D., Prayson, R. A., Cendes, F., Lopes‐Cendes, Í., Rogério, F., de Almeida, V. S., et al. (2021) · Epilepsia · doi:10.1111/epi.16899 · Cited by 96 · see citing works
Self-citationNeuroinflammation: A Signature or a Cause of Epilepsy?
Pracucci, E., Pillai, V., Lamers, D., Parra, R., & Landi, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22136981 · Cited by 94 · see citing works
Iffland, P. H., Carson, V., Bordey, A., & Crino, P. B. (2019) · Epilepsia · doi:10.1111/epi.16370 · Cited by 84 · see citing works
mTOR pathway: Insights into an established pathway for brain mosaicism in epilepsy.
Gerasimenko, A., Baldassari, S., & Baulac, S. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106144 · Cited by 76 · see citing works
Self-citationSomatic variants in diverse genes leads to a spectrum of focal cortical malformations
Lai, D., Gade, M., Yang, E., Koh, H. Y., Lü, J., Walley, N. M., Buckley, A. F., Sands, T. T., Akman, Ç. I., Mikati, M. A., et al. (2022) · Brain · doi:10.1093/brain/awac117 · Cited by 84 · see citing works
Genetic mosaicism in the human brain: from lineage tracing to neuropsychiatric disorders
Bizzotto, S., & Walsh, C. A. (2022) · Nature reviews. Neuroscience · doi:10.1038/s41583-022-00572-x · Cited by 84 · see citing works
Second‐hit DEPDC5 mutation is limited to dysmorphic neurons in cortical dysplasia type IIA
Lee, W. S., Stephenson, S. E. M., Howell, K. B., Pope, K., Gillies, G., Wray, A. C., Maixner, W. J., Mandelstam, S. A., Berkovic, S. F., Scheffer, I. E., et al. (2019) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.50815 · Cited by 80 · see citing works
The genomic landscape across 474 surgically accessible epileptogenic human brain lesions
López-Rivera, J. A., Leu, C., Macnee, M., Khoury, J., Hoffmann, L., Coras, R., Kobow, K., Bhattarai, N., Pérez‐Palma, E., Hamer, H. M., et al. (2022) · Brain · doi:10.1093/brain/awac376 · Cited by 74 · see citing works
Disorders of neurogenesis and cortical development
Guarnieri, F. C., de Chevigny, A., Falace, A., & Cardoso, C. (2018) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2018.20.4/ccardoso · Cited by 74 · see citing works
Convergent and Divergent Mechanisms of Epileptogenesis in mTORopathies
Nguyen, L. H., & Bordey, A. (2021) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2021.664695 · Cited by 72 · see citing works
Current Approaches and Future Directions for the Treatment of mTORopathies
Karalis, V., & Bateup, H. S. (2021) · Developmental Neuroscience · doi:10.1159/000515672 · Cited by 67 · see citing works
Focal epilepsies: Update on diagnosis and classification
Nascimento, F. A., Friedman, D. J., Peters, J. M., Bensalem‐Owen, M., Cendes, F., Rampp, S., Wirrell, E. C., Blümcke, I., Tatum, W. O., & Beniczky, S. (2023) · Epileptic Disorders · doi:10.1002/epd2.20045 · Cited by 68 · see citing works
Regulation and repurposing of nutrient sensing and autophagy in innate immunity
Sanchez‐Garrido, J., & Shenoy, A. R. (2020) · Autophagy · doi:10.1080/15548627.2020.1783119 · Cited by 66 · see citing works
Focal cortical dysplasia: an update on diagnosis and treatment
Guerrini, R., & Barba, C. (2021) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2021.1915135 · Cited by 64 · see citing works
Somatic double-hit in MTOR and RPS6 in hemimegalencephaly with intractable epilepsy
Pelorosso, C., Françoise Watrin, A., Conti, V., Buhler, E., Gélot, A., Yang, X., Mei, D., McEvoy‐Venneri, J., Manent, J., Cetica, V., et al. (2019) · Human Molecular Genetics · doi:10.1093/hmg/ddz194 · Cited by 63 · see citing works
Marmiesse, A. F., Roca, I., Díaz-Flores, F., Cantarín, V., Pérez-Poyato, M. S., Fontalba, A., Laranjeira, F., Quintans, S., Moldovan, O., Felgueroso, B., et al. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.01135 · Cited by 64 · see citing works
Somatic mutation: The hidden genetics of brain malformations and focal epilepsies
Ye, Z., McQuillan, L., Poduri, A., Green, T. E., Matsumoto, N., Mefford, H. C., Scheffer, I. E., Berkovic, S. F., & Hildebrand, M. S. (2019) · Epilepsy Research · doi:10.1016/j.eplepsyres.2019.106161 · Cited by 61 · see citing works
Ribierre, T., Bacq, A., Donneger, F., Doladilhe, M., Maletic, M., Roussel, D., Roux, I. L., Chassoux, F., Devaux, B. C., Adle‐Biassette, H., et al. (2024) · Nature Neuroscience · doi:10.1038/s41593-024-01634-2 · Cited by 62 · see citing works
Self-citationEctopic HCN4 expression drives mTOR-dependent epilepsy in mice
Hsieh, L. S., Wen, J. H., Nguyen, L. H., Zhang, L., Getz, S. A., Torres-Reveron, J., Wang, Y., Spencer, D. D., & Bordey, A. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.abc1492 · Cited by 51 · see citing works
DEPDC5-related epilepsy: A comprehensive review.
