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1. Cannabidiol (Epidyolex®) for severe behavioral manifestations in patients with tuberous sclerosis complex, mucopolysaccharidosis type III and fragile X syndrome: protocol for a series of randomized, placebo-controlled N-of-1 trials

Author

Müller, A. R., den Hollander, B., van de Ven, P. M., Roes, K. C. B., Geertjens, L., Bruining, H., van Karnebeek, C. D. M., Jansen, F. E., de Wit, M. C. Y., ten Hoopen, L. W., Rietman, A. B., Dierckx, B., Wijburg, F. A., Boot, E., Brands, M. M. G., and van Eeghen, A. M.

Published
2024
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2. Cannabidiol (Epidyolex®) for severe behavioral manifestations in patients with tuberous sclerosis complex, mucopolysaccharidosis type III and fragile X syndrome: protocol for a series of randomized, placebo-controlled N-of-1 trials

Author

CTM & Statistical consultation, Cancer, Neurologen, Brain, TN groep Pasterkamp, Müller, A. R., den Hollander, B., van de Ven, P. M., Roes, K. C.B., Geertjens, L., Bruining, H., van Karnebeek, C. D.M., Jansen, F. E., de Wit, M. C.Y., ten Hoopen, L. W., Rietman, A. B., Dierckx, B., Wijburg, F. A., Boot, E., Brands, M. M.G., van Eeghen, A. M., CTM & Statistical consultation, Cancer, Neurologen, Brain, TN groep Pasterkamp, Müller, A. R., den Hollander, B., van de Ven, P. M., Roes, K. C.B., Geertjens, L., Bruining, H., van Karnebeek, C. D.M., Jansen, F. E., de Wit, M. C.Y., ten Hoopen, L. W., Rietman, A. B., Dierckx, B., Wijburg, F. A., Boot, E., Brands, M. M.G., and van Eeghen, A. M.

Published
2024

3. Cannabidiol (Epidyolex®) for severe behavioral manifestations in patients with tuberous sclerosis complex, mucopolysaccharidosis type III and fragile X syndrome:protocol for a series of randomized, placebo-controlled N-of-1 trials

Author

Müller, A. R., den Hollander, B., van de Ven, P. M., Roes, K. C.B., Geertjens, L., Bruining, H., van Karnebeek, C. D.M., Jansen, F. E., de Wit, M. C.Y., ten Hoopen, L. W., Rietman, A. B., Dierckx, B., Wijburg, F. A., Boot, E., Brands, M. M.G., van Eeghen, A. M., Müller, A. R., den Hollander, B., van de Ven, P. M., Roes, K. C.B., Geertjens, L., Bruining, H., van Karnebeek, C. D.M., Jansen, F. E., de Wit, M. C.Y., ten Hoopen, L. W., Rietman, A. B., Dierckx, B., Wijburg, F. A., Boot, E., Brands, M. M.G., and van Eeghen, A. M.

Abstract

Background: Many rare genetic neurodevelopmental disorders (RGNDs) are characterized by intellectual disability (ID), severe cognitive and behavioral impairments, potentially diagnosed as a comorbid autism spectrum disorder or attention-deficit hyperactivity disorder. Quality of life is often impaired due to irritability, aggression and self-injurious behavior, generally refractory to standard therapies. There are indications from previous (case) studies and patient reporting that cannabidiol (CBD) may be an effective treatment for severe behavioral manifestations in RGNDs. However, clear evidence is lacking and interventional research is challenging due to the rarity as well as the heterogeneity within and between disease groups and interindividual differences in treatment response. Our objective is to examine the effectiveness of CBD on severe behavioral manifestations in three RGNDs, including Tuberous Sclerosis Complex (TSC), mucopolysaccharidosis type III (MPS III), and Fragile X syndrome (FXS), using an innovative trial design. Methods: We aim to conduct placebo-controlled, double-blind, block-randomized, multiple crossover N-of-1 studies with oral CBD (twice daily) in 30 patients (aged ≥ 6 years) with confirmed TSC, MPS III or FXS and severe behavioral manifestations. The treatment is oral CBD up to a maximum of 25 mg/kg/day, twice daily. The primary outcome measure is the subscale irritability of the Aberrant Behavior Checklist. Secondary outcome measures include (personalized) patient-reported outcome measures with regard to behavioral and psychiatric outcomes, disease-specific outcome measures, parental stress, seizure frequency, and adverse effects of CBD. Questionnaires will be completed and study medication will be taken at the participants’ natural setting. Individual treatment effects will be determined based on summary statistics. A mixed model analysis will be applied for analyzing the effectiveness of the intervention per disorder and across dis

