Febrile SeizureNCT04368936
Relationship Between Polymorphisms of TRPV1 and KCC2 Gene in Children With Febrile Seizures
An observational study of Febrile Seizure, run by Institut za Rehabilitaciju Sokobanjska Beograd.
Trial summary
Febrile seizures (FS) are the most common neurological disorder in chilhood. The etiology of FN is still the subject of numerous studies and it is known that it can depend on genetic predisposition. Read more about this study
- Who is it for?
- Ages 1 year to 14 yearsHealthy volunteers can take part
- Conditions the study is for
- Febrile Seizure
- What is being tested?
- Isolated DNA, Real Time PCR
- How many people
- 121 participants
- Where
- No sites listed yet
- Study dates
- 31 Mar 2015to Aug 2021
- How long will I take part?
- 2 Years
- 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 1 year to 14 years
- All sexes
- Healthy volunteers accepted
- Child
Study population: The Febrile Seizure affected children as well as the individuals from the control group were members of the same population (Serbian).
Who may be able to join
- Our research involve patient with diagnosed Febrile Seizure which were hospitalized or recieved ambulatory treatment in University Children´s Hospital in Belgrade
- For each patient, a diagnosis of FS was made based on the ILAE definition (International Leage
- The main criterion for inclusion in the study was enhanced FS without prior occurrence of afebrile seizure.
Who cannot join
- Patients with evidence of intracranial infections and metabolic disbalance
- Patients with incomplited medical documentation
About this study
Febrile seizures (FS) are the most common neurological disorder in chilhood. The etiology of FN is still the subject of numerous studies and it is known that it can depend on genetic predisposition.
Read the detailed description
Febrile seizures (FS) are the most common neurological disorder in chilhood. It is precisely because of the high incidence of the disease, the age that includes the tendency of repetition, represent a particular challenge in pediatric practice.
FS, as defined by the American Academy of Pediatrics (AAP), are " seizure occurring in febrile children between the ages of 6 and 60 months who do not have an intracranial infection, metabolic disturbance, or history of afebrile seizures ".
Simple febrