Anxiety-like behavior and anxiolytic treatment in the Rett syndrome natural history study / Caroline B. BUCHANAN in Journal of Neurodevelopmental Disorders, 14 (2022)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 14 (2022) Titre : Anxiety-like behavior and anxiolytic treatment in the Rett syndrome natural history study Type de document : texte imprimé Auteurs : Caroline B. BUCHANAN, Auteur ; Jennifer L. STALLWORTH, Auteur ; Aubin E. JOY, Auteur ; Rebekah E. DIXON, Auteur ; Alexandra E. SCOTT, Auteur ; Arthur A. BEISANG, Auteur ; Timothy A. BENKE, Auteur ; Daniel G. GLAZE, Auteur ; Richard H. HAAS, Auteur ; Peter T. HEYDEMANN, Auteur ; Mary D. JONES, Auteur ; Jane B. LANE, Auteur ; David N. LIEBERMAN, Auteur ; Eric D. MARSH, Auteur ; Jeffrey L. NEUL, Auteur ; Sarika U. PETERS, Auteur ; Robin C. RYTHER, Auteur ; Steve A. SKINNER, Auteur ; Shannon M. STANDRIDGE, Auteur ; Walter E. KAUFMANN, Auteur ; Alan K. PERCY, Auteur Langues : Anglais (eng) Mots-clés : Anti-Anxiety Agents/therapeutic use  Anxiety/drug therapy/epidemiology  Female  Humans  Rett Syndrome/complications/drug therapy/epidemiology  Anti-anxiety agents  Anxiety  Methyl-CpG-binding protein 2  Natural history studies  Rett syndrome  Fellowship under U54 HD 061222 grant) and has done clinical trials with Acadia,  Anavex, GW Pharmaceuticals, and Zynerba. Timothy A. Benke received funding from  the NIH (U54 HD061222, R21 NS101288, R01 NS081248), International Foundation for  CDKL5 Research, Loulou Foundation, and Children’s Hospital Colorado Foundation  Ponzio Family Chair in Neurology Research. He is also a consultant for AveXis,  Ovid, GW Pharmaceuticals, International Rett Syndrome Foundation, Takeda, and  Marinus and has done clinical trials with Acadia, Ovid, GW Pharmaceuticals,  Marinus, and Rett Syndrome Research Trust  all remuneration has been made to his  department. Daniel G Glaze received funding from the NIH, Rettsyndrome.org, and  the Blue Bird Circle. He has done clinical trials with Acadia, Neuren, and  GW Pharmaceuticals. Richard H. Haas received funding from the NIH 5U54HD061222  grant and has done clinical trials sponsored by Acadia, GW Pharmaceuticals, and  Newron Pharmaceuticals. Jane B. Lane received funding from the NIH and is a  consultant for International Rett Syndrome Foundation and GW Pharmaceuticals.  David N. Lieberman has done clinical trials with Anavex, Acadia, GW  Pharmaceuticals, and Rett Syndrome Research Trust. Eric D. Marsh received funding  from Rett Syndrome Research Trust, NIH, State of Pennsylvania, Penn Orphan  Disease Center, International Rett Syndrome Foundation, LouLou Foundation, and  Eagles Autism Foundation. He is a consultant for Cilpa Therapeutics and Stoke  Therapeutics. He has done clinical trials with Zogenix, GW Pharmaceuticals,  Acadia, Marinus, Stoke Therapeutics, and Rett Syndrome Research Trust. Jeffrey L.  Neul received funding from the NIH and is a consultant for AveXis, Biohaven,  Eloxx Pharmaceuticals, Ovid, Takeda, and Teva Pharmaceuticals. He has done  clinical trials with Acadia and Newron Pharmaceuticals. Sarika U. Peters received  funding from NIH, Rettsyndrome.org and is a consultant for Acadia  Pharmaceuticals. Steve A. Skinner has done clinical trials with Acadia, Anavex,  and GW Pharmaceuticals. Shannon M. Standridge is a speaker for Greenwich  Biosciences and Scientific Advisory Board of Acadia. Walter E. Kaufmann received  funding from the NIH and CDC, and is a consultant for Anavex, AveXis, Acadia,  EryDel, Newron, GW Pharmaceuticals, Marinus, Biohaven, Zynerba, Ovid  Therapeutics, and Stalicla. Currently, he is Chief Medical Officer of Anavex Life  Sciences Corp. Alan K. Percy received funding from the NIH and is a consultant  for Anavex, AveXis, Acadia, and GW Pharmaceuticals. He has done clinical trials  with Anavex, Acadia, GW Pharmaceuticals, and Rett Syndrome Research Trust. The  rest of the authors, Jennifer L. Stallworth, Aubin E. Joy, Rebekah E. Dixon,  Alexandra E. Scott, Arthur A. Beisang, Peter T. Heydemann, Mary D. Jones, and  Robin C. Ryther, declare that they have no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Rett syndrome (RTT) is a neurodevelopmental disorder most often related to a pathogenic variant in the X-linked MECP2 gene. Internalizing behaviors appear to be common, but standard methods of diagnosing anxiety are not readily applied in this population which typically has cognitive impairment and limited expressive language. This study aims to describe the frequency of anxiety-like behavior and anxiolytic treatments along with associated clinical features in individuals with RTT. METHODS: Parental reports and medication logs provided data from 1380 females with RTT participating in two iterations of the multicenter U.S. RTT Natural History Study (RNHS) from 2006 to 2019. RESULTS: Most participants with RTT (77.5%) had at least occasional anxious or nervous behavior. Anxiety was reported to be the most troublesome concern for 2.6%, and within the top 3 concerns for 10.0%, of participants in the second iteration. Parents directly reported treatment for anxious or nervous behavior in 16.6% of participants in the second iteration with most reporting good control of the behavior (71.6%). In the medication logs of both RNHS iterations, the indication of anxiety was listed for a similar number of participants (15% and 14.5%, respectively). Increased use of anxiolytics and selective serotonin reuptake inhibitors (SSRIs) was related to more frequent anxiety-like behaviors (P < 0.001), older age (P < 0.001), and mild MECP2 variants (P = 0.002). CONCLUSION: Anxiety-like behavior is frequent at all ages and is a significant parental concern in RTT. Older individuals and