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Documents disponibles écrits par cet auteur (4)
Faire une suggestion Affiner la rechercheCortisol profiles and clinical severity in MECP2 duplication syndrome / Sarika U. PETERS in Journal of Neurodevelopmental Disorders, 12 (2020)
Titre : Cortisol profiles and clinical severity in MECP2 duplication syndrome Type de document : texte imprimé Auteurs : Sarika U. PETERS, Auteur ; Cary FU, Auteur ; Jeffrey L. NEUL, Auteur ; Douglas A. GRANGER, Auteur Langues : Anglais (eng) Mots-clés : Adolescent Biomarkers Child Child, Preschool Chromosome Duplication Female Humans Hydrocortisone/metabolism Male X-Linked Intellectual Disability/metabolism Saliva Severity of Illness Index Young Adult Index. décimale : PER Périodiques Résumé : BACKGROUND: MECP2 duplication syndrome (MDS) is a rare X-linked genomic disorder primarily affecting males which is caused by interstitial chromosomal duplications at Xq28 encompassing the MECP2 gene. Core clinical features of MDS include choreiform movements, progressive spasticity, recurrent respiratory infections, developmental delays in the first 6 months of life, hypotonia, vasomotor disturbances, constipation, drooling, and bruxism. Prior studies suggest that HPA axis activity may be altered in MDS and measures of HPA axis activity may offer insight into disease severity. METHODS: To ascertain whether cortisol profiles are a potential biomarker of clinical severity, diurnal profiles of cortisol and the cortisol awakening response were examined from saliva samples in 31 participants with MDS (ages 2-24 years), and 27 of these samples were usable. Documentation of a positive diagnostic test for MECP2 duplication was required for entry into the study. Samples were collected on each of two consecutive weekdays at four time points during the day: immediately after waking, 30 min after waking, between 3 and 4 PM, and in the evening before bedtime. Correlations with duplication size, clinical severity, sleep problems, and behavior were also examined. RESULTS: Results revealed that a majority of participants with MDS exhibit a declining cortisol awakening response (n = 17). A declining CAR was significantly associated with increased clinical severity scores (r = - .508; p = .03), larger duplication size, waking later, and an increased number of hospitalizations for infections. CONCLUSIONS: Future mechanistic studies will have to determine whether the declining CAR in MDS is attributable to problems with "flip-flop switching" of regional brain activation (involving the suprachiasmatic nucleus and the hippocampus, and the HPA axis) that is responsible for the switch from reduced to increased adrenal sensitivity. Taken together, results suggest the possibility that cortisol profiles could potentially be a biomarker of clinical severity and utilized for the purposes of patient stratification for future clinical trials in MDS. En ligne : https://dx.doi.org/10.1186/s11689-020-09322-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573
in Journal of Neurodevelopmental Disorders > 12 (2020)[article] Cortisol profiles and clinical severity in MECP2 duplication syndrome [texte imprimé] / Sarika U. PETERS, Auteur ; Cary FU, Auteur ; Jeffrey L. NEUL, Auteur ; Douglas A. GRANGER, Auteur.