Published
2024

5. De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy

Author

Tran Mau-Them, F., Guibaud, L., Duplomb, L., Keren, B., Lindstrom, K., Marey, I., Mochel, F., van den Boogaard, M. J., Oegema, R., Nava, C., Masurel, A., Jouan, T., Jansen, F. E., Au, M., Chen, Agnes H., Cho, M., Duffourd, Y., Lozier, E., Konovalov, F., Sharkov, A., Korostelev, S., Urteaga, B., Dickson, P., Vera, M., Martínez-Agosto, Julián A., Begemann, A., Zweier, M., Schmitt-Mechelke, T., Rauch, A., Philippe, C., van Gassen, K., Nelson, S., Graham, Jr, J. M., Friedman, J., Faivre, L., Lin, H. J., Thauvin-Robinet, C., and Vitobello, A.

Published
2019
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6. Gastrointestinal and eating problems in SCN1A-related seizure disorders

Author

Opleiding Neurologie, Projectafdeling CVZ, Neurologen, Brain, MS Mondziekten/Kaakchirurgie, Afdeling Dietetiek, Projectafdeling KIND, Genetica Klinische Genetica, Minderhoud, C A, Postma, A, Jansen, F E, Verhoeven, J S, Schrijver, J J, Goudswaard, J, Andreae, G, Otte, W M, Braun, K P J, Brilstra, E H, Opleiding Neurologie, Projectafdeling CVZ, Neurologen, Brain, MS Mondziekten/Kaakchirurgie, Afdeling Dietetiek, Projectafdeling KIND, Genetica Klinische Genetica, Minderhoud, C A, Postma, A, Jansen, F E, Verhoeven, J S, Schrijver, J J, Goudswaard, J, Andreae, G, Otte, W M, Braun, K P J, and Brilstra, E H

Published
2023

8. Expression of microRNAs miR21, miR146a, and miR155 in tuberous sclerosis complex cortical tubers and their regulation in human astrocytes and SEGA-derived cell cultures

Author

van Scheppingen, J., Iyer, A. M., Prabowo, A. S., Mühlebner, A., Anink, J. J., Scholl, T., Feucht, M., Jansen, F. E., Spliet, W. G., Krsek, P., Zamecnik, J., Buccoliero, A. M., Giordano, F., Genitori, L., Kotulska, K., Jozwiak, S., Jaworski, J., Liszewska, E., van Vliet, E. A., and Aronica, E.

Published
2016
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10. MicroRNA-34a activation in tuberous sclerosis complex during early brain development may lead to impaired corticogenesis

Author

Korotkov, A, Sim, N S, Luinenburg, M J, Anink, J J, van Scheppingen, J, Zimmer, T S, Bongaarts, A, Broekaart, D W M, Mijnsbergen, C, Jansen, F E, Van Hecke, W, Spliet, W G M, van Rijen, P C, Feucht, M, Hainfellner, J A, Krsek, P, Zamecnik, J, Crino, P B, Kotulska, K, Lagae, L, Jansen, Anna C, Kwiatkowski, D J, Jozwiak, S, Curatolo, P, Mühlebner, A, Lee, J H, Mills, J D, van Vliet, E A, Aronica, E, Korotkov, A, Sim, N S, Luinenburg, M J, Anink, J J, van Scheppingen, J, Zimmer, T S, Bongaarts, A, Broekaart, D W M, Mijnsbergen, C, Jansen, F E, Van Hecke, W, Spliet, W G M, van Rijen, P C, Feucht, M, Hainfellner, J A, Krsek, P, Zamecnik, J, Crino, P B, Kotulska, K, Lagae, L, Jansen, Anna C, Kwiatkowski, D J, Jozwiak, S, Curatolo, P, Mühlebner, A, Lee, J H, Mills, J D, van Vliet, E A, and Aronica, E