those with mild MECP2 variants are more likely to be treated with medications. Better diagnosis and treatment of anxiety in RTT should be a goal of both future studies and clinical care. TRIAL REGISTRATION: NCT00299312 and NCT02738281. En ligne : https://dx.doi.org/10.1186/s11689-022-09432-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574 [article] Anxiety-like behavior and anxiolytic treatment in the Rett syndrome natural history study [texte imprimé] / Caroline B. BUCHANAN, Auteur ; Jennifer L. STALLWORTH, Auteur ; Aubin E. JOY, Auteur ; Rebekah E. DIXON, Auteur ; Alexandra E. SCOTT, Auteur ; Arthur A. BEISANG, Auteur ; Timothy A. BENKE, Auteur ; Daniel G. GLAZE, Auteur ; Richard H. HAAS, Auteur ; Peter T. HEYDEMANN, Auteur ; Mary D. JONES, Auteur ; Jane B. LANE, Auteur ; David N. LIEBERMAN, Auteur ; Eric D. MARSH, Auteur ; Jeffrey L. NEUL, Auteur ; Sarika U. PETERS, Auteur ; Robin C. RYTHER, Auteur ; Steve A. SKINNER, Auteur ; Shannon M. STANDRIDGE, Auteur ; Walter E. KAUFMANN, Auteur ; Alan K. PERCY, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 14 (2022) Mots-clés : Anti-Anxiety Agents/therapeutic use  Anxiety/drug therapy/epidemiology  Female  Humans  Rett Syndrome/complications/drug therapy/epidemiology  Anti-anxiety agents  Anxiety  Methyl-CpG-binding protein 2  Natural history studies  Rett syndrome  Fellowship under U54 HD 061222 grant) and has done clinical trials with Acadia,  Anavex, GW Pharmaceuticals, and Zynerba. Timothy A. Benke received funding from  the NIH (U54 HD061222, R21 NS101288, R01 NS081248), International Foundation for  CDKL5 Research, Loulou Foundation, and Children’s Hospital Colorado Foundation  Ponzio Family Chair in Neurology Research. He is also a consultant for AveXis,  Ovid, GW Pharmaceuticals, International Rett Syndrome Foundation, Takeda, and  Marinus and has done clinical trials with Acadia, Ovid, GW Pharmaceuticals,  Marinus, and Rett Syndrome Research Trust  all remuneration has been made to his  department. Daniel G Glaze received funding from the NIH, Rettsyndrome.org, and  the Blue Bird Circle. He has done clinical trials with Acadia, Neuren, and  GW Pharmaceuticals. Richard H. Haas received funding from the NIH 5U54HD061222  grant and has done clinical trials sponsored by Acadia, GW Pharmaceuticals, and  Newron Pharmaceuticals. Jane B. Lane received funding from the NIH and is a  consultant for International Rett Syndrome Foundation and GW Pharmaceuticals.  David N. Lieberman has done clinical trials with Anavex, Acadia, GW  Pharmaceuticals, and Rett Syndrome Research Trust. Eric D. Marsh received funding  from Rett Syndrome Research Trust, NIH, State of Pennsylvania, Penn Orphan  Disease Center, International Rett Syndrome Foundation, LouLou Foundation, and  Eagles Autism Foundation. He is a consultant for Cilpa Therapeutics and Stoke  Therapeutics. He has done clinical trials with Zogenix, GW Pharmaceuticals,  Acadia, Marinus, Stoke Therapeutics, and Rett Syndrome Research Trust. Jeffrey L.  Neul received funding from the NIH and is a consultant for AveXis, Biohaven,  Eloxx Pharmaceuticals, Ovid, Takeda, and Teva Pharmaceuticals. He has done  clinical trials with Acadia and Newron Pharmaceuticals. Sarika U. Peters received  funding from NIH, Rettsyndrome.org and is a consultant for Acadia  Pharmaceuticals. Steve A. Skinner has done clinical trials with Acadia, Anavex,  and GW Pharmaceuticals. Shannon M. Standridge is a speaker for Greenwich  Biosciences and Scientific Advisory Board of Acadia. Walter E. Kaufmann received  funding from the NIH and CDC, and is a consultant for Anavex, AveXis, Acadia,  EryDel, Newron, GW Pharmaceuticals, Marinus, Biohaven, Zynerba, Ovid  Therapeutics, and Stalicla. Currently, he is Chief Medical Officer of Anavex Life  Sciences Corp. Alan K. Percy received funding from the NIH and is a consultant  for Anavex, AveXis, Acadia, and GW Pharmaceuticals. He has done clinical trials  with Anavex, Acadia, GW Pharmaceuticals, and Rett Syndrome Research Trust. The  rest of the authors, Jennifer L. Stallworth, Aubin E. Joy, Rebekah E. Dixon,  Alexandra E. Scott, Arthur A. Beisang, Peter T. Heydemann, Mary D. Jones, and  Robin C. Ryther, declare that they have no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Rett syndrome (RTT) is a neurodevelopmental disorder most often related to a pathogenic variant in the X-linked MECP2 gene. Internalizing behaviors appear to be common, but standard methods of diagnosing anxiety are not readily applied in this population which typically has cognitive impairment and limited expressive language. This study aims to describe the frequency of anxiety-like behavior and anxiolytic treatments along with associated clinical features in individuals with RTT. METHODS: Parental reports and medication logs provided data from 1380 females with RTT participating in two iterations of the multicenter U.S. RTT Natural History Study (RNHS) from 2006 to 2019. RESULTS: Most participants with RTT (77.5%) had at least occasional anxious or nervous behavior. Anxiety was reported to be the most troublesome concern for 2.6%, and within the top 3 concerns for 10.0%, of participants in the second iteration. Parents directly reported treatment for anxious or nervous behavior in 16.6% of participants in the second iteration with most reporting good control of the behavior (71.6%). In the medication logs of both RNHS iterations, the indication of anxiety was listed for a similar number of participants (15% and 14.5%, respectively). Increased use of anxiolytics and selective serotonin reuptake inhibitors (SSRIs) was related to more frequent anxiety-like behaviors (P < 0.001), older age (P < 0.001), and mild MECP2 variants (P = 0.002). CONCLUSION: Anxiety-like behavior is frequent at all ages and is a significant parental concern in RTT. Older individuals and those with mild MECP2 variants are more likely to be treated with medications. Better diagnosis and treatment of anxiety in RTT should be a goal of both future studies and clinical care. TRIAL REGISTRATION: NCT00299312 and NCT02738281. En ligne : https://dx.doi.org/10.1186/s11689-022-09432-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574