Langues : Anglais (eng)
in Journal of Neurodevelopmental Disorders > 12 (2020)
Mots-clés : Adolescent Biomarkers Child Child, Preschool Chromosome Duplication Female Humans Hydrocortisone/metabolism Male X-Linked Intellectual Disability/metabolism Saliva Severity of Illness Index Young Adult Index. décimale : PER Périodiques Résumé : BACKGROUND: MECP2 duplication syndrome (MDS) is a rare X-linked genomic disorder primarily affecting males which is caused by interstitial chromosomal duplications at Xq28 encompassing the MECP2 gene. Core clinical features of MDS include choreiform movements, progressive spasticity, recurrent respiratory infections, developmental delays in the first 6 months of life, hypotonia, vasomotor disturbances, constipation, drooling, and bruxism. Prior studies suggest that HPA axis activity may be altered in MDS and measures of HPA axis activity may offer insight into disease severity. METHODS: To ascertain whether cortisol profiles are a potential biomarker of clinical severity, diurnal profiles of cortisol and the cortisol awakening response were examined from saliva samples in 31 participants with MDS (ages 2-24 years), and 27 of these samples were usable. Documentation of a positive diagnostic test for MECP2 duplication was required for entry into the study. Samples were collected on each of two consecutive weekdays at four time points during the day: immediately after waking, 30 min after waking, between 3 and 4 PM, and in the evening before bedtime. Correlations with duplication size, clinical severity, sleep problems, and behavior were also examined. RESULTS: Results revealed that a majority of participants with MDS exhibit a declining cortisol awakening response (n = 17). A declining CAR was significantly associated with increased clinical severity scores (r = - .508; p = .03), larger duplication size, waking later, and an increased number of hospitalizations for infections. CONCLUSIONS: Future mechanistic studies will have to determine whether the declining CAR in MDS is attributable to problems with "flip-flop switching" of regional brain activation (involving the suprachiasmatic nucleus and the hippocampus, and the HPA axis) that is responsible for the switch from reduced to increased adrenal sensitivity. Taken together, results suggest the possibility that cortisol profiles could potentially be a biomarker of clinical severity and utilized for the purposes of patient stratification for future clinical trials in MDS. En ligne : https://dx.doi.org/10.1186/s11689-020-09322-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573
Titre : A randomized, placebo-controlled, cross-over trial of ketamine in Rett syndrome Type de document : texte imprimé Auteurs : Kathleen CAMPBELL, Auteur ; Jeffrey L. NEUL, Auteur ; David N. LIEBERMAN, Auteur ; Elizabeth BERRY-KRAVIS, Auteur ; Tim A. BENKE, Auteur ; Cary FU, Auteur ; Alan PERCY, Auteur ; Bernhard SUTER, Auteur ; David MORRIS, Auteur ; Randall L. CARPENTER, Auteur ; Eric D. MARSH, Auteur ; Jana VON HEHN, Auteur Langues : Anglais (eng) Mots-clés : Child Female Humans Cross-Over Studies Dose-Response Relationship, Drug Double-Blind Method Electroencephalography Ketamine/administration & dosage/adverse effects/therapeutic use/pharmacology Rett Syndrome/drug therapy Clinical trial Ketamine Rett syndrome and approved by the Food and Drug Administration, by the institutional review boards at each participating site, and was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Appropriate written informed consent for study participation was obtained prior to completing any study procedures. Consent for publication: Not applicable. Competing interests: KC has no competing interests. EBK has no competing interests. DNL has acted as a consultant for Acadia Pharmaceuticals, Neurogene, and Taysha Gene Therapies. He has been a Site PI for industry sponsored trials from Acadia Pharmaceuticals, GW Pharmaceuticals, Anavex Life Sciences, and Neurogene. He has received research support from RSRT. TAB has received research funding from GRIN2B Foundation, the International Foundation for CDKL5 Research, Loulou Foundation, the National Institutes of Health, and Simons Foundation consultancy for Alcyone, AveXis, GRIN Therapeutics, GW Pharmaceuticals, the International Rett Syndrome Foundation, Marinus Pharmaceuticals, Neurogene, Ovid Therapeutics, Takeda Pharmaceutical Company Limited and Taysha clinical trials with Acadia Pharmaceuticals Inc., GW Pharmaceuticals, Marinus Pharmaceuticals, Neurogene, Ovid Therapeutics, and Rett Syndrome Research Trust all remuneration has been made to his department. CF has been a site investigator for industry sponsored clinical trials from Zogenix