Rett Syndrome, Preserved Speech VariantNCT03077308
Rare Diseases Clinical Research Network: Neurophysiological Correlates
An observational study of Rett Syndrome, Preserved Speech Variant and Mecp2 Duplication Syndrome, run by University of Alabama at Birmingham at 5 sites in United States.
Trial summary
The overall purpose of this project is to advance understanding of the neurophysiological features of Rett syndrome (RTT), MECP2 Duplication (MECP2 Dup) and RTT-related disorders (CDKL5, FOXG1) to gain insight into disease pathogenesis, with an emphasis on identifying biomarkers of disease evolution and severity. Read more about this study
- Who is it for?
- Ages 2 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- Rett Syndrome, Preserved Speech Variant, Mecp2 Duplication Syndrome, Rett-related Disorders
- What is being tested?
- Auditory and Visual Event-related Potentials and EEG
- Type of treatment
- Surgery or procedure
- How many people
- 185 participants
- Where
- 5 sitesUnited States
- Study dates
- 2 Jan 2017to 31 Jul 2021
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 2 to 65 years
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
Study population: Individuals with RTT, MECP2 Dup, and RTT-related disorders (mutations or deletions in CDKL5 and FOXG1 genes) who are also enrolled in the RTT5211 Protocol, which collects longitudinal clinical and neurobehavioral data in the above mentioned disorders. Participants will be linked to the RTT5211 Protocol by their RDCRN identification numbers. All participants will be tested for MECP2, CDKL5, and/or FOXG1 mutations; those with RTT phenotype will be assessed in terms of diagnostic criteria for classic or atypical RTT. No phenotypic selection will be performed; the cohort will be representative of each disorder. 60 typically developing girls and boys (30 each) will be enrolled to serve as controls for all three cohorts with age matching to the RTT/CDKL5 girls and MECP2 Dup/FOXG1 boy cohorts.
Inclusion Criteria: Individuals with RTT, MECP2 Dup, and RTT-related disorders (mutations or deletions in CDKL5 and FOXG1 genes) who are also enrolled in the RTT5211 Protocol, which collects longitudinal clinical and neurobehavioral data will be linked to the RTT5211 Protocol by their RDCRN identification numbers. No phenotypical selection of subjects will be performed; we expect the cohort will be representative of each disorder.
A cohort of 60 typically developing girls and boys (30 each) will be enrolled to serve as controls. Typical development in the control group will be confirmed by normal intelligence quotient scores or equivalent scores on developmental tests using standardized measures and negative psychiatric diagnoses on a standardized diagnostic interview administered to their mothers, fathers or guardians (Diagnostic Interview for Children and Adolescents, Revised: Parents' Version). All control subjects must have a negative history of neurologic impairment or neuropsychiatric conditions and show no clinical evidence of a genetic disorder.
Exclusion Criteria: Individuals who do not meet the above criteria will be excluded.
Trial locations and contacts
5 sites in 1 country.
5 sites in 1 country
United States5 sites
Boston Children's Hospital
Boston, Massachusetts, 02115-5724
Cincinnati Children's Hospital
Cincinnati, Ohio, 45229
University of Colorado Denver
Denver, Colorado, 80045-2571
Vanderbilt University
Nashville, Tennessee, 37212
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, 19104-4318
About this study
Official title: Rett Syndrome, MECP2 Duplication, and Rett-Related Disorders Consortium, Rare Disease Clinical Research Network: Neurophysiologic Correlates
The overall purpose of this project is to advance understanding of the neurophysiological features of Rett syndrome (RTT), MECP2 Duplication (MECP2 Dup) and RTT-related disorders (CDKL5, FOXG1) to gain insight into disease pathogenesis, with an emphasis on identifying biomarkers of disease evolution and severity. This specific study is intertwined to the core study Natural History of Rett Syndrome and Related Disorders (RTT5211), which characterizes range of clinical involvement and genotype-phenotype correlations and will provide phenotypical data for determining the clinical relevance of the neurophysiologic parameters; study subjects here are co- and primarily enrolled in RTT5211. The proposed studies will serve as basis of future translational investigations, including further refinement of biomarkers, development of outcome measures, and clinical trials per se.