Abstract

AIMS: Tuberous sclerosis complex (TSC) is a genetic disorder associated with dysregulation of the mechanistic target of rapamycin complex 1 (mTORC1) signalling pathway. Neurodevelopmental disorders, frequently present in TSC, are linked to cortical tubers in the brain. We previously reported microRNA-34a (miR-34a) among the most up-regulated miRs in tubers. Here, we characterized miR-34a expression in tubers with the focus on the early brain development and assessed the regulation of mTORC1 pathway and corticogenesis by miR-34a.METHODS: We analysed the expression of miR-34a in resected cortical tubers (n = 37) compared to autopsy-derived control tissue (n = 27). The effect of miR-34a overexpression on corticogenesis was assessed in mice at E18. The regulation of the mTORC1 pathway and the expression of the bioinformatically predicted target genes were assessed in primary astrocyte cultures from 3 patients with TSC and in SH-SY5Y cells following miR-34a transfection.RESULTS: The peak of miR-34a overexpression in tubers was observed during infancy, concomitant with the presence of pathological markers, particularly in giant cells and dysmorphic neurons. MiR-34a was also strongly expressed in fetal TSC cortex. Overexpression of miR-34a in mouse embryos decreased the percentage of cells migrated to the cortical plate. The transfection of miR-34a mimic in TSC astrocytes negatively regulated mTORC1 and decreased the expression of the target genes RAS related (RRAS) and NOTCH1.CONCLUSIONS: MiR-34a is most highly overexpressed in tubers during fetal and early postnatal brain development. MiR-34a can negatively regulate mTORC1, however, it may also contribute to abnormal corticogenesis in TSC.

Published
2021

11. MicroRNA-34a activation in tuberous sclerosis complex during early brain development may lead to impaired corticogenesis

Author

Pathologie, Neurologen, Brain, Pathologie Pathologen staf, Cancer, Neurochirurgen, Unit Opleiding MDL, PMC Medisch specialisten, Korotkov, A, Sim, N S, Luinenburg, M J, Anink, J J, van Scheppingen, J, Zimmer, T S, Bongaarts, A, Broekaart, D W M, Mijnsbergen, C, Jansen, F E, Van Hecke, W, Spliet, W G M, van Rijen, P C, Feucht, M, Hainfellner, J A, Krsek, P, Zamecnik, J, Crino, P B, Kotulska, K, Lagae, L, Jansen, A C, Kwiatkowski, D J, Jozwiak, S, Curatolo, P, Mühlebner, A, Lee, J H, Mills, J D, van Vliet, E A, Aronica, E, Pathologie, Neurologen, Brain, Pathologie Pathologen staf, Cancer, Neurochirurgen, Unit Opleiding MDL, PMC Medisch specialisten, Korotkov, A, Sim, N S, Luinenburg, M J, Anink, J J, van Scheppingen, J, Zimmer, T S, Bongaarts, A, Broekaart, D W M, Mijnsbergen, C, Jansen, F E, Van Hecke, W, Spliet, W G M, van Rijen, P C, Feucht, M, Hainfellner, J A, Krsek, P, Zamecnik, J, Crino, P B, Kotulska, K, Lagae, L, Jansen, A C, Kwiatkowski, D J, Jozwiak, S, Curatolo, P, Mühlebner, A, Lee, J H, Mills, J D, van Vliet, E A, and Aronica, E

Published
2021

12. Increased matrix metalloproteinases expression in tuberous sclerosis complex: modulation by microRNA 146a and 147b in vitro

Author

ZL Kinder Ner en Nec Medisch, Brain, Pathologie mortuarium en obductie, Pathologie Pathologen staf, Cancer, Zorglijn FNE Medisch, Broekaart, D. W.M., van Scheppingen, J., Anink, J. J., Wierts, L., van het Hof, B., Jansen, F. E., Spliet, W. G., van Rijen, P. C., Kamphuis, W. W., de Vries, H. E., Aronica, E., van Vliet, E. A., ZL Kinder Ner en Nec Medisch, Brain, Pathologie mortuarium en obductie, Pathologie Pathologen staf, Cancer, Zorglijn FNE Medisch, Broekaart, D. W.M., van Scheppingen, J., Anink, J. J., Wierts, L., van het Hof, B., Jansen, F. E., Spliet, W. G., van Rijen, P. C., Kamphuis, W. W., de Vries, H. E., Aronica, E., and van Vliet, E. A.