Samanta, D. (2022) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2022.108678 · Cited by 52 · see citing works
Onori, M. P., Koene, L. M. C., Schäfer, C. B., Nellist, M. D., van Velze, M. D. B., Gao, Z., Elgersma, Y., & van Woerden, G. M. (2021) · PLoS Biology · doi:10.1371/journal.pbio.3001279 · Cited by 57 · see citing works
Why Malformations of Cortical Development Cause Epilepsy
Represa, A. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00250 · Cited by 57 · see citing works
Detection of brain somatic variation in epilepsy‐associated developmental lesions
Bedrosian, T. A., Miller, K. E., Grischow, O. E., Schieffer, K. M., LaHaye, S., Yoon, H., Miller, A. R., Navarro, J. B., Westfall, J. J., Leraas, K., et al. (2022) · Epilepsia · doi:10.1111/epi.17323 · Cited by 55 · see citing works
Pirozzi, F., Berkseth, M., Shear, R., Gonzalez, L., Timms, A. E., Sulc, J., Pao, E., Oyama, N., Forzano, F., Conti, V., et al. (2022) · Brain · doi:10.1093/brain/awab376 · Cited by 54 · see citing works
The role of de novo mutations in adult-onset neurodegenerative disorders
Nicolas, G., & Veltman, J. A. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1939-3 · Cited by 51 · see citing works
Yuskaitis, C. J., Rossitto, L.-A. M., Gurnani, S., Bainbridge, E. A., Poduri, A., & Şahin, M. (2019) · Human Molecular Genetics · doi:10.1093/hmg/ddz123 · Cited by 45 · see citing works
Non–Cell Autonomous Epileptogenesis in Focal Cortical Dysplasia
Koh, H. Y., Jang, J., Ju, S. H., Kim, R., Cho, G., Kim, D. S., Sohn, J., Paik, S., & Lee, J. H. (2021) · Annals of Neurology · doi:10.1002/ana.26149 · Cited by 51 · see citing works
Man, A., Scipio, M. D., Grewal, S., Suk, Y., Trinari, E., Ejaz, R., & Whitney, R. (2024) · Genes · doi:10.3390/genes15030332 · Cited by 50 · see citing works
Dawson, R. E., Guil, A. N. N., Robertson, L., Piltz, S. G., Hughes, J. N., & Thomas, P. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.104640 · Cited by 42 · see citing works
What are the epileptic encephalopathies?