Read the detailed description
Individuals with RTT, MECP2 Dup and RTT-related disorders have significant abnormalities on a number of neurophysiological measures such as EEG and Evoked Potentials (EP). Studies in representative animal models reproduce many of these abnormalities. Little is known about the relationship between these neurophysiological findings to disease evolution, severity and specific clinical features. Therefore, it is considered likely that detailed understanding of such neurophysiological features would provide additional insight into disease pathogenesis and will lead to biomarkers of disease state and severity of different features. Consequently, specialized neurophysiological assessments will be acquired, without sedation or any other type of pharmacological manipulation, on a subset of 170 subjects: 60 RTT, 18 MECP2 Dup, 32 RTT-related disorders, and 60 age-matched typically developing controls (30 females, 30 males). Primary evaluations will include auditory ERP (AEP) and visual ERP (VEP), as well as secondary analyses of specific rhythms/band activities obtained during the ERP acquisitions (gamma band changes and frontal alpha band asymmetry). Individuals will be recruited across the spectra of ages and severity. The main goal of the project is to identify potential biomarkers that can become measures for intervention and other translational studies and, at the same time, provide insight into abnormal synaptic activity and pathogenesis of RTT, MECP2 Dup, and RTT-related disorders. Therefore, the proposed assessments will be performed in all three groups of subjects enrolled in this consortium (RTT5211): RTT, MECP2 Dup, and RTT-related disorders. Findings in each set of disorders will be linked to the objectives of the the longitudinal clinical and neurobehavioral data (RTT5211) as well as to biological factors and genotyping that may be linked to clinical severity (RTT5213). The neurophysiological parameters for RTT, MECP2 Dup, and RTT-related disorders will not only be correlated with each other but also to disease staging, overall clinical severity scores and through exploratory analyses with specific clinical features; these will be repeated up to 3 times (i.e., annual [every 10-14 month] evaluations, in the context of visits for the RTT5211 protocol) during the course of study. For this purpose, linear regression and linear mixed models will be used. Preliminary and published data indicate that RTT and MECP2 Dup have distinct patterns of cortical processing on AEP, VEP demonstrates disorder and age/disease-stage dependent changes. Phenotypic severity may be related to specific ERP parameters, as some modest effects of (severity) category of mutations were observed. In addition, the secondary analyses of specific EEG rhythms/band activities will expand our preliminary studies demonstrating alpha band asymmetry as a marker of an anxiety-like response in RTT.
- Conditions
- Rett Syndrome, Preserved Speech Variant, Mecp2 Duplication Syndrome, Rett-related Disorders
- Being tested
- Auditory and Visual Event-related Potentials and EEG
- Keywords
- Auditory ERP, Visual ERP, EEG
- Medical subject headings
- Rett Syndrome, Preserved Speech Variant, Lubs X-linked mental retardation syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Auditory and Visual Event-related Potentials and EEGProcedure or surgery
Specifically, through up to three standardized sessions (i.e., annual [every 10-14 months]), we will assess AEP and VEP. ERP recordings will also provide data for specific rhythms/band (gamma and alpha) pattern analyses as secondary measures as well as technical control data, which will help to exclude those with co-current seizures.
| Study group | Role | What they receive |
|---|---|---|
| Rett Syndrome | Auditory and Visual event-related potentials (ERP) and EEG in 60 individuals with Rett syndrome. Receives: Procedure: Auditory and Visual Event-related Potentials and EEG | |
| MECP2 Duplication Syndrome | Auditory and Visual event-related potentials (ERP) and EEG in 18 individuals with MECP2 Duplication syndrome. Receives: Procedure: Auditory and Visual Event-related Potentials and EEG | |
| Rett-related disorders | Auditory and Visual event-related potentials (ERP) and EEG in 18 individuals with CDKL5 syndrome and 14 individuals with FOXG1 syndrome. Receives: Procedure: Auditory and Visual Event-related Potentials and EEG | |
| Controls | Auditory and Visual event-related potentials (ERP) and EEG in 60 Control individuals (30 males and 30 females). Receives: Procedure: Auditory and Visual Event-related Potentials and EEG |
What is being measured
The primary outcome is the main question the study is designed to answer.
Auditory Event-related potentials
EEG will be filtered between 0.5 and 400Hz. The EEG will be segmented around each stimulus presentation. 200msec prior to 1000msec post each stimulus will be collected and averaged for each trial for each electrode. The electrodes with highest averaged N1 waveforms, predicted to be posterior temporal (T5/P3/T3) electrodes, will be used for subsequent analysis. The averaged waveforms will be analyzed for latency to N1 and P1 peak frm which the auditory event related potentials will be the main parameter for statistical analysis.
Measured: 3 years
Visual Event-related potentials
VEP analysis will be similar to the AEP analysis. EEG will be prepared using the same methodology but using occipital electrodes with Oz as the primary electrode of analysis. The EEG will be averaged from 200msec prior to 1000ms post stimulus. The N1, P1, and N2 components will be identified and will be averaged and the latency and amplitude of the peaks quantified. P1 latency and N1-P1 time will be the primary end point of the study. The latency will be used for the statistical parameter.
Measured: 3 years
EEG
For frequency based analysis, 10-20 ten-second epochs of noise free EEG without clear eye blinks during wakefulness and eyes open; 10 ten-second epochs of wakefulness and eyes closed (assessed by video); and 10-20 ten-second epochs of EEG during each stage of sleep will be analyzed. A prescreen of EEG using a template matching algorithm (EEGlab) can be used to reduce amount of data to be reviewed. For theta and gamma band activity, the EEG will be band passed filtered between 2-10 and 25-70Hz, respectively, and a FFT performed on the filtered data. Spike location, frequency, and activity (change with sleep, eye closure, stimulation) will be calculated.
Measured: 3 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Mar 2017
- Study start2 Jan 2017
- Primary completion31 Jul 2021
- Study completion31 Jul 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (26)Papers the sponsor has linked to this study.
- Other trials for Rett Syndrome, Preserved Speech VariantStudies of the same condition, open and under way.
- More trials run by University of Alabama at BirminghamThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 185 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Alabama at Birmingham
- Sponsor type
- University, hospital or other
- Collaborators
- Children's Hospital of Philadelphia, University of Colorado, Denver, Boston Children's Hospital, Vanderbilt University, University of South Florida, International Rett Syndrome Foundation, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Responsible party
- Principal investigator, Alan Percy, University of Alabama at Birmingham
- Investigators
- Eric Marsh, MD, PhD, Principal investigator, Children's Hospital of Philadelphia
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03077308
- Sponsor's protocol ID
- RDCRN 5212
- Status last verified
- Aug 2021
- First submitted
- 1 Mar 2017
- Last updated
- 5 Aug 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Data will be submitted to NDAR/dbGAP.
Publications
Gandal MJ, Edgar JC, Ehrlichman RS, Mehta M, Roberts TP, Siegel SJ. Validating gamma oscillations and delayed auditory responses as translational biomarkers of autism. Biol Psychiatry. 2010 Dec 15;68(12):1100-6. doi: 10.1016/j.biopsych.2010.09.031.
PubMed 21130222Peters SU, Gordon RL, Key AP. Induced gamma oscillations differentiate familiar and novel voices in children with MECP2 duplication and Rett syndromes. J Child Neurol. 2015 Feb;30(2):145-52. doi: 10.1177/0883073814530503. Epub 2014 Apr 27.
PubMed 24776956Deregnier RA, Nelson CA, Thomas KM, Wewerka S, Georgieff MK. Neurophysiologic evaluation of auditory recognition memory in healthy newborn infants and infants of diabetic mothers. J Pediatr. 2000 Dec;137(6):777-84. doi: 10.1067/mpd.2000.109149.
PubMed 11113833Rojas DC, Teale PD, Maharajh K, Kronberg E, Youngpeter K, Wilson LB, Wallace A, Hepburn S. Transient and steady-state auditory gamma-band responses in first-degree relatives of people with autism spectrum disorder. Mol Autism. 2011 Jul 5;2:11. doi: 10.1186/2040-2392-2-11.
PubMed 21729257Liao W, Gandal MJ, Ehrlichman RS, Siegel SJ, Carlson GC. MeCP2+/- mouse model of RTT reproduces auditory phenotypes associated with Rett syndrome and replicate select EEG endophenotypes of autism spectrum disorder. Neurobiol Dis. 2012 Apr;46(1):88-92. doi: 10.1016/j.nbd.2011.12.048. Epub 2012 Jan 9.