Published
2020

13. Chronic activation of anti-oxidant pathways and iron accumulation in epileptogenic malformations

Author

Pathologie, ZL Kinder Ner en Nec Medisch, Brain, Pathologie mortuarium en obductie, Pathologie Pathologen staf, Cancer, Zorglijn FNE Medisch, MMB Medische Staf, Unit Opleiding MDL, Zimmer, T. S., Ciriminna, G., Arena, A., Anink, J. J., Korotkov, A., Jansen, F. E., van Hecke, W., Spliet, W. G., van Rijen, P. C., Baayen, J. C., Idema, S., Rensing, N. R., Wong, M., Mills, J. D., van Vliet, E. A., Aronica, E., Pathologie, ZL Kinder Ner en Nec Medisch, Brain, Pathologie mortuarium en obductie, Pathologie Pathologen staf, Cancer, Zorglijn FNE Medisch, MMB Medische Staf, Unit Opleiding MDL, Zimmer, T. S., Ciriminna, G., Arena, A., Anink, J. J., Korotkov, A., Jansen, F. E., van Hecke, W., Spliet, W. G., van Rijen, P. C., Baayen, J. C., Idema, S., Rensing, N. R., Wong, M., Mills, J. D., van Vliet, E. A., and Aronica, E.

Published
2020

14. Chronic activation of anti‐oxidant pathways and iron accumulation in epileptogenic malformations

Author

Zimmer, T. S., primary, Ciriminna, G., additional, Arena, A., additional, Anink, J. J., additional, Korotkov, A., additional, Jansen, F. E., additional, Hecke, W., additional, Spliet, W. G., additional, Rijen, P. C., additional, Baayen, J. C., additional, Idema, S., additional, Rensing, N. R., additional, Wong, M., additional, Mills, J. D., additional, Vliet, E. A., additional, and Aronica, E., additional

Published
2020
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15. Increased matrix metalloproteinases expression in tuberous sclerosis complex: modulation by microRNA 146a and 147b in vitro

Author

Broekaart, D. W. M., primary, Scheppingen, J., additional, Anink, J. J., additional, Wierts, L., additional, Hof, B., additional, Jansen, F. E., additional, Spliet, W. G., additional, van Rijen, P. C., additional, Kamphuis, W. W., additional, de Vries, H. E., additional, Aronica, E., additional, and van Vliet, E. A., additional

Published
2019
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17. De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy

Author

Genetica, Genetica Klinische Genetica, Child Health, Brain, ZL Kinder Ner en Nec Medisch, Genetica Sectie Genoomdiagnostiek, Tran Mau-Them, F., Guibaud, L., Duplomb, L., Keren, B., Lindstrom, K., Marey, I., Mochel, F., van den Boogaard, M. J., Oegema, R., Nava, C., Masurel, A., Jouan, T., Jansen, F. E., Au, M., Chen, Agnes H., Cho, M., Duffourd, Y., Lozier, E., Konovalov, F., Sharkov, A., Korostelev, S., Urteaga, B., Dickson, P., Vera, M., Martínez-Agosto, Julián A., Begemann, A., Zweier, M., Schmitt-Mechelke, T., Rauch, A., Philippe, C., van Gassen, K., Nelson, S., Graham, J. M., Friedman, J., Faivre, L., Lin, H. J., Thauvin-Robinet, C., Vitobello, A., Genetica, Genetica Klinische Genetica, Child Health, Brain, ZL Kinder Ner en Nec Medisch, Genetica Sectie Genoomdiagnostiek, Tran Mau-Them, F., Guibaud, L., Duplomb, L., Keren, B., Lindstrom, K., Marey, I., Mochel, F., van den Boogaard, M. J., Oegema, R., Nava, C., Masurel, A., Jouan, T., Jansen, F. E., Au, M., Chen, Agnes H., Cho, M., Duffourd, Y., Lozier, E., Konovalov, F., Sharkov, A., Korostelev, S., Urteaga, B., Dickson, P., Vera, M., Martínez-Agosto, Julián A., Begemann, A., Zweier, M., Schmitt-Mechelke, T., Rauch, A., Philippe, C., van Gassen, K., Nelson, S., Graham, J. M., Friedman, J., Faivre, L., Lin, H. J., Thauvin-Robinet, C., and Vitobello, A.

Published
2019

18. Refractory juvenile myoclonic epilepsy: a meta-analysis of prevalence and risk factors

Author

Genetica, Genetica Groep Koeleman, Brain, Child Health, Circulatory Health, ZL Kinder Ner en Nec Medisch, Stevelink, R., Koeleman, B. P.C., Sander, J. W., Jansen, F. E., Braun, K. P.J., Genetica, Genetica Groep Koeleman, Brain, Child Health, Circulatory Health, ZL Kinder Ner en Nec Medisch, Stevelink, R., Koeleman, B. P.C., Sander, J. W., Jansen, F. E., and Braun, K. P.J.

Published
2019

20. Increased matrix metalloproteinases expression in tuberous sclerosis complex: modulation by microRNA 146a and 147b in vitro.

Author

Broekaart, D. W. M., Scheppingen, J., Anink, J. J., Wierts, L., Hof, B., Jansen, F. E., Spliet, W. G., van Rijen, P. C., Kamphuis, W. W., de Vries, H. E., Aronica, E., and van Vliet, E. A.

Subjects
TUBEROUS sclerosis, MATRIX metalloproteinases, MICRORNA, ENCEPHALITIS, ASTROCYTES, BLOOD-brain barrier, POTATOES
Abstract

Aim: Matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs) control proteolysis within the extracellular matrix (ECM) of the brain. Dysfunction of this enzymatic system due to brain inflammation can disrupt the blood‐brain barrier (BBB) and has been implicated in the pathogenesis of epilepsy. However, this has not been extensively studied in the epileptogenic human brain. Methods: We investigated the expression and cellular localization of major MMPs (MMP2, MMP3, MMP9 and MMP14) and TIMPs (TIMP1, TIMP2, TIMP3 and TIMP4) using quantitative real‐time polymerase chain reaction (RT‐PCR) and immunohistochemistry in resected epileptogenic brain tissue from patients with tuberous sclerosis complex (TSC), a severe neurodevelopmental disorder characterized by intractable epilepsy and prominent neuroinflammation. Furthermore, we determined whether anti‐inflammatory microRNAs, miR146a and miR147b, which can regulate gene expression at the transcriptional level, could attenuate dysregulated MMP and TIMP expression in TSC tuber‐derived astroglial cultures. Results: We demonstrated higher mRNA and protein expression of MMPs and TIMPs in TSC tubers compared to control and perituberal brain tissue, particularly in dysmorphic neurons and giant cells, as well as in reactive astrocytes, which was associated with BBB dysfunction. More importantly, IL‐1β‐induced dysregulation of MMP3, TIMP2, TIMP3 and TIMP4 could be rescued by miR146a and miR147b in tuber‐derived TSC cultures. Conclusions: This study provides evidence of dysregulation of the MMP/TIMP proteolytic system in TSC, which is associated with BBB dysfunction. As dysregulated MMP and TIMP expression can be ameliorated in vitro by miR146a and miR147b, these miRNAs deserve further investigation as a novel therapeutic approach. [ABSTRACT FROM AUTHOR]

Published
2020
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21. Refractory juvenile myoclonic epilepsy: a meta‐analysis of prevalence and risk factors.

Author

Jansen, F. E., Braun, K. P. J., Stevelink, R., Koeleman, B. P. C., and Sander, J. W.