pharmaceuticals, Acadia pharmaceuticals, GW pharmaceuticals, Neurogene, and Taysha. AP was a site investigator for Acadia Pharmaceuticals and is a consultant for Acadia, Neurogene, and Taysha Gene Therapies. BS has received research funding from the NIH, IRSF, and the Blue Bird Circle he has provided consultancy for IONIS pharmaceuticals, Neurogene, and Taysha clinical trials with Acadia Pharmaceuticals Inc., Marinus Pharmaceuticals, Neurogene, and the Rett Syndrome Research Trust. EDM has acted as a consultant for Stoke therapeutics, Acadia Pharmaceuticals, and Novartis Pharmaceuticals. He has been a Site PI for industry sponsored trials for Stoke Theraputics, Acadia Pharmaceuticals, GW Pharmaceuticals, Zogenix Pharmaceuticals, Marinus Pharmaceuticals, Takeda Pharmaceuticals and Epygenic Pharmaceuticals. He has received research support from the NIH, Penn Orphan Disease center, RettSyndrome.org, RSRT, and International CDKL5 Research Foundation. DM has no competing interests. RLC has no competing interests. JLN has acted as a consultant for Acadia Pharmaceuticals, Alycone Pharmaceuticals, AveXis, GW Pharmaceuticals, Hoffmann-La Roche, IONIS Pharmaceuticals, Neurogene, Newron Pharmaceuticals, Ovid Therapeutics, Taysha Gene Therapies, and Ultragenyx. He has been a site PI for industry sponsored clinical research for Acadia Pharmaceuticals, GW Pharmaceuticals, IONIS Pharmaceuticals, Newron Pharmaceuticals. He has received research support from the National Institutes of Health, International Rett Syndrome Foundation, and RSRT. JvH has no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Preclinical studies and anecdotal case reports support the potential therapeutic benefit of low-dose oral ketamine as a treatment of clinical symptoms in Rett syndrome (RTT); however, no controlled studies have been conducted in RTT to evaluate safety, tolerability and efficacy. DESIGN: This was a sequentially initiated, dose-escalating cohort, placebo-controlled, double blind, randomized sequence, cross-over study of oral ketamine in 6-12-year-old girls with RTT to evaluate short-term safety and tolerability and explore efficacy. METHODS: Participants were randomized to either five days treatment with oral ketamine or matched placebo, followed by a nine-day wash-out period and then crossed-over to the opposite treatment. Ketamine was dosed twice daily at 0.75 mg/kg/dose (Cohort 1) or 1.5 mg/kg/dose (Cohort 2). An independent safety monitoring committee evaluated safety and approved proceeding to the next dose cohort. Caregivers, participants, outcome assessors, and study staff except pharmacists were blinded to allocation. The primary endpoint was safety and tolerability. Exploratory efficacy endpoints included change in clinician- and caregiver-rated measures of RTT features, brain activity on electroencephalography, and wearable biosensors to measure respiration, heart rate, sleep, and activity. RESULTS: Twenty-three participants enrolled (11 in Cohort 1, 12 in Cohort 2) from 3/12/2019-11/22/2021. One participant was excluded from analysis due to not meeting inclusion criteria on blinded review prior to analysis. One participant was withdrawn from the study due to an adverse event (vomiting) after the first dose of ketamine. Although planned for four dose cohorts, the trial was stopped after Cohort 2 due to enrollment challenges associated with the COVID-19 pandemic. Ketamine was safe and tolerated in both cohorts, with 1 related treatment emergent adverse event of vomiting. No difference was observed in efficacy between ketamine and placebo. Electroencephalography showed the expected increase in high frequency power with ketamine. CONCLUSIONS: Short-term, low-dose oral ketamine was safe and well tolerated in girls with RTT. No clinical efficacy of ketamine in treating symptoms of RTT was observed with 5 days of treatment, despite electroencephalography evidence of ketamine target engagement during the first dose. Further studies are needed to evaluate safety and efficacy of higher dose and longer exposure to ketamine in RTT. TRIAL REGISTRATION: Registered at clinicaltrials.gov NCT03633058. En ligne : https://dx.doi.org/10.1186/s11689-025-09591-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576
in Journal of Neurodevelopmental Disorders > 17 (2025)[article] A randomized, placebo-controlled, cross-over trial of ketamine in Rett syndrome [texte imprimé] / Kathleen CAMPBELL, Auteur ; Jeffrey L. NEUL, Auteur ; David N. LIEBERMAN, Auteur ; Elizabeth BERRY-KRAVIS, Auteur ; Tim A. BENKE, Auteur ; Cary FU, Auteur ; Alan PERCY, Auteur ; Bernhard SUTER, Auteur ; David MORRIS, Auteur ; Randall L. CARPENTER, Auteur ; Eric D. MARSH, Auteur ; Jana VON HEHN, Auteur.