Trivisano, M., & Specchio, N. (2020) · Current Opinion in Neurology · doi:10.1097/wco.0000000000000793 · Cited by 48 · see citing works
Lee, W. S., Baldassari, S., Stephenson, S. E. M., Lockhart, P. J., Baulac, S., & Leventer, R. J. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23031344 · Cited by 45 · see citing works
Self-citationEffects of antiepileptic drugs in a new TSC/mTOR‐dependent epilepsy mouse model
Koene, L. M. C., van Grondelle, S. E., Onori, M. P., Wallaard, I., Kooijman, N. H. R. M., van Oort, A., Schreiber, J., & Elgersma, Y. (2019) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.50829 · Cited by 45 · see citing works
Klofas, L. K., Short, B. P., Zhou, C.-W., & Carson, R. P. (2020) · Human Molecular Genetics · doi:10.1093/hmg/ddaa068 · Cited by 42 · see citing works
Raikwar, S. P., Kikkeri, N. S., Sakuru, R. C., Saeed, D., Zahoor, H., Premkumar, K., Mentor, S., Thangavel, R., Dubova, I., Ahmed, M. E., et al. (2019) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-019-09849-y · Cited by 47 · see citing works
Genomic and Epigenetic Advances in Focal Cortical Dysplasia Types I and II: A Scoping Review
Jesus‐Ribeiro, J., Pires, L. M., Melo, J. D., Ribeiro, I. P., Rebelo, O., Sales, F., Freire, A., & Melo, J. B. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.580357 · Cited by 43 · see citing works
Rubboli, G., Plazzi, G., Picard, F., Nobili, L., Hirsch, É., Chelly, J., Prayson, R. A., Boutonnât, J., Bramerio, M., Kahane, P., et al. (2018) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.708 · Cited by 42 · see citing works
Self-citationComplexity in Genetic Epilepsies: A Comprehensive Review
Rastin, C., Schenkel, L. C., & Sadiković, B. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241914606 · Cited by 41 · see citing works
Genetic characterization identifies bottom-of-sulcus dysplasia as an mTORopathy
Lee, W., Stephenson, S. E. M., Pope, K., Gillies, G., Maixner, W., Macdonald-Laurs, E., MacGregor, D., D'Arcy, C., Jackson, G., Harvey, A., et al. (2020) · Neurology · doi:10.1212/wnl.0000000000010670 · Cited by 31 · see citing works
DNA methylation-based classification of malformations of cortical development in the human brain
Jabari, S., Kobow, K., Pieper, T., Hartlieb, T., Kudernatsch, M., Polster, T., Bien, C. G., Kalbhenn, T., Simon, M., Hamer, H. M., et al. (2021) · Acta Neuropathologica · doi:10.1007/s00401-021-02386-0 · Cited by 41 · see citing works
Precision Therapy for Epilepsy Related to Brain Malformations
D’Gama, A. M., & Poduri, A. (2021) · Neurotherapeutics · doi:10.1007/s13311-021-01122-6 · Cited by 40 · see citing works
Detection of brain somatic mutations in focal cortical dysplasia during epilepsy presurgical workup
Checri, R., Chipaux, M., Ferrand‐Sorbets, S., Raffo, E., Bulteau, C., Rosenberg, S. D., Doladilhe, M., Dorfmüller, G., Adle‐Biassette, H., Baldassari, S., et al. (2023) · Brain Communications · doi:10.1093/braincomms/fcad174 · Cited by 38 · see citing works
Self-citationAcute knockdown of Depdc5 leads to synaptic defects in mTOR-related epileptogenesis.