Subjects
*DISEASE risk factors, *LENNOX-Gastaut syndrome, *META-analysis, *CHILDHOOD epilepsy, *EPILEPSY, *THERAPEUTICS
Abstract

Background and purpose: Juvenile myoclonic epilepsy (JME) is a common epilepsy syndrome for which treatment response is generally assumed to be good. We aimed to determine the prevalence and prognostic risk factors for refractoriness of JME. Methods: We systematically searched PubMed and EMBASE and included 43 eligible studies, reporting seizure outcome after antiepileptic drug (AED) treatment in JME cohorts. We defined refractory JME as persistence of any seizure despite AED treatment and performed a random‐effects meta‐analysis to assess the prevalence of refractory JME and of seizure recurrence after AED withdrawal in individuals with well‐controlled seizures. Studies reporting potential prognostic risk factors in relation to seizure outcome were included for subsequent meta‐analysis of risk factors for refractoriness. Results: Overall, 35% (95% confidence interval, 29–41%) of individuals (n = 3311) were refractory. There was marked heterogeneity between studies. Seizures recurred in 78% (95% confidence interval, 52–94%) of individuals who attempted to withdraw from treatment after a period of seizure freedom (n = 246). Seizure outcome by publication year suggested that prognosis did not improve over time. Meta‐analysis suggested six variables as prognostic factors for refractoriness, i.e. having three seizure types, absence seizures, psychiatric comorbidities, earlier age at seizure onset, history of childhood absence epilepsy and praxis‐induced seizures. Conclusion: One‐third of people with JME were refractory, which is a higher prevalence than expected. Risk factors were identified and can be used to guide treatment and counselling of people with JME. [ABSTRACT FROM AUTHOR]

Published
2019
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23. Expression of microRNAs miR21, miR146a, and miR155 in tuberous sclerosis complex cortical tubers and their regulation in human astrocytes and SEGA-derived cell cultures

Author

van Scheppingen, J, Iyer, A M, Prabowo, A S, Mühlebner, A, Anink, J J, Scholl, T, Feucht, M, Jansen, F E, Spliet, W G, Krsek, P, Zamecnik, J, Buccoliero, A M, Giordano, F, Genitori, L, Kotulska, K, Jozwiak, S, Jaworski, J, Liszewska, E, van Vliet, E A, Aronica, E, van Scheppingen, J, Iyer, A M, Prabowo, A S, Mühlebner, A, Anink, J J, Scholl, T, Feucht, M, Jansen, F E, Spliet, W G, Krsek, P, Zamecnik, J, Buccoliero, A M, Giordano, F, Genitori, L, Kotulska, K, Jozwiak, S, Jaworski, J, Liszewska, E, van Vliet, E A, and Aronica, E

Published
2016

24. Expression of microRNAs miR21, miR146a, and miR155 in tuberous sclerosis complex cortical tubers and their regulation in human astrocytes and SEGA-derived cell cultures

Author

Pathologie, ZL Kinder Ner en Nec Medisch, Brain, ZL Algemene Neurologie Medisch, Pathologie Pathologen staf, Cancer, van Scheppingen, J, Iyer, A M, Prabowo, A S, Mühlebner, A, Anink, J J, Scholl, T, Feucht, M, Jansen, F E, Spliet, W G, Krsek, P, Zamecnik, J, Buccoliero, A M, Giordano, F, Genitori, L, Kotulska, K, Jozwiak, S, Jaworski, J, Liszewska, E, van Vliet, E A, Aronica, E, Pathologie, ZL Kinder Ner en Nec Medisch, Brain, ZL Algemene Neurologie Medisch, Pathologie Pathologen staf, Cancer, van Scheppingen, J, Iyer, A M, Prabowo, A S, Mühlebner, A, Anink, J J, Scholl, T, Feucht, M, Jansen, F E, Spliet, W G, Krsek, P, Zamecnik, J, Buccoliero, A M, Giordano, F, Genitori, L, Kotulska, K, Jozwiak, S, Jaworski, J, Liszewska, E, van Vliet, E A, and Aronica, E

Published
2016

25. Damaging de novo missense variants in EEF1A2lead to a developmental and degenerative epileptic-dyskinetic encephalopathy