Comparison of evoked potentials across four related developmental encephalopathies / Joni N. SABY in Journal of Neurodevelopmental Disorders, 15 (2023)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 15 (2023) Titre : Comparison of evoked potentials across four related developmental encephalopathies Type de document : texte imprimé Auteurs : Joni N. SABY, Auteur ; Sarika U. PETERS, Auteur ; Timothy A. BENKE, Auteur ; Shannon M. STANDRIDGE, Auteur ; Lindsay C. SWANSON, Auteur ; David N. LIEBERMAN, Auteur ; Heather E. OLSON, Auteur ; Alexandra P. KEY, Auteur ; Alan K. PERCY, Auteur ; Jeffrey L. NEUL, Auteur ; Charles A. NELSON, Auteur ; Timothy P.L. ROBERTS, Auteur ; Eric D. MARSH, Auteur Langues : Anglais (eng) Mots-clés : Epileptic Syndromes  Rett Syndrome  X-Linked Intellectual Disability  Child  Humans  Spasms, Infantile  Evoked Potentials  Evoked Potentials, Visual Index. décimale : PER Périodiques Résumé : BACKGROUND: Developing biomarkers is a priority for drug development for all conditions, but vital in the rare neurodevelopmental disorders where sensitive outcome measures are lacking. We have previously demonstrated the feasibility and tracking of evoked potentials to disease severity in Rett syndrome and CDKL5 deficiency disorder. The aim of the current study is to characterize evoked potentials in two related developmental encephalopathies, MECP2 duplication syndrome and FOXG1 syndrome, and compare across all four groups to better understand the potential of these measures to serve as biomarkers of clinical severity for the developmental encephalopathies. METHODS: Visual and auditory evoked potentials were acquired from participants with MECP2 duplication syndrome and FOXG1 syndrome across five sites of the Rett Syndrome and Rett-Related Disorders Natural History Study. A group of age-matched individuals (mean = 7.8 years; range = 1-17) with Rett syndrome, CDKL5 deficiency disorder, and typically-developing participants served as a comparison group. The analysis focused on group-level differences as well as associations between the evoked potentials and measures of clinical severity from the Natural History Study. RESULTS: As reported previously, group-level comparisons revealed attenuated visual evoked potentials (VEPs) in participants with Rett syndrome (n = 43) and CDKL5 deficiency disorder (n = 16) compared to typically-developing participants. VEP amplitude was also attenuated in participants with MECP2 duplication syndrome (n = 15) compared to the typically-developing group. VEP amplitude correlated with clinical severity for Rett syndrome and FOXG1 syndrome (n = 5). Auditory evoked potential (AEP) amplitude did not differ between groups, but AEP latency was prolonged in individuals with MECP2 duplication syndrome (n = 14) and FOXG1 syndrome (n = 6) compared to individuals with Rett syndrome (n = 51) and CDKL5 deficiency disorder (n = 14). AEP amplitude correlated with severity in Rett syndrome and CDKL5 deficiency disorder. AEP latency correlated with severity in CDKL5 deficiency disorder, MECP2 duplication syndrome, and FOXG1 syndrome. CONCLUSIONS: There are consistent abnormalities in the evoked potentials in four developmental encephalopathies some of which correlate with clinical severity. While there are consistent changes amongst these four disorders, there are also condition specific findings that need to be further refined and validated. Overall, these results provide a foundation for further refinement of these measures for use in future clinical trials for these conditions. En ligne : https://dx.doi.org/10.1186/s11689-023-09479-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575 [article] Comparison of evoked potentials across four related developmental encephalopathies [texte imprimé] / Joni N. SABY, Auteur ; Sarika U. PETERS, Auteur ; Timothy A. BENKE, Auteur ; Shannon M. STANDRIDGE, Auteur ; Lindsay C. SWANSON, Auteur ; David N. LIEBERMAN, Auteur ; Heather E. OLSON, Auteur ; Alexandra P. KEY, Auteur ; Alan K. PERCY, Auteur ; Jeffrey L. NEUL, Auteur ; Charles A. NELSON, Auteur ; Timothy P.L. ROBERTS, Auteur ; Eric D. MARSH, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 15 (2023) Mots-clés : Epileptic Syndromes  Rett Syndrome  X-Linked Intellectual Disability  Child  Humans  Spasms, Infantile  Evoked Potentials  Evoked Potentials, Visual Index. décimale : PER Périodiques Résumé : BACKGROUND: Developing biomarkers is a priority for drug development for all conditions, but vital in the rare neurodevelopmental disorders where sensitive outcome measures are lacking. We have previously demonstrated the feasibility and tracking of evoked potentials to disease severity in Rett syndrome and CDKL5 deficiency disorder. The aim of the current study is to characterize evoked potentials in two related developmental encephalopathies, MECP2 duplication syndrome and FOXG1 syndrome, and compare across all four groups to better understand the potential of these measures to serve as biomarkers of clinical severity for the developmental encephalopathies. METHODS: Visual and auditory evoked potentials were acquired from participants with MECP2 duplication syndrome and FOXG1 syndrome across five sites of the Rett Syndrome and Rett-Related