Fusco, A. D., Cerullo, M., Marte, A., Michetti, C., Romei, A., Castroflorio, E., Baulac, S., & Benfenati, F. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104822 · Cited by 29 · see citing works
Self-citationLiu, L., Chen, Z.-R., Xu, H., Liu, D.-T., Mao, Y., Liu, H.-K., Liu, X.-R., Zhou, P., Lin, S.-M., Li, B., et al. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00821 · Cited by 32 · see citing works
Nguyen, L. H., Xu, Y., Nair, M., & Bordey, A. (2024) · eLife · doi:10.7554/elife.91010 · Cited by 37 · see citing works
NPRL3 loss alters neuronal morphology, mTOR localization, cortical lamination and seizure threshold
Iffland, P. H., Everett, M. E., Cobb-Pitstick, K., Bowser, L. E., Barnes, A. E., Babus, J. K., Romanowski, A. J., Baybis, M., Elziny, S., Puffenberger, E. G., et al. (2022) · Brain · doi:10.1093/brain/awac044 · Cited by 37 · see citing works
Cardiac Investigations in Sudden Unexpected Death in DEPDC5 ‐Related Epilepsy
Bacq, A., Roussel, D., Bonduelle, T., Zagaglia, S., Maletić, M. M., Ribierre, T., Adle-Biassette, H., Marchal, C., Jennesson, M., An, I., et al. (2021) · Annals of Neurology · doi:10.1002/ana.26256 · Cited by 27 · see citing works
Self-citationExpression of 4E-BP1 in juvenile mice alleviates mTOR-induced neuronal dysfunction and epilepsy
Nguyen, L. H., Xu, Y., Mahadeo, T., Zhang, L., Lin, T. V., Born, H. A., Anderson, A. E., & Bordey, A. (2021) · Brain · doi:10.1093/brain/awab390 · Cited by 35 · see citing works
Genomics in the presurgical epilepsy evaluation
Moloney, P. B., Dugan, P. C., Widdess‐Walsh, P., Devinsky, O., & Delanty, N. (2022) · Epilepsy Research · doi:10.1016/j.eplepsyres.2022.106951 · Cited by 35 · see citing works
Large-scale neurophysiology and single-cell profiling in human neuroscience
Lee, A. T., Chang, E. F., Paredes, M. F., & Nowakowski, T. J. (2024) · Nature · doi:10.1038/s41586-024-07405-0 · Cited by 33 · see citing works
Salinas, V., Vega, P., Piccirilli, M. V., Chicco, C., Ciraolo, C. A., Christiansen, S. B., Consalvo, D., Perez-Maturo, J., Medina, N. M., González‐Morón, D., et al. (2018) · European Journal of Medical Genetics · doi:10.1016/j.ejmg.2018.11.005 · Cited by 34 · see citing works
Pathogenic variants of DYNC2H1 , KIAA0556 , and PTPN11 associated with hypothalamic hamartoma
Fujita, A., Higashijima, T., Shirozu, H., Masuda, H., Sonoda, M., Tohyama, J., Kato, M., Nakashima, M., Tsurusaki, Y., Mitsuhashi, S., et al. (2019) · Neurology · doi:10.1212/wnl.0000000000007774 · Cited by 34 · see citing works
Ultra‐Low Level Somatic Mutations and Structural Variations in Focal Cortical Dysplasia Type II
Kim, J. H., Park, J., Lee, J., Park, J. W., Kim, H. J., Chang, W. S., Kim, D., Ju, Y. S., Aronica, E., & Lee, J. H. (2023) · Annals of Neurology · doi:10.1002/ana.26609 · Cited by 33 · see citing works
Mechanistic Target of Rapamycin Pathway in Epileptic Disorders
Kim, J., & Lee, J. H. (2019) · Journal of Korean Neurosurgical Society · doi:10.3340/jkns.2019.0027 · Cited by 32 · see citing works
Ying, Z., Wang, Z. I., Blümcke, I., Bulacio, J. C., Alexopoulos, A. V., Jehi, L. E., Bingaman, W. E., Gonzalez-Martinez, J. A., Kobow, K., Niestroj, L., et al. (2019) · Epileptic Disorders · doi:10.1684/epd.2019.1028 · Cited by 32 · see citing works
Brain Somatic Mutations in Epileptic Disorders.