PubMed 22249109LeBlanc JJ, DeGregorio G, Centofante E, Vogel-Farley VK, Barnes K, Kaufmann WE, Fagiolini M, Nelson CA. Visual evoked potentials detect cortical processing deficits in Rett syndrome. Ann Neurol. 2015 Nov;78(5):775-86. doi: 10.1002/ana.24513. Epub 2015 Sep 18.
PubMed 26332183Khwaja OS, Ho E, Barnes KV, O'Leary HM, Pereira LM, Finkelstein Y, Nelson CA 3rd, Vogel-Farley V, DeGregorio G, Holm IA, Khatwa U, Kapur K, Alexander ME, Finnegan DM, Cantwell NG, Walco AC, Rappaport L, Gregas M, Fichorova RN, Shannon MW, Sur M, Kaufmann WE. Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome. Proc Natl Acad Sci U S A. 2014 Mar 25;111(12):4596-601. doi: 10.1073/pnas.1311141111. Epub 2014 Mar 12.
PubMed 24623853Larimore JL, Chapleau CA, Kudo S, Theibert A, Percy AK, Pozzo-Miller L. Bdnf overexpression in hippocampal neurons prevents dendritic atrophy caused by Rett-associated MECP2 mutations. Neurobiol Dis. 2009 May;34(2):199-211. doi: 10.1016/j.nbd.2008.12.011. Epub 2009 Jan 3.
PubMed 19217433Blackman MP, Djukic B, Nelson SB, Turrigiano GG. A critical and cell-autonomous role for MeCP2 in synaptic scaling up. J Neurosci. 2012 Sep 26;32(39):13529-36. doi: 10.1523/JNEUROSCI.3077-12.2012.
PubMed 23015442Stuss DP, Boyd JD, Levin DB, Delaney KR. MeCP2 mutation results in compartment-specific reductions in dendritic branching and spine density in layer 5 motor cortical neurons of YFP-H mice. PLoS One. 2012;7(3):e31896. doi: 10.1371/journal.pone.0031896. Epub 2012 Mar 7.
PubMed 22412847Kaufmann WE, Johnston MV, Blue ME. MeCP2 expression and function during brain development: implications for Rett syndrome's pathogenesis and clinical evolution. Brain Dev. 2005 Nov;27 Suppl 1:S77-S87. doi: 10.1016/j.braindev.2004.10.008. Epub 2005 Sep 22.
PubMed 16182491Na ES, Nelson ED, Adachi M, Autry AE, Mahgoub MA, Kavalali ET, Monteggia LM. A mouse model for MeCP2 duplication syndrome: MeCP2 overexpression impairs learning and memory and synaptic transmission. J Neurosci. 2012 Feb 29;32(9):3109-17. doi: 10.1523/JNEUROSCI.6000-11.2012.
PubMed 22378884Wang IT, Allen M, Goffin D, Zhu X, Fairless AH, Brodkin ES, Siegel SJ, Marsh ED, Blendy JA, Zhou Z. Loss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-like phenotypes in mice. Proc Natl Acad Sci U S A. 2012 Dec 26;109(52):21516-21. doi: 10.1073/pnas.1216988110. Epub 2012 Dec 10.
PubMed 23236174Na ES, Nelson ED, Kavalali ET, Monteggia LM. The impact of MeCP2 loss- or gain-of-function on synaptic plasticity. Neuropsychopharmacology. 2013 Jan;38(1):212-9. doi: 10.1038/npp.2012.116. Epub 2012 Jul 11.
PubMed 22781840Chao HT, Zoghbi HY, Rosenmund C. MeCP2 controls excitatory synaptic strength by regulating glutamatergic synapse number. Neuron. 2007 Oct 4;56(1):58-65. doi: 10.1016/j.neuron.2007.08.018.