Langues : Anglais (eng)
in Journal of Neurodevelopmental Disorders > 17 (2025)
Mots-clés : Child Female Humans Cross-Over Studies Dose-Response Relationship, Drug Double-Blind Method Electroencephalography Ketamine/administration & dosage/adverse effects/therapeutic use/pharmacology Rett Syndrome/drug therapy Clinical trial Ketamine Rett syndrome and approved by the Food and Drug Administration, by the institutional review boards at each participating site, and was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Appropriate written informed consent for study participation was obtained prior to completing any study procedures. Consent for publication: Not applicable. Competing interests: KC has no competing interests. EBK has no competing interests. DNL has acted as a consultant for Acadia Pharmaceuticals, Neurogene, and Taysha Gene Therapies. He has been a Site PI for industry sponsored trials from Acadia Pharmaceuticals, GW Pharmaceuticals, Anavex Life Sciences, and Neurogene. He has received research support from RSRT. TAB has received research funding from GRIN2B Foundation, the International Foundation for CDKL5 Research, Loulou Foundation, the National Institutes of Health, and Simons Foundation consultancy for Alcyone, AveXis, GRIN Therapeutics, GW Pharmaceuticals, the International Rett Syndrome Foundation, Marinus Pharmaceuticals, Neurogene, Ovid Therapeutics, Takeda Pharmaceutical Company Limited and Taysha clinical trials with Acadia Pharmaceuticals Inc., GW Pharmaceuticals, Marinus Pharmaceuticals, Neurogene, Ovid Therapeutics, and Rett Syndrome Research Trust all remuneration has been made to his department. CF has been a site investigator for industry sponsored clinical trials from Zogenix pharmaceuticals, Acadia pharmaceuticals, GW pharmaceuticals, Neurogene, and Taysha. AP was a site investigator for Acadia Pharmaceuticals and is a consultant for Acadia, Neurogene, and Taysha Gene Therapies. BS has received research funding from the NIH, IRSF, and the Blue Bird Circle he has provided consultancy for IONIS pharmaceuticals, Neurogene, and Taysha clinical trials with Acadia Pharmaceuticals Inc., Marinus Pharmaceuticals, Neurogene, and the Rett Syndrome Research Trust. EDM has acted as a consultant for Stoke therapeutics, Acadia Pharmaceuticals, and Novartis Pharmaceuticals. He has been a Site PI for industry sponsored trials for Stoke Theraputics, Acadia Pharmaceuticals, GW Pharmaceuticals, Zogenix Pharmaceuticals, Marinus Pharmaceuticals, Takeda Pharmaceuticals and Epygenic Pharmaceuticals. He has received research support from the NIH, Penn Orphan Disease center, RettSyndrome.org, RSRT, and International CDKL5 Research Foundation. DM has no competing interests. RLC has no competing interests. JLN has acted as a consultant for Acadia Pharmaceuticals, Alycone Pharmaceuticals, AveXis, GW Pharmaceuticals, Hoffmann-La Roche, IONIS Pharmaceuticals, Neurogene, Newron Pharmaceuticals, Ovid Therapeutics, Taysha Gene Therapies, and Ultragenyx. He has been a site PI for industry sponsored clinical research for Acadia Pharmaceuticals, GW Pharmaceuticals, IONIS Pharmaceuticals, Newron Pharmaceuticals. He has received research support from the National Institutes of Health, International Rett Syndrome Foundation, and RSRT. JvH has no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Preclinical studies and anecdotal case reports support the potential therapeutic benefit of low-dose oral ketamine as a treatment of clinical symptoms in Rett syndrome (RTT); however, no controlled studies have been conducted in RTT to evaluate safety, tolerability and efficacy. DESIGN: This was a sequentially initiated, dose-escalating cohort, placebo-controlled, double blind, randomized sequence, cross-over study of oral ketamine in 6-12-year-old girls with RTT to evaluate short-term safety and tolerability and explore efficacy. METHODS: Participants were randomized to either five days treatment with oral ketamine or matched placebo, followed by a nine-day wash-out period