Author

Laurine Perrin, Sha Tang, Brandon S. Guida, Tjitske Kleefstra, Marjolein H. Willemsen, Heather Stickney, Michael C. Kruer, Keri Ramsey, Heather C Mefford, Lynette G. Sadleir, Bobby P. C. Koeleman, Evelyn Sattlegger, Angela E. Lin, Sara A. Lewis, Marcello Scala, Sergio Padilla-Lopez, Luis O. Rohena, Joaquim Sa, Marie Laure Mathieu, Floor E. Jansen, Joy Y. Sebe, David W. Raible, Giorgio Casari, Gemma L. Carvill, Ingrid E. Scheffer, Paul A. Caruso, Robert Huether, Mariasavina Severino, Candace T. Myers, Eva H. Brilstra, Ashwin A. Bhandiwad, Katherine L. Helbig, Somayeh Bakhtiari, Sehribani Ulusoy Oktay, Gaetan Lesca, Vinodh Narayanan, Georgina Hollingsworth, Tyler N. Kruer, Christel Depienne, Valeria Capra, Pasquale Striano, Timothy Feyma, Deepak Gill, Andrea Accogli, Caroline Nava, Carvill, G. L., Helbig, K. L., Myers, C. T., Scala, M., Huether, R., Lewis, S., Kruer, T. N., Guida, B. S., Bakhtiari, S., Sebe, J., Tang, S., Stickney, H., Oktay, S. U., Bhandiwad, A. A., Ramsey, K., Narayanan, V., Feyma, T., Rohena, L. O., Accogli, A., Severino, M., Hollingsworth, G., Gill, D., Depienne, C., Nava, C., Sadleir, L. G., Caruso, P. A., Lin, A. E., Jansen, F. E., Koeleman, B., Brilstra, E., Willemsen, M. H., Kleefstra, T., Sa, J., Mathieu, M. -L., Perrin, L., Lesca, G., Striano, P., Casari, G., Scheffer, I. E., Raible, D., Sattlegger, E., Capra, V., Padilla-Lopez, S., Mefford, H. C., and Kruer, M. C.

Subjects
Adult, Male, de novo, Heterozygote, Adolescent, Encephalopathy, Choreoathetosis, Mutation, Missense, EEF1A2, Haploinsufficiency, Biology, Article, 03 medical and health sciences, Epilepsy, All institutes and research themes of the Radboud University Medical Center, Peptide Elongation Factor 1, Genetics, medicine, Missense mutation, Humans, Child, Genetics (clinical), 030304 developmental biology, Dystonia, 0303 health sciences, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], 030305 genetics & heredity, Genetic Complementation Test, medicine.disease, yeast complementation assay, Protein Structure, Tertiary, dyskinesia, Child, Preschool, epilepsy, Cerebellar atrophy, Epilepsy, Generalized, Female, medicine.symptom, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract

Heterozygous de novo variants in the eukaryotic elongation factor EEF1A2 have previously been described in association with intellectual disability and epilepsy but never functionally validated. Here we report 14 new individuals with heterozygous EEF1A2 variants. We functionally validate multiple variants as protein-damaging using heterologous expression and complementation analysis. Our findings allow us to confirm multiple variants as pathogenic and broaden the phenotypic spectrum to include dystonia/choreoathetosis, and in some cases a degenerative course with cerebral and cerebellar atrophy. Pathogenic variants appear to act via a haploinsufficiency mechanism, disrupting both the protein synthesis and integrated stress response functions of EEF1A2. Our studies provide evidence that EEF1A2 is highly intolerant to variation and that de novo pathogenic variants lead to an epileptic-dyskinetic encephalopathy with both neurodevelopmental and neurodegenerative features. Developmental features may be driven by impaired synaptic protein synthesis during early brain development while progressive symptoms may be linked to an impaired ability to handle cytotoxic stressors.

Published
2020

26. Gastrointestinal and eating problems in SCN1A-related seizure disorders.

Author

Minderhoud CA, Postma A, Jansen FE, Verhoeven JS, Schrijver JJ, Goudswaard J, Andreae G, Otte WM, Braun KPJ, and Brilstra EH

Subjects
Humans, NAV1.1 Voltage-Gated Sodium Channel genetics, Quality of Life, Mutation, Deglutition Disorders epidemiology, Deglutition Disorders etiology, Epilepsy complications, Epilepsy epidemiology, Epilepsy diagnosis, Epilepsies, Myoclonic diagnosis
Abstract

Objective: Our study aimed to describe the prevalence and characteristics of gastrointestinal and eating problems in Dravet syndrome (DS) and other SCN1A-related seizure disorders and to determine the association between the occurrence of gastrointestinal and eating problems and core features of DS., Methods: Gastrointestinal and eating problems were assessed with a questionnaire in a Dutch cohort of participants with an SCN1A-related seizure disorder. Associations between the number of gastrointestinal and eating problems and core features of DS, seizure severity, level of intellectual disability, impaired mobility, behavioral problems, and use of anti-seizure medication, were explored by multivariate ordinal regression analyses. Symptoms were divided into the categories dysphagia-related, behavioral, and gastrointestinal, and were assessed separately., Results: One hundred sixty-nine participants with an SCN1A-related seizure disorder, of whom 118 (69.8%) with DS and 51 (30.2%) with Generalized Epilepsy with Febrile Seizures Plus / Febrile Seizures (GEFS+/FS), the non-DS phenotype, were evaluated. Gastrointestinal and eating problems were highly prevalent in DS participants, 50.8% had more than three symptoms compared to 3.9% of non-DS participants. Of participants with DS, 17.8% were fully or partly fed by a gastric tube. Within the three different symptom categories, the most prevalent dysphagia-related symptom was drooling (60.7%), distraction during mealtimes (61.4%) the most prevalent behavioral symptom, and constipation and loss of appetite (both 50.4%) the most prevalent gastrointestinal symptoms. DS participants who use a wheelchair (odds ratio (OR) 4.9 95%CI (1.9-12.8) compared to walking without aid), who use ≥3 anti-seizure medications (ASM) (OR 5.9 95%CI (1.9-18.2) compared to <3 ASM) and who have behavioral problems (OR 3.0 95%CI (1.1-8.1) compared to no behavioral problems) had more gastrointestinal and eating problems., Conclusion: Gastrointestinal and eating problems are frequently reported symptoms in DS. Distinguishing between symptom categories will lead to tailored management of patients at risk, will improve early detection, and enable a timely referral to a dietitian, behavioral expert, and/or speech therapist, ultimately aiming to improve the quality of life of both patients and caregivers., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2023
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27. Introduction of Ultra-High-Field MR Imaging in Infants: Preparations and Feasibility.

Author

Annink KV, van der Aa NE, Dudink J, Alderliesten T, Groenendaal F, Lequin M, Jansen FE, Rhebergen KS, Luijten P, Hendrikse J, Hoogduin HJM, Huijing ER, Versteeg E, Visser F, Raaijmakers AJE, Wiegers EC, Klomp DWJ, Wijnen JP, and Benders MJNL

Subjects
Feasibility Studies, Female, Humans, Male, Pilot Projects, Prospective Studies, Infant, Infant, Newborn, Magnetic Resonance Imaging instrumentation, Magnetic Resonance Imaging methods
Abstract

Background and Purpose: Cerebral MR imaging in infants is usually performed with a field strength of up to 3T. In adults, a growing number of studies have shown added diagnostic value of 7T MR imaging. 7T MR imaging might be of additional value in infants with unexplained seizures, for example. The aim of this study was to investigate the feasibility of 7T MR imaging in infants. We provide information about the safety preparations and show the first MR images of infants at 7T., Materials and Methods: Specific absorption rate levels during 7T were simulated in Sim4life using infant and adult models. A newly developed acoustic hood was used to guarantee hearing protection. Acoustic noise damping of this hood was measured and compared with the 3T Nordell hood and no hood. In this prospective pilot study, clinically stable infants, between term-equivalent age and the corrected age of 3 months, underwent 7T MR imaging immediately after their standard 3T MR imaging. The 7T scan protocols were developed and optimized while scanning this cohort., Results: Global and peak specific absorption rate levels in the infant model in the centered position and 50-mm feet direction did not exceed the levels in the adult model. Hearing protection was guaranteed with the new hood. Twelve infants were scanned. No MR imaging-related adverse events occurred. It was feasible to obtain good-quality imaging at 7T for MRA, MRV, SWI, single-shot T2WI, and MR spectroscopy. T1WI had lower quality at 7T., Conclusions: 7T MR imaging is feasible in infants, and good-quality scans could be obtained., (© 2020 by American Journal of Neuroradiology.)

Published
2020
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