PubMed 17920015
Study at a glance
From the registry record, last updated by the sponsor on 5 Aug 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Rett Syndrome, MECP2 Duplication, and Rett-Related Disorders Consortium, Rare Disease Clinical Research Network: Neurophysiologic Correlates
- ClinicalTrials.gov ID
- NCT03077308
- Acronym / sponsor ID
- RDCRN 5212
- Conditions
- Rett Syndrome, Preserved Speech Variant, Mecp2 Duplication Syndrome, Rett-related Disorders
- Keywords
- Auditory ERP, Visual ERP, EEG
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 185 participants (actual)
- Lead sponsor
- University of Alabama at BirminghamUniversity, hospital or other
- Collaborators
- Children's Hospital of Philadelphia, University of Colorado, Denver, Boston Children's Hospital, Vanderbilt University, University of South Florida, International Rett Syndrome Foundation, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Study start
- 2 Jan 2017 (actual)
- Primary completion
- 31 Jul 2021 (actual)
- Study completion
- 31 Jul 2021 (actual)
- First posted
- 10 Mar 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The overall purpose of this project is to advance understanding of the neurophysiological features of Rett syndrome (RTT), MECP2 Duplication (MECP2 Dup) and RTT-related disorders (CDKL5, FOXG1) to gain insight into disease pathogenesis, with an emphasis on identifying biomarkers of disease evolution and severity. This specific study is intertwined to the core study Natural History of Rett Syndrome and Related Disorders (RTT5211), which characterizes range of clinical involvement and genotype-phenotype correlations and will provide phenotypical data for determining the clinical relevance of the neurophysiologic parameters; study subjects here are co- and primarily enrolled in RTT5211. The proposed studies will serve as basis of future translational investigations, including further refinement of biomarkers, development of outcome measures, and clinical trials per se.
Detailed description
Individuals with RTT, MECP2 Dup and RTT-related disorders have significant abnormalities on a number of neurophysiological measures such as EEG and Evoked Potentials (EP). Studies in representative animal models reproduce many of these abnormalities. Little is known about the relationship between these neurophysiological findings to disease evolution, severity and specific clinical features. Therefore, it is considered likely that detailed understanding of such neurophysiological features would provide additional insight into disease pathogenesis and will lead to biomarkers of disease state and severity of different features. Consequently, specialized neurophysiological assessments will be acquired, without sedation or any other type of pharmacological manipulation, on a subset of 170 subjects: 60 RTT, 18 MECP2 Dup, 32 RTT-related disorders, and 60 age-matched typically developing controls (30 females, 30 males). Primary evaluations will include auditory ERP (AEP) and visual ERP (VEP), as well as secondary analyses of specific rhythms/band activities obtained during the ERP acquisitions (gamma band changes and frontal alpha band asymmetry). Individuals will be recruited across the spectra of ages and severity. The main goal of the project is to identify potential biomarkers that can become measures for intervention and other translational studies and, at the same time, provide insight into abnormal synaptic activity and pathogenesis of RTT, MECP2 Dup, and RTT-related disorders. Therefore, the proposed assessments will be performed in all three groups of subjects enrolled in this consortium (RTT5211): RTT, MECP2 Dup, and RTT-related disorders. Findings in each set of disorders will be linked to the objectives of the the longitudinal clinical and neurobehavioral data (RTT5211) as well as to biological factors and genotyping that may be linked to clinical severity (RTT5213). The neurophysiological parameters for RTT, MECP2 Dup, and RTT-related disorders will not only be correlated with each other but also to disease staging, overall clinical severity scores and through exploratory analyses with specific clinical features; these will be repeated up to 3 times (i.e., annual [every 10-14 month] evaluations, in the context of visits for the RTT5211 protocol) during the course of study. For this purpose, linear regression and linear mixed models will be used. Preliminary and published data indicate that RTT and MECP2 Dup have distinct patterns of cortical processing on AEP, VEP demonstrates disorder and age/disease-stage dependent changes. Phenotypic severity may be related to specific ERP parameters, as some modest effects of (severity) category of mutations were observed. In addition, the secondary analyses of specific EEG rhythms/band activities will expand our preliminary studies demonstrating alpha band asymmetry as a marker of an anxiety-like response in RTT.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Rett Syndrome | – | Procedure: Auditory and Visual Event-related Potentials and EEGAuditory and Visual event-related potentials (ERP) and EEG in 60 individuals with Rett syndrome. |