and then crossed-over to the opposite treatment. Ketamine was dosed twice daily at 0.75 mg/kg/dose (Cohort 1) or 1.5 mg/kg/dose (Cohort 2). An independent safety monitoring committee evaluated safety and approved proceeding to the next dose cohort. Caregivers, participants, outcome assessors, and study staff except pharmacists were blinded to allocation. The primary endpoint was safety and tolerability. Exploratory efficacy endpoints included change in clinician- and caregiver-rated measures of RTT features, brain activity on electroencephalography, and wearable biosensors to measure respiration, heart rate, sleep, and activity. RESULTS: Twenty-three participants enrolled (11 in Cohort 1, 12 in Cohort 2) from 3/12/2019-11/22/2021. One participant was excluded from analysis due to not meeting inclusion criteria on blinded review prior to analysis. One participant was withdrawn from the study due to an adverse event (vomiting) after the first dose of ketamine. Although planned for four dose cohorts, the trial was stopped after Cohort 2 due to enrollment challenges associated with the COVID-19 pandemic. Ketamine was safe and tolerated in both cohorts, with 1 related treatment emergent adverse event of vomiting. No difference was observed in efficacy between ketamine and placebo. Electroencephalography showed the expected increase in high frequency power with ketamine. CONCLUSIONS: Short-term, low-dose oral ketamine was safe and well tolerated in girls with RTT. No clinical efficacy of ketamine in treating symptoms of RTT was observed with 5 days of treatment, despite electroencephalography evidence of ketamine target engagement during the first dose. Further studies are needed to evaluate safety and efficacy of higher dose and longer exposure to ketamine in RTT. TRIAL REGISTRATION: Registered at clinicaltrials.gov NCT03633058. En ligne : https://dx.doi.org/10.1186/s11689-025-09591-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576
Titre : Top caregiver concerns in Rett syndrome and related disorders: data from the US natural history study Type de document : texte imprimé Auteurs : Jeffrey L. NEUL, Auteur ; Timothy A. BENKE, Auteur ; Eric D. MARSH, Auteur ; Bernhard SUTER, Auteur ; Lori SILVEIRA, Auteur ; Cary FU, Auteur ; Sarika U. PETERS, Auteur ; Alan K. PERCY, Auteur Langues : Anglais (eng) Mots-clés : Humans Rett Syndrome/complications/diagnosis Caregivers X-Linked Intellectual Disability/genetics Seizures Spasms, Infantile Cdkl5 Caregiver concerns Foxg1 MECP2 duplication Neurodevelopmental disorders Rett syndrome International Rett Syndrome Foundation, and Rett Syndrome Research Trust clinical trials with Acadia Pharmaceuticals Inc., GW Pharmaceuticals personal consultancy for Acadia Pharmaceuticals Inc., Analysis Group, AveXis, GW Pharmaceuticals, Hoffmann-La Roche, Myrtelle, Neurogene, Newron Pharmaceuticals, Signant Health, Taysha Gene Therapies, and the preparation of CME activities for PeerView Institute, MedEdicus, and Medscape serves on the scientific advisory board of Alcyone Lifesciences is a scientific cofounder of LizarBio Therapeutics and was a member of a data safety monitoring board for clinical trials conducted by Ovid Therapeutics. TAB received research funding from GRIN2B Foundation, International Rett Syndrome Foundation, the International Foundation for CDKL5 Research, Loulou Foundation, the National Institutes of Health, and Simons Foundation consultancy for Alcyone, AveXis, GRIN Therapeutics, GW Pharmaceuticals, the International Rett Syndrome Foundation, Marinus Pharmaceuticals, Neurogene, Ovid Therapeutics, and Takeda Pharmaceutical Company Limited clinical trials with Acadia Pharmaceuticals Inc., GW Pharmaceuticals, Marinus Pharmaceuticals, Ovid Therapeutics, and Rett Syndrome Research Trust all remuneration has been made to his department. EDM received research support from the National Institutes of Health, Penn Orphan Disease Center, the International Rett Syndrome Foundation, Rett Syndrome Research Trust, International CDKL5 