Disorders Natural History Study. A group of age-matched individuals (mean = 7.8 years; range = 1-17) with Rett syndrome, CDKL5 deficiency disorder, and typically-developing participants served as a comparison group. The analysis focused on group-level differences as well as associations between the evoked potentials and measures of clinical severity from the Natural History Study. RESULTS: As reported previously, group-level comparisons revealed attenuated visual evoked potentials (VEPs) in participants with Rett syndrome (n = 43) and CDKL5 deficiency disorder (n = 16) compared to typically-developing participants. VEP amplitude was also attenuated in participants with MECP2 duplication syndrome (n = 15) compared to the typically-developing group. VEP amplitude correlated with clinical severity for Rett syndrome and FOXG1 syndrome (n = 5). Auditory evoked potential (AEP) amplitude did not differ between groups, but AEP latency was prolonged in individuals with MECP2 duplication syndrome (n = 14) and FOXG1 syndrome (n = 6) compared to individuals with Rett syndrome (n = 51) and CDKL5 deficiency disorder (n = 14). AEP amplitude correlated with severity in Rett syndrome and CDKL5 deficiency disorder. AEP latency correlated with severity in CDKL5 deficiency disorder, MECP2 duplication syndrome, and FOXG1 syndrome. CONCLUSIONS: There are consistent abnormalities in the evoked potentials in four developmental encephalopathies some of which correlate with clinical severity. While there are consistent changes amongst these four disorders, there are also condition specific findings that need to be further refined and validated. Overall, these results provide a foundation for further refinement of these measures for use in future clinical trials for these conditions. En ligne : https://dx.doi.org/10.1186/s11689-023-09479-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575

Current neurologic treatment and emerging therapies in CDKL5 deficiency disorder / Heather E. OLSON in Journal of Neurodevelopmental Disorders, 13 (2021)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 13 (2021) Titre : Current neurologic treatment and emerging therapies in CDKL5 deficiency disorder Type de document : texte imprimé Auteurs : Heather E. OLSON, Auteur ; Carolyn I. DANIELS, Auteur ; Isabel HAVILAND, Auteur ; Lindsay C. SWANSON, Auteur ; Caitlin A. GREENE, Auteur ; Anne Marie M. DENNY, Auteur ; Scott T. DEMAREST, Auteur ; Elia PESTANA-KNIGHT, Auteur ; Xiaoming ZHANG, Auteur ; Ahsan N. MOOSA, Auteur ; Andrea FIDELL, Auteur ; Judith L. WEISENBERG, Auteur ; Bernhard SUTER, Auteur ; Cary FU, Auteur ; Jeffrey L. NEUL, Auteur ; Alan K. PERCY, Auteur ; Eric D. MARSH, Auteur ; Timothy A. BENKE, Auteur ; Annapurna PODURI, Auteur Langues : Anglais (eng) Mots-clés : Epilepsy/genetics/therapy  Epileptic Syndromes/genetics/therapy  Humans  Protein Serine-Threonine Kinases/genetics  Spasms, Infantile/genetics/therapy  CDKL5 deficiency disorder  Clinical trials  Developmental encephalopathy  Emerging therapies  Epileptic encephalopathy  Ketogenic diet  Movement disorders  Vagus nerve stimulator  Therapeutics and Marinus Pharmaceuticals. PI of "Diagnosis and genotype-phenotype  correlations in early life epilepsy and CDKL5 disorder" NINDS award  (1K23NS107646). Funding for the Boston Children’s Hospital CDKL5 Center of  Excellence provided by the International Foundation for CDKL5 Research.  Consulting for Takeda and Ovid Therapeutics. Scott T. Demarest: site PI of  clinical trials in CDD sponsored by Ovid Therapeutics and Marinus  Pharmaceuticals. Consulting for Upsher-Smith and BioMarin. All remuneration has  been made to his department. Elia Pestana-Knight: site PI of clinical trial in  CDD sponsored by Marinus Pharmaceuticals. Co-PI of Cleveland Clinic CDD Center of  Excellence established by the International Foundation for CDKL5 Research.  Consultant for Marinus Pharmaceuticals. Ahsan N. Moosa: site co-investigator for  clinical trials in CDD sponsored by Marinus Pharmaceuticals. Bernhard Suter: site  PI of a clinical trial in CDD sponsored by Marinus Pharmaceuticals. Site PI of a  clinical trial in Rett syndrome sponsored by RSRT, the investigator-initiated  trial using ketamine. PI of Texas Children’s Hospital CDD Center of Excellence  established by the International Foundation for CDKL5 Research. Jeffrey L. Neul:  consultancy to GW Pharmaceuticals, Acadia, AveXis, Ovid Therapeutics. Data and  Safety Monitoring Board for Roche, Ovid Therapeutics. Alan K. Percy: PI of the  NICHD-funded Natural History Study. Site PI of clinical trials in Rett syndrome  sponsored by Anavex and Acadia and the investigator-initiated trial using  ketamine. Consultant with Acadia. Eric D. Marsh: site PI of clinical trial in CDD  sponsored by Marinus Pharmaceuticals. Site PI for clinical trials for DS and LGS  trials sponsored by Zogenix. Provides research support and clinical Center of  Excellence support for the International Foundation for CDKL5 Research. Timothy  A. Benke: site co-PI of clinical trials in CDD sponsored by Ovid Therapeutics and  Marinus Pharmaceuticals. Consulting for AveXis, Ovid Therapeutics, Takeda, and  Marinus Pharmeceuticals. All remuneration has been made to his department.  Annapurna Poduri: SAB for TevardBio, no personal remuneration. Carolyn Daniels,  Isabel Haviland, Lindsay Swanson, Caitlin Greene, AnneMarie M. Denny, Andrea  Fidell, Cary Fu, Xiaoming Zhang, Judith L. Weisenberg: no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: CDKL5 deficiency disorder (CDD) is associated with refractory infantile onset epilepsy, global developmental delay, and variable features that include sleep, behavioral disturbances, and movement disorders. Current treatment is primarily symptom-based and informed by experience in caring for this population. METHODS: We describe medication and non-medication approaches to treatment of epilepsy and additional key neurologic symptoms (sleep disturbances, behavioral issues, movement disorders, and swallowing dysfunction) in a cohort of 177 individuals meeting criteria for CDD, 154 evaluated at 4 CDKL5 Centers of Excellence in the USA and 40 identified through the NIH Natural History Study of Rett and Related Disorders. RESULTS: The four most frequently prescribed anti-seizure medications were broad spectrum, prescribed in over 50% of individuals. While the goal was not to ascertain efficacy, we obtained data from 86 individuals regarding response to treatment, with 2-week response achieved in 14-48% and sustained 3-month response in 5-36%, of those with known response. Additional treatments for seizures included cannabis derivatives, tried in over one-third of individuals, and clinical trial medications. In combination with pharmacological treatment, 50% of individuals were treated with ketogenic diet for attempted seizure control. Surgical approaches included vagus nerve stimulators, functional hemispherectomy, and corpus callosotomy, but numbers were too limited to assess response. Nearly one-third of individuals received pharmacologic treatment for sleep disturbances, 13% for behavioral dysregulation and movement disorders, and 43% had gastrostomy tubes. CONCLUSIONS: Treatment for neurologic features of CDD is currently symptom-based and empiric rather than CDD-specific, though clinical trials for CDD are emerging. Epilepsy in this population is highly refractory, and no specific anti-seizure medication was associated with improved seizure control. Ketogenic diet is commonly used in patients with CDD. While behavioral interventions are commonly instituted, information on the use of medications for sleep, behavioral management, and movement disorders is sparse and would benefit from further characterization and optimization of treatment approaches. The heterogeneity in treatment approaches highlights the need for systematic review and guidelines for CDD. Additional disease-specific and disease-modifying treatments are in development. En ligne : https://dx.doi.org/10.1186/s11689-021-09384-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574 [article] Current neurologic treatment and emerging therapies in CDKL5 deficiency disorder [texte imprimé] / Heather E. OLSON, Auteur ; Carolyn I. DANIELS, Auteur ; Isabel HAVILAND, Auteur ; Lindsay C. SWANSON, Auteur ; Caitlin A. GREENE, Auteur ; Anne Marie M. DENNY, Auteur ; Scott T. DEMAREST, Auteur ; Elia PESTANA-KNIGHT, Auteur ; Xiaoming ZHANG, Auteur ; Ahsan N. MOOSA, Auteur ; Andrea FIDELL, Auteur ; Judith L. WEISENBERG, Auteur ; Bernhard SUTER, Auteur ; Cary FU, Auteur ; Jeffrey L. NEUL, Auteur ; Alan K. PERCY, Auteur ; Eric D. MARSH, Auteur ; Timothy A. BENKE, Auteur ; Annapurna PODURI, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 13 (2021) Mots-clés : Epilepsy/genetics/therapy  Epileptic Syndromes/genetics/therapy  Humans  Protein Serine-Threonine Kinases/genetics  Spasms, Infantile/genetics/therapy  CDKL5 deficiency disorder  Clinical trials  Developmental encephalopathy  Emerging therapies  Epileptic encephalopathy  Ketogenic diet  Movement disorders  Vagus nerve stimulator  Therapeutics and Marinus Pharmaceuticals. PI of "Diagnosis and genotype-phenotype  correlations in early life epilepsy and CDKL5 disorder" NINDS award  (1K23NS107646). Funding for the Boston Children’s Hospital CDKL5 Center of  Excellence provided by the International Foundation for CDKL5 Research.  Consulting for Takeda and Ovid Therapeutics. Scott T. Demarest: site PI of  clinical trials in CDD sponsored by Ovid Therapeutics and Marinus  Pharmaceuticals. Consulting for Upsher-Smith and BioMarin. All remuneration has  been made to his department. Elia Pestana-Knight: site PI of clinical trial in  CDD sponsored by Marinus Pharmaceuticals. Co-PI of Cleveland Clinic CDD Center of  Excellence established by the International Foundation for CDKL5 Research.  Consultant for Marinus Pharmaceuticals. Ahsan N. Moosa: site co-investigator for  clinical trials in CDD sponsored by Marinus Pharmaceuticals. Bernhard Suter: site  PI of a clinical trial in CDD sponsored by Marinus Pharmaceuticals. Site PI of a  clinical trial in Rett syndrome sponsored by RSRT, the investigator-initiated  trial using ketamine. PI of Texas Children’s Hospital CDD Center of Excellence  established by the International Foundation for CDKL5 Research. Jeffrey L. Neul:  consultancy to GW Pharmaceuticals, Acadia, AveXis, Ovid Therapeutics. Data and  Safety Monitoring Board for Roche, Ovid Therapeutics. Alan K. Percy: PI of the  NICHD-funded Natural History Study. Site PI of clinical trials in Rett syndrome  sponsored by Anavex and Acadia and the investigator-initiated trial using  ketamine. Consultant with Acadia. Eric D. Marsh: site PI of clinical trial in CDD  sponsored by Marinus Pharmaceuticals. Site PI for clinical trials for DS and LGS  trials sponsored by Zogenix. Provides research support and clinical Center of  Excellence support for the International Foundation for CDKL5 Research. Timothy  A. Benke: site co-PI of clinical trials in CDD sponsored by Ovid Therapeutics and  Marinus Pharmaceuticals. Consulting for AveXis, Ovid Therapeutics, Takeda, and  Marinus Pharmeceuticals. All remuneration has been made to his department.  