| MECP2 Duplication Syndrome | – | Procedure: Auditory and Visual Event-related Potentials and EEGAuditory and Visual event-related potentials (ERP) and EEG in 18 individuals with MECP2 Duplication syndrome. |
| Rett-related disorders | – | Procedure: Auditory and Visual Event-related Potentials and EEGAuditory and Visual event-related potentials (ERP) and EEG in 18 individuals with CDKL5 syndrome and 14 individuals with FOXG1 syndrome. |
| Controls | – | Procedure: Auditory and Visual Event-related Potentials and EEGAuditory and Visual event-related potentials (ERP) and EEG in 60 Control individuals (30 males and 30 females). |
Who may qualify
- Ages
- 2 to 65 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult, Older adult
- Study population
- Individuals with RTT, MECP2 Dup, and RTT-related disorders (mutations or deletions in CDKL5 and FOXG1 genes) who are also enrolled in the RTT5211 Protocol, which collects longitudinal clinical and neurobehavioral data in the above mentioned disorders. Participants will be linked to the RTT5211 Protocol by their RDCRN identification numbers. All participants will be tested for MECP2, CDKL5, and/or FOXG1 mutations; those with RTT phenotype will be assessed in terms of diagnostic criteria for classic or atypical RTT. No phenotypic selection will be performed; the cohort will be representative of each disorder. 60 typically developing girls and boys (30 each) will be enrolled to serve as controls for all three cohorts with age matching to the RTT/CDKL5 girls and MECP2 Dup/FOXG1 boy cohorts.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Auditory and Visual Event-related Potentials and EEGSpecifically, through up to three standardized sessions (i.e., annual [every 10-14 months]), we will assess AEP and VEP. ERP recordings will also provide data for specific rhythms/band (gamma and alpha) pattern analyses as secondary measures as well as technical control data, which will help to exclude those with co-current seizures. | Procedure or surgery | Controls, MECP2 Duplication Syndrome, Rett Syndrome, Rett-related disorders |
Primary outcome
Auditory Event-related potentials
Time frame: 3 years
EEG will be filtered between 0.5 and 400Hz. The EEG will be segmented around each stimulus presentation. 200msec prior to 1000msec post each stimulus will be collected and averaged for each trial for each electrode. The electrodes with highest averaged N1 waveforms, predicted to be posterior temporal (T5/P3/T3) electrodes, will be used for subsequent analysis. The averaged waveforms will be analyzed for latency to N1 and P1 peak frm which the auditory event related potentials will be the main parameter for statistical analysis.
Visual Event-related potentials
Time frame: 3 years
VEP analysis will be similar to the AEP analysis. EEG will be prepared using the same methodology but using occipital electrodes with Oz as the primary electrode of analysis. The EEG will be averaged from 200msec prior to 1000ms post stimulus. The N1, P1, and N2 components will be identified and will be averaged and the latency and amplitude of the peaks quantified. P1 latency and N1-P1 time will be the primary end point of the study. The latency will be used for the statistical parameter.
EEG
Time frame: 3 years
For frequency based analysis, 10-20 ten-second epochs of noise free EEG without clear eye blinks during wakefulness and eyes open; 10 ten-second epochs of wakefulness and eyes closed (assessed by video); and 10-20 ten-second epochs of EEG during each stage of sleep will be analyzed. A prescreen of EEG using a template matching algorithm (EEGlab) can be used to reduce amount of data to be reviewed. For theta and gamma band activity, the EEG will be band passed filtered between 2-10 and 25-70Hz, respectively, and a FFT performed on the filtered data. Spike location, frequency, and activity (change with sleep, eye closure, stimulation) will be calculated.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Aug 2021.
- Background: PubMed 21130222Gandal MJ, Edgar JC, Ehrlichman RS, Mehta M, Roberts TP, Siegel SJ. Validating gamma oscillations and delayed auditory responses as translational biomarkers of autism. Biol Psychiatry. 2010 Dec 15;68(12):1100-6. doi: 10.1016/j.biopsych.2010.09.031.
- Background: PubMed 24776956Peters SU, Gordon RL, Key AP. Induced gamma oscillations differentiate familiar and novel voices in children with MECP2 duplication and Rett syndromes. J Child Neurol. 2015 Feb;30(2):145-52. doi: 10.1177/0883073814530503. Epub 2014 Apr 27.
- Background: PubMed 11113833Deregnier RA, Nelson CA, Thomas KM, Wewerka S, Georgieff MK. Neurophysiologic evaluation of auditory recognition memory in healthy newborn infants and infants of diabetic mothers. J Pediatr. 2000 Dec;137(6):777-84. doi: 10.1067/mpd.2000.109149.