Research Foundation, and the Loulou Foundation. He has been a site principal investigator for trials from Stoke Therapeutics, Zogenix, Acadia Pharmaceuticals Inc., Takeda Pharmaceuticals, Epygenix Pharmaceuticals, and Marinus Pharmaceuticals. He has received personal compensation for consulting from Acadia Pharmaceuticals Inc. and the preparation of CME activities for Medscape. BS has been a site investigator for clinical trials with Acadia, Marinus, and Newron consultancy for Neurogene and Taysha all remuneration has been paid to his department. LS declares no competing interests. CF has been a site investigator for clinical trials with Acadia. SUP received research funding from the National Institutes of Health, the MECP2 Duplication Foundation, and the ActiGraph Corporation. AKP received research funding from the National Institutes of Health, International Rett Syndrome Foundation, Rett Syndrome Research Trust clinical trials with Acadia Pharmaceuticals Inc. and Anavex Life Sciences Corp. and personal consultancy for Acadia Pharmaceuticals Inc. and Anavex Life Sciences Corp. Index. décimale : PER Périodiques Résumé : OBJECTIVE: Recent advances in the understanding of neurodevelopmental disorders such as Rett syndrome (RTT) have enabled the discovery of novel therapeutic approaches that require formal clinical evaluation of efficacy. Clinical trial success depends on outcome measures that assess clinical features that are most impactful for affected individuals. To determine the top concerns in RTT and RTT-related disorders we asked caregivers to list the top caregiver concerns to guide the development and selection of appropriate clinical trial outcome measures for these disorders. METHODS: Caregivers of participants enrolled in the US Natural History Study of RTT and RTT-related disorders (n = 925) were asked to identify the top 3 concerning problems impacting the affected participant. We generated a weighted list of top caregiver concerns for each of the diagnostic categories and compared results between the disorders. Further, for classic RTT, caregiver concerns were analyzed by age, clinical severity, and common RTT-causing mutations in MECP2. RESULTS: The top caregiver concerns for classic RTT were effective communication, seizures, walking/balance issues, lack of hand use, and constipation. The frequency of the top caregiver concerns for classic RTT varied by age, clinical severity, and specific mutations, consistent with known variation in the frequency of clinical features across these domains. Caregivers of participants with increased seizure severity often ranked seizures as the first concern, whereas caregivers of participants without active seizures often ranked hand use or communication as the top concern. Comparison across disorders found commonalities in the top caregiver concerns between classic RTT, atypical RTT, MECP2 duplication syndrome, CDKL5 deficiency disorder, and FOXG1 syndrome; however, distinct differences in caregiver concerns between these disorders are consistent with the relative prevalence and impact of specific clinical features. CONCLUSION: The top caregiver concerns for individuals with RTT and RTT-related disorders reflect the impact of the primary clinical symptoms of these disorders. This work is critical in the development of meaningful therapies, as optimal therapy should address these concerns. Further, outcome measures to be utilized in clinical trials should assess these clinical issues identified as most concerning by caregivers. En ligne : https://dx.doi.org/10.1186/s11689-023-09502-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575
in Journal of Neurodevelopmental Disorders > 15 (2023)[article] Top caregiver concerns in Rett syndrome and related disorders: data from the US natural history study [texte imprimé] / Jeffrey L. NEUL, Auteur ; Timothy A. BENKE, Auteur ; Eric D. MARSH, Auteur ; Bernhard SUTER, Auteur ; Lori SILVEIRA, Auteur ; Cary FU, Auteur ; Sarika U. PETERS, Auteur ; Alan K. PERCY, Auteur.