Koh, H. Y., & Lee, J. H. (2018) · Europe PMC (PubMed Central) · doi:10.14348/molcells.2018.0247 · Cited by 31 · see citing works
The role of somatic mosaicism in brain disease
Jourdon, A., Fasching, L., Scuderi, S., Abyzov, A. S., & Vaccarino, F. M. (2020) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2020.05.002 · Cited by 29 · see citing works
The role of somatic mutational events in the pathogenesis of epilepsy
Iffland, P. H., & Crino, P. B. (2019) · Current Opinion in Neurology · doi:10.1097/wco.0000000000000667 · Cited by 28 · see citing works
Low-Level Brain Somatic Mutations Are Implicated in Schizophrenia
Kim, M.-H., Kim, I. B., Lee, J., Cha, D. H., Park, S. M., Kim, J. H., Kim, R., Park, J. S., An, Y., Kim, K., et al. (2021) · Biological Psychiatry · doi:10.1016/j.biopsych.2021.01.014 · Cited by 28 · see citing works
Targeted suppression of mTORC2 reduces seizures across models of epilepsy
Okoh, J. T., Mays, J., Bacq, A., Osés-Prieto, J. A., Tyanova, S., Chen, C.-J., Imanbeyev, K., Doladilhe, M., Zhou, H., Jafar‐Nejad, P., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-42922-y · Cited by 25 · see citing works
Self-citationBeňová, B., & Jacques, T. S. (2018) · Brain Pathology · doi:10.1111/bpa.12686 · Cited by 26 · see citing works
Genetic testing in children enrolled in epilepsy surgery program. A real-life study
Straka, B., Splítková, B., Vlčková, M., Tesner, P., Zůnová, H., Krsková, L., Koblížek, M., Kynčl, M., Maulisová, A., Bukačová, K., et al. (2023) · European Journal of Paediatric Neurology · doi:10.1016/j.ejpn.2023.09.009 · Cited by 25 · see citing works
Beňová, B., Sanders, M. W. C. B., Mészárosová, A. U., Bělohlávková, A., Splítková, B., Novák, V., Staněk, D., Vlčková, M., Zámečnı́k, J., Aronica, E., et al. (2021) · European Journal of Paediatric Neurology · doi:10.1016/j.ejpn.2020.12.001 · Cited by 25 · see citing works
Review: Neuropathology findings in autonomic brain regions in SUDEP and future research directions
Patodia, S., Somani, A., & Thom, M. (2021) · Autonomic Neuroscience · doi:10.1016/j.autneu.2021.102862 · Cited by 24 · see citing works
Evidence for a Dual-Pathway, 2-Hit Genetic Model for Focal Cortical Dysplasia and Epilepsy
Bennett, M., Hildebrand, M., Kayumi, S., Corbett, M., Gupta, S., Ye, Z.-M., Krivanek, M., Burgess, R., Henry, O. J., Damiano, J., et al. (2022) · Neurology: Genetics · doi:10.1212/nxg.0000000000000652 · Cited by 19 · see citing works
Brain Organoids and Assembloids—From Disease Modeling to Drug Discovery
Ajongbolo, A. O., & Langhans, S. A. (2025) · Cells · doi:10.3390/cells14110842 · Cited by 24 · see citing works
Klofas, L. K., Short, B. P., Snow, J. P., Sinnaeve, J., Rushing, G. V., Westlake, G., Weinstein, W. K., Ihrie, R. A., Ess, K. C., & Carson, R. P. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104975 · Cited by 17 · see citing works
Dorsal telencephalon-specific Nprl2- and Nprl3-knockout mice: novel mouse models for GATORopathy
Ishida, S., Zhao, D., Sawada, Y., Hiraoka, Y., Mashimo, T., & Tanaka, K. (2021) · Human Molecular Genetics · doi:10.1093/hmg/ddab337 · Cited by 22 · see citing works
Wang, H., Liu, W., Zhang, Y.-H., Liu, Q.-Z., Cai, L.-X., & Jiang, Y.-W. (2023) · Epilepsia Open · doi:10.1002/epi4.12770 · Cited by 23 · see citing works
Kao, H.-Y., Yao, Y., Yang, T., Ziobro, J. M., Zylinski, M., Mir, M. Y., Hu, S., Cao, R.-N., Borna, N., Banerjee, R., et al. (2023) · Annals of Neurology · doi:10.1002/ana.26773 · Cited by 23 · see citing works
Molecular diagnostics in drug‐resistant focal epilepsy define new disease entities
Kobow, K., Baulac, S., von Deimling, A., & Lee, J. H. (2021) · Brain Pathology · doi:10.1111/bpa.12963 · Cited by 22 · see citing works
Self-citationBizzotto, S., Talukdar, M., Stronge, E., Ramirez, R. B., Yang, Y., Huang, A. Y., Hu, Q., Hou, Y., Hylton, N. K., Finander, B., et al. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2509622122 · Cited by 21 · see citing works
do Canto, A. M., Vieira, A. S., de Matos, A. H. B., Carvalho, B. S., Henning, B., Norwood, B. A., Bauer, S., Rosenow, F., Gilioli, R., Cendes, F., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-61401-8 · Cited by 20 · see citing works
Sporadic hypothalamic hamartoma is a ciliopathy with somatic and bi-allelic contributions
Green, T. E., Motelow, J. E., Bennett, M. F., Ye, Z., Bennett, C. A., Griffin, N. G., Damiano, J. A., Leventer, R. J., Freeman, J. L., Harvey, A. S., et al. (2021) · Human Molecular Genetics · doi:10.1093/hmg/ddab366 · Cited by 21 · see citing works
Assessment of somatic single-nucleotide variation in brain tissue of cases with schizophrenia
Fullard, J. F., Charney, A. W., Voloudakis, G., Uzilov, A. V., Haroutunian, V. H., & Roussos, P. (2019) · Translational Psychiatry · doi:10.1038/s41398-018-0342-0 · Cited by 21 · see citing works
Auvin, S., & Baulac, S. (2023) · Revue Neurologique · doi:10.1016/j.neurol.2022.12.007 · Cited by 20 · see citing works
Self-citationAnimal models and human tissue compared to better understand and treat the epilepsies
Milior, G., Morin‐Brureau, M., Pallud, J., Miles, R., & Huberfeld, G. (2023) · Epilepsia · doi:10.1111/epi.17552 · Cited by 19 · see citing works
Self-citationHonke, J., Hoffmann, L., Coras, R., Kobow, K., Leu, C., Pieper, T., Hartlieb, T., Bien, C., Woermann, F., Cloppenborg, T., et al. (2023) · Acta Neuropathologica Communications · doi:10.1186/s40478-023-01675-x · Cited by 19 · see citing works
Self-citationKao, H., Hu, S., Mihaylova, T. G., Ziobro, J. M., Ahn, E., Fine, C., Brang, D., Watson, B. O., & Wang, Y. (2021) · Epilepsia · doi:10.1111/epi.16868 · Cited by 18 · see citing works
Zhang, X., Huang, Z., Liu, J., Li, M., Zhao, X., Ye, J., & Wang, Y. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.641019 · Cited by 18 · see citing works
Vasić, V., Jones, M. S. O., Haslinger, D., Knaus, L. S., Schmeißer, M. J., Novarino, G., & Chiocchetti, A. G. (2021) · Genes · doi:10.3390/genes12111746 · Cited by 17 · see citing works
Somatic mosaicism in the diseased brain
Iourov, I. Y., Vorsanova, S. G., Куринная, О. С., Kutsev, S. I., & Yurov, Y. B. (2022) · Molecular Cytogenetics · doi:10.1186/s13039-022-00624-y · Cited by 17 · see citing works
Genetics of Epileptic Networks: from Focal to Generalized Genetic Epilepsies
Qaiser, F., Yuen, R. K. C., & Andrade, D. M. (2020) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-020-01059-x · Cited by 17 · see citing works
Ververi, A., Zagaglia, S., Menzies, L. A., Baptista, J., Caswell, R. C., Baulac, S., Ellard, S., Lynch, S. A., Jacques, T. S., Chawla, M. S., et al. (2022) · Human Molecular Genetics · doi:10.1093/hmg/ddac225 · Cited by 16 · see citing works
Self-citation
- Authors
- Ribierre, T., Deleuze, C., Bacq, A., Baldassari, S., Marsan, E., Chipaux, M., Muraca, G., Roussel, D., Navarro, V., Leguern, E., Miles, R., & Baulac, S.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Fondation de Rothschild (FR)
- Corresponding author
- Baulac, Stéphanie
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2018-04-30
- Volume
- 128
- Issue
- 6
- Pages
- 2452-2458
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC5983335
- OpenAlex
- W2802211669
- Cited by
- 241
- References
- 28
- Citations by year
- 2026: 17 · 2025: 28 · 2024: 30 · 2023: 37 · 2022: 27 · 2021: 38 · 2020: 27 · 2019: 26 · 2018: 10 · 2017: 1
- FWCI
- 19.73
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- European Research Council (No 322721, No 682345)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- DEPDC5, mTORC1, focal cortical dysplasia, focal epilepsy, second-hit mutations, somatic mosaicism, sudden unexpected death in epilepsy, amino acid sensing, seizure onset zone, excitatory neurons, drug-resistant epilepsy
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Animals, Dendrites, Epilepsies, Partial, Female, Humans, Male, Mice, Mutant Strains, Neurons, Repressor Proteins, Spine, Germ-Line Mutation, GTPase-Activating Proteins, Mice, Malformations of Cortical Development, CRISPR-Cas Systems
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