- Background: PubMed 21729257Rojas DC, Teale PD, Maharajh K, Kronberg E, Youngpeter K, Wilson LB, Wallace A, Hepburn S. Transient and steady-state auditory gamma-band responses in first-degree relatives of people with autism spectrum disorder. Mol Autism. 2011 Jul 5;2:11. doi: 10.1186/2040-2392-2-11.
- Background: PubMed 22249109Liao W, Gandal MJ, Ehrlichman RS, Siegel SJ, Carlson GC. MeCP2+/- mouse model of RTT reproduces auditory phenotypes associated with Rett syndrome and replicate select EEG endophenotypes of autism spectrum disorder. Neurobiol Dis. 2012 Apr;46(1):88-92. doi: 10.1016/j.nbd.2011.12.048. Epub 2012 Jan 9.
- Background: PubMed 26332183LeBlanc JJ, DeGregorio G, Centofante E, Vogel-Farley VK, Barnes K, Kaufmann WE, Fagiolini M, Nelson CA. Visual evoked potentials detect cortical processing deficits in Rett syndrome. Ann Neurol. 2015 Nov;78(5):775-86. doi: 10.1002/ana.24513. Epub 2015 Sep 18.
- Background: PubMed 24623853Khwaja OS, Ho E, Barnes KV, O'Leary HM, Pereira LM, Finkelstein Y, Nelson CA 3rd, Vogel-Farley V, DeGregorio G, Holm IA, Khatwa U, Kapur K, Alexander ME, Finnegan DM, Cantwell NG, Walco AC, Rappaport L, Gregas M, Fichorova RN, Shannon MW, Sur M, Kaufmann WE. Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome. Proc Natl Acad Sci U S A. 2014 Mar 25;111(12):4596-601. doi: 10.1073/pnas.1311141111. Epub 2014 Mar 12.
- Background: PubMed 19217433Larimore JL, Chapleau CA, Kudo S, Theibert A, Percy AK, Pozzo-Miller L. Bdnf overexpression in hippocampal neurons prevents dendritic atrophy caused by Rett-associated MECP2 mutations. Neurobiol Dis. 2009 May;34(2):199-211. doi: 10.1016/j.nbd.2008.12.011. Epub 2009 Jan 3.
- Background: PubMed 23015442Blackman MP, Djukic B, Nelson SB, Turrigiano GG. A critical and cell-autonomous role for MeCP2 in synaptic scaling up. J Neurosci. 2012 Sep 26;32(39):13529-36. doi: 10.1523/JNEUROSCI.3077-12.2012.
- Background: PubMed 22412847Stuss DP, Boyd JD, Levin DB, Delaney KR. MeCP2 mutation results in compartment-specific reductions in dendritic branching and spine density in layer 5 motor cortical neurons of YFP-H mice. PLoS One. 2012;7(3):e31896. doi: 10.1371/journal.pone.0031896. Epub 2012 Mar 7.
- Background: PubMed 16182491Kaufmann WE, Johnston MV, Blue ME. MeCP2 expression and function during brain development: implications for Rett syndrome's pathogenesis and clinical evolution. Brain Dev. 2005 Nov;27 Suppl 1:S77-S87. doi: 10.1016/j.braindev.2004.10.008. Epub 2005 Sep 22.
- Background: PubMed 22378884Na ES, Nelson ED, Adachi M, Autry AE, Mahgoub MA, Kavalali ET, Monteggia LM. A mouse model for MeCP2 duplication syndrome: MeCP2 overexpression impairs learning and memory and synaptic transmission. J Neurosci. 2012 Feb 29;32(9):3109-17. doi: 10.1523/JNEUROSCI.6000-11.2012.
- Individual participant dataSharing planned: Yes. Data will be submitted to NDAR/dbGAP.
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Eric Marsh, MD, PhD principal investigator
Children's Hospital of Philadelphia
5 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Rett Syndrome, Preserved Speech Variant and Mecp2 Duplication Syndrome, run by University of Alabama at Birmingham at 5 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 5 Aug 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Auditory Event-related potentials (time frame: 3 years). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03077308, which also lists 26 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Aug 2021.