Langues : Anglais (eng)
in Journal of Neurodevelopmental Disorders > 15 (2023)
Mots-clés : Humans Rett Syndrome/complications/diagnosis Caregivers X-Linked Intellectual Disability/genetics Seizures Spasms, Infantile Cdkl5 Caregiver concerns Foxg1 MECP2 duplication Neurodevelopmental disorders Rett syndrome International Rett Syndrome Foundation, and Rett Syndrome Research Trust clinical trials with Acadia Pharmaceuticals Inc., GW Pharmaceuticals personal consultancy for Acadia Pharmaceuticals Inc., Analysis Group, AveXis, GW Pharmaceuticals, Hoffmann-La Roche, Myrtelle, Neurogene, Newron Pharmaceuticals, Signant Health, Taysha Gene Therapies, and the preparation of CME activities for PeerView Institute, MedEdicus, and Medscape serves on the scientific advisory board of Alcyone Lifesciences is a scientific cofounder of LizarBio Therapeutics and was a member of a data safety monitoring board for clinical trials conducted by Ovid Therapeutics. TAB received research funding from GRIN2B Foundation, International Rett Syndrome Foundation, the International Foundation for CDKL5 Research, Loulou Foundation, the National Institutes of Health, and Simons Foundation consultancy for Alcyone, AveXis, GRIN Therapeutics, GW Pharmaceuticals, the International Rett Syndrome Foundation, Marinus Pharmaceuticals, Neurogene, Ovid Therapeutics, and Takeda Pharmaceutical Company Limited clinical trials with Acadia Pharmaceuticals Inc., GW Pharmaceuticals, Marinus Pharmaceuticals, Ovid Therapeutics, and Rett Syndrome Research Trust all remuneration has been made to his department. EDM received research support from the National Institutes of Health, Penn Orphan Disease Center, the International Rett Syndrome Foundation, Rett Syndrome Research Trust, International CDKL5 Research Foundation, and the Loulou Foundation. He has been a site principal investigator for trials from Stoke Therapeutics, Zogenix, Acadia Pharmaceuticals Inc., Takeda Pharmaceuticals, Epygenix Pharmaceuticals, and Marinus Pharmaceuticals. He has received personal compensation for consulting from Acadia Pharmaceuticals Inc. and the preparation of CME activities for Medscape. BS has been a site investigator for clinical trials with Acadia, Marinus, and Newron consultancy for Neurogene and Taysha all remuneration has been paid to his department. LS declares no competing interests. CF has been a site investigator for clinical trials with Acadia. SUP received research funding from the National Institutes of Health, the MECP2 Duplication Foundation, and the ActiGraph Corporation. AKP received research funding from the National Institutes of Health, International Rett Syndrome Foundation, Rett Syndrome Research Trust clinical trials with Acadia Pharmaceuticals Inc. and Anavex Life Sciences Corp. and personal consultancy for Acadia Pharmaceuticals Inc. and Anavex Life Sciences Corp. Index. décimale : PER Périodiques Résumé : OBJECTIVE: Recent advances in the understanding of neurodevelopmental disorders such as Rett syndrome (RTT) have enabled the discovery of novel therapeutic approaches that require formal clinical evaluation of efficacy. Clinical trial success depends on outcome measures that assess clinical features that are most impactful for affected individuals. To determine the top concerns in RTT and RTT-related disorders we asked caregivers to list the top caregiver concerns to guide the development and selection of appropriate clinical trial outcome measures for these disorders. METHODS: Caregivers of participants enrolled in the US Natural History Study of RTT and RTT-related disorders (n = 925) were asked to identify the top 3 concerning problems impacting the affected participant. We generated a weighted list of top caregiver concerns for each of the diagnostic categories and compared results between the disorders. Further, for classic RTT, caregiver concerns were analyzed by age, clinical severity, and common RTT-causing mutations in MECP2. RESULTS: The top caregiver concerns for classic RTT were effective communication, seizures, walking/balance issues, lack of hand use, and constipation. The frequency of the top caregiver concerns for classic RTT varied by age, clinical severity, and specific mutations, consistent with known variation in the frequency of clinical features across these domains. Caregivers of participants with increased seizure severity often ranked seizures as the first concern, whereas caregivers of participants without active seizures often ranked hand use or communication as the top concern. Comparison across disorders found commonalities in the top caregiver concerns between classic RTT, atypical RTT, MECP2 duplication syndrome, CDKL5 deficiency disorder, and FOXG1 syndrome; however, distinct differences in caregiver concerns between these disorders are consistent with the relative prevalence and impact of specific clinical features. CONCLUSION: The top caregiver concerns for individuals with RTT and RTT-related disorders reflect the impact of the primary clinical symptoms of these disorders. This work is critical in the development of meaningful therapies, as optimal therapy should address these concerns. Further, outcome measures to be utilized in clinical trials should assess these clinical issues identified as most concerning by caregivers. En ligne : https://dx.doi.org/10.1186/s11689-023-09502-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575