Annapurna Poduri: SAB for TevardBio, no personal remuneration. Carolyn Daniels,  Isabel Haviland, Lindsay Swanson, Caitlin Greene, AnneMarie M. Denny, Andrea  Fidell, Cary Fu, Xiaoming Zhang, Judith L. Weisenberg: no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: CDKL5 deficiency disorder (CDD) is associated with refractory infantile onset epilepsy, global developmental delay, and variable features that include sleep, behavioral disturbances, and movement disorders. Current treatment is primarily symptom-based and informed by experience in caring for this population. METHODS: We describe medication and non-medication approaches to treatment of epilepsy and additional key neurologic symptoms (sleep disturbances, behavioral issues, movement disorders, and swallowing dysfunction) in a cohort of 177 individuals meeting criteria for CDD, 154 evaluated at 4 CDKL5 Centers of Excellence in the USA and 40 identified through the NIH Natural History Study of Rett and Related Disorders. RESULTS: The four most frequently prescribed anti-seizure medications were broad spectrum, prescribed in over 50% of individuals. While the goal was not to ascertain efficacy, we obtained data from 86 individuals regarding response to treatment, with 2-week response achieved in 14-48% and sustained 3-month response in 5-36%, of those with known response. Additional treatments for seizures included cannabis derivatives, tried in over one-third of individuals, and clinical trial medications. In combination with pharmacological treatment, 50% of individuals were treated with ketogenic diet for attempted seizure control. Surgical approaches included vagus nerve stimulators, functional hemispherectomy, and corpus callosotomy, but numbers were too limited to assess response. Nearly one-third of individuals received pharmacologic treatment for sleep disturbances, 13% for behavioral dysregulation and movement disorders, and 43% had gastrostomy tubes. CONCLUSIONS: Treatment for neurologic features of CDD is currently symptom-based and empiric rather than CDD-specific, though clinical trials for CDD are emerging. Epilepsy in this population is highly refractory, and no specific anti-seizure medication was associated with improved seizure control. Ketogenic diet is commonly used in patients with CDD. While behavioral interventions are commonly instituted, information on the use of medications for sleep, behavioral management, and movement disorders is sparse and would benefit from further characterization and optimization of treatment approaches. The heterogeneity in treatment approaches highlights the need for systematic review and guidelines for CDD. Additional disease-specific and disease-modifying treatments are in development. En ligne : https://dx.doi.org/10.1186/s11689-021-09384-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574

Epigenetics modifiers: potential hub for understanding and treating neurodevelopmental disorders from hypoxic injury / Ana G. CRISTANCHO in Journal of Neurodevelopmental Disorders, 12 (2020)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 12 (2020) Titre : Epigenetics modifiers: potential hub for understanding and treating neurodevelopmental disorders from hypoxic injury Type de document : texte imprimé Auteurs : Ana G. CRISTANCHO, Auteur ; Eric D. MARSH, Auteur Langues : Anglais (eng) Mots-clés : Brain  Child  DNA Methylation  Epigenesis, Genetic  Humans  Hypoxia  Infant, Newborn  Neurodevelopmental Disorders  Brain development  Epigenetics  Histone modification  Neurodevelopmental disorders Index. décimale : PER Périodiques Résumé : BACKGROUND: The fetal brain is adapted to the hypoxic conditions present during normal in utero development. Relatively more hypoxic states, either chronic or acute, are pathologic and can lead to significant long-term neurodevelopmental sequelae. In utero hypoxic injury is associated with neonatal mortality and millions of lives lived with varying degrees of disability. MAIN BODY: Genetic studies of children with neurodevelopmental disease indicate that epigenetic modifiers regulating DNA methylation and histone remodeling are critical for normal brain development. Epigenetic modifiers are also regulated by environmental stimuli, such as hypoxia. Indeed, epigenetic modifiers that are mutated in children with genetic neurodevelopmental diseases are regulated by hypoxia in a number of preclinical models and may be part of the mechanism for the long-term neurodevelopmental sequelae seem in children with hypoxic brain injury. Thus, a comprehensive understanding the role of DNA methylation and histone modifications in hypoxic injury is critical for developing novel strategies to treat children with hypoxic injury. CONCLUSIONS: This review focuses on our current understanding of the intersection between epigenetics, brain development, and hypoxia. Opportunities for the use of epigenetics as biomarkers of neurodevelopmental disease after hypoxic injury and potential clinical epigenetics targets to improve outcomes after injury are also discussed. While there have been many published studies on the epigenetics of hypoxia, more are needed in the developing brain in order to determine which epigenetic pathways may be most important for mitigating the long-term consequences of hypoxic brain injury. En ligne : https://dx.doi.org/10.1186/s11689-020-09344-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573 [article] Epigenetics modifiers: potential hub for understanding and treating neurodevelopmental disorders from hypoxic injury [texte imprimé] / Ana G. CRISTANCHO, Auteur ; Eric D. MARSH, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 12 (2020) Mots-clés : Brain  Child  DNA Methylation  Epigenesis, Genetic  Humans  Hypoxia  Infant, Newborn  Neurodevelopmental Disorders  Brain development  Epigenetics  Histone modification  Neurodevelopmental disorders Index. décimale : PER Périodiques Résumé : BACKGROUND: The fetal brain is adapted to the hypoxic conditions present during normal in utero development. Relatively more hypoxic states, either chronic or acute, are pathologic and can lead to significant long-term neurodevelopmental sequelae. In utero hypoxic injury is associated with neonatal mortality and millions of lives lived with varying degrees of disability. MAIN BODY: Genetic studies of children with neurodevelopmental disease indicate that epigenetic modifiers regulating DNA methylation and histone remodeling are critical for normal brain development. Epigenetic modifiers are also regulated by environmental stimuli, such as hypoxia. Indeed, epigenetic modifiers that are mutated in children with genetic neurodevelopmental diseases are regulated by hypoxia in a number of preclinical models and may be part of the mechanism for the long-term neurodevelopmental sequelae seem in children with hypoxic brain injury. Thus, a comprehensive understanding the role of DNA methylation and histone modifications in hypoxic injury is critical for developing novel strategies to treat children with hypoxic injury. CONCLUSIONS: This review focuses on our current understanding of the intersection between epigenetics, brain development, and hypoxia. Opportunities for the use of epigenetics as biomarkers of neurodevelopmental disease after hypoxic injury and potential clinical epigenetics targets to improve outcomes after injury are also discussed. While there have been many published studies on the epigenetics of hypoxia, more are needed in the developing brain in order to determine which epigenetic pathways may be most important for mitigating the long-term consequences of hypoxic brain injury. En ligne : https://dx.doi.org/10.1186/s11689-020-09344-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573

Longitudinal characterization of clinical, developmental, and behavioral phenotypes in 101 children and adults with FOXG1 syndrome / Elise BRIMBLE in Journal of Neurodevelopmental Disorders, 17 (2025)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 17 (2025) Titre : Longitudinal characterization of clinical, developmental, and behavioral phenotypes in 101 children and adults with FOXG1 syndrome Type de document : texte imprimé Auteurs : Elise BRIMBLE, Auteur ; Pam VENTOLA, Auteur ; Elizabeth BLOMENBERG, Auteur ; Kelsey FRAHLICH, Auteur ; Kopika KUHATHAAS, Auteur ; Christopher E. HART, Auteur ; Nadia BAHI-BUISSON, Auteur ; Heather E. OLSON, Auteur ; Eric D. MARSH, Auteur ; Gai AYALON, Auteur Langues : Anglais (eng) Mots-clés : Clinical trial readiness  FOXG1 syndrome  Genotype-phenotype correlations  Natural history studies  Neurodevelopmental disorders  Rare disorders  Real-world data  Real-world evidence  guardians of study participants provided broad consent to share de-identified  data for research. This study received determinations of exemption through a  central institutional review board via exemption categories 2, 7, and 8 of the  revised Common Rule. Consent for publication: Not applicable. Competing  interests: Elise Brimble, Elizabeth Blomenberg, and Kelsey Frahlich are current  employees of Citizen Health with vested and unvested stock options. Kopika  Kuhathaas and Gai Ayalon are current employees of FOXG1 Research Foundation. Index. décimale : PER Périodiques Résumé : BACKGROUND: FOXG1 syndrome is a severe genetic neurodevelopmental disorder characterized by intellectual and developmental disabilities (IDD), postnatal microcephaly, epilepsy, and movement disorder. With the advent of molecular therapies, establishing the natural history of FOXG1 syndrome is critical to enable clinical trial readiness. However, traditional study designs are challenging to implement for rare disorders without significant burden to participants. METHODS: The study population included 101 children and adults with (likely) pathogenic variants in or involving FOXG1 (ages 0.4 - 34.8 years). Participant medical records underwent systematic annotation and harmonization of recorded clinical phenotypes, interventions, and outcomes through use of a patient-centric real-world data (RWD) platform. Retrospective medical record data were paired with prospective administration of validated measures of development and behavior, including the Vineland-3, the Aberrant Behavior Checklist, and the Children’s Sleep Habits Questionnaire. Descriptive and inferential statistics were employed to characterize longitudinal phenotypes and to explore genotype-phenotype correlations. RESULTS: Through systematic evaluation of 101 people with FOXG1 syndrome, we generated a robust dataset encompassing >40,000 annotated clinical terminology concepts that represent >770 cumulative patient data years. Core clinical phenotypes include IDD, gastrointestinal disorders, strabismus, epilepsy, movement disorders, and sleep problems. The FOXG1 syndrome behavioral phenotype is characterized by irritability, including aggressive behaviors, stereotypies, social withdrawal, and lethargy; in those with missense variants, features of autism spectrum disorders are also reported. Data derived from both medical records and validated measures confirm and expand upon previously described genotype-phenotype correlations, whereby truncating variants are associated with greater limitations across motor and communication domains, as well as increased frequency of core FOXG1 syndrome phenotypes. Further, individuals with truncating variants had higher scores on a composite measure of FOXG1 syndrome severity, which persists when modeled longitudinally. Employing the same composite measure, we demonstrate that FOXG1 syndrome is a static encephalopathy without evidence of neurodegeneration. CONCLUSIONS: By combining retrospective RWD with prospective survey administration in a large sample population, we establish the natural history of FOXG1 syndrome and highlight candidate clinical endpoints for use in clinical trials, including quantitative evaluations of communication and movement disorders. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s11689-025-09653-1. En ligne : https://dx.doi.org/10.1186/s11689-025-09653-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576 [article] Longitudinal characterization of clinical, developmental, and behavioral phenotypes in 101 children and adults with FOXG1 syndrome [texte imprimé] / Elise BRIMBLE, Auteur ; Pam VENTOLA, Auteur ; Elizabeth BLOMENBERG, Auteur ; Kelsey FRAHLICH, Auteur ; Kopika KUHATHAAS, Auteur ; Christopher E. HART, Auteur ; Nadia BAHI-BUISSON, Auteur ; Heather E. OLSON, Auteur ; Eric D. MARSH, Auteur ; Gai AYALON, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 17 (2025) Mots-clés : Clinical trial readiness  FOXG1 syndrome  Genotype-phenotype correlations  Natural history studies  Neurodevelopmental disorders  Rare disorders  Real-world data  Real-world evidence  guardians of study participants provided broad consent to share de-identified  data for research. This study received determinations of exemption through a  central institutional review board via exemption categories 2, 7, and 8 of the  revised Common Rule. Consent for publication: Not applicable. Competing  interests: Elise Brimble, Elizabeth Blomenberg, and Kelsey Frahlich are current  employees of Citizen Health with vested and unvested stock options. Kopika  Kuhathaas and Gai Ayalon are current employees of FOXG1 Research Foundation. Index. décimale : PER Périodiques Résumé : BACKGROUND: FOXG1 syndrome is a severe genetic neurodevelopmental disorder characterized by intellectual and developmental disabilities (IDD), postnatal microcephaly, epilepsy, and movement disorder. With the advent of molecular therapies, establishing the natural history of FOXG1 syndrome is critical to enable clinical trial readiness. However, traditional study designs are challenging to implement for rare disorders without significant burden to participants. METHODS: The study population included 101 children and adults with (likely) pathogenic variants in or involving FOXG1 (ages 0.4 - 34.8 years). Participant medical records underwent systematic annotation and harmonization of recorded clinical phenotypes, interventions, and outcomes through use of a patient-centric real-world data (RWD) platform. Retrospective medical record data were paired with prospective administration of validated measures of development and behavior, including the Vineland-3, the Aberrant Behavior Checklist, and the Children’s Sleep Habits Questionnaire. Descriptive and inferential statistics were employed to characterize longitudinal phenotypes and to explore genotype-phenotype correlations. RESULTS: Through systematic evaluation of 101 people with FOXG1 syndrome, we generated a robust dataset encompassing >40,000 annotated clinical terminology concepts that represent >770 cumulative patient data years. Core clinical phenotypes include IDD, gastrointestinal disorders, strabismus, epilepsy, movement disorders, and sleep problems. The FOXG1 syndrome behavioral phenotype is characterized by irritability, including aggressive behaviors, stereotypies, social withdrawal, and lethargy; in those with missense variants, features of autism spectrum disorders are also reported. Data derived from both medical records and validated measures confirm and expand upon previously described genotype-phenotype correlations, whereby truncating variants are associated with greater limitations across motor and communication domains, as well as increased frequency of core FOXG1 syndrome phenotypes. Further, individuals with truncating variants had higher scores on a composite measure of FOXG1 syndrome severity, which persists when modeled longitudinally. Employing the same composite measure, we demonstrate that FOXG1 syndrome is a static encephalopathy without evidence of neurodegeneration. CONCLUSIONS: By combining retrospective RWD with prospective survey administration in a large sample population, we establish the natural history of FOXG1 syndrome and highlight candidate clinical endpoints for use in clinical trials, including quantitative evaluations of communication and movement disorders. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s11689-025-09653-1. En ligne : https://dx.doi.org/10.1186/s11689-025-09653-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576

Psychometric Assessment of the Rett Syndrome Caregiver Assessment of Symptom Severity (RCASS) / Melissa RASPA in Journal of Autism and Developmental Disorders, 55-3 (March 2025)  

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A randomized, placebo-controlled, cross-over trial of ketamine in Rett syndrome / Kathleen CAMPBELL in Journal of Neurodevelopmental Disorders, 17 (2025)  

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Top caregiver concerns in Rett syndrome and related disorders: data from the US natural history study / Jeffrey L. NEUL in Journal of Neurodevelopmental Disorders, 15 (2023)  

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Validating the Communication and Symbolic Behavior Scales-Developmental Profile Infant-Toddler Checklist (CSBS-DP ITC) Beyond Infancy in the CDKL5 Deficiency Disorder / Helen LEONARD ; Kingsley WONG ; Peter JACOBY ; Mary SPENCE ; Eric D. MARSH ; Timothy A. BENKE ; Scott DEMAREST ; Jenny DOWNS in Journal of Autism and Developmental Disorders, 54-7 (July 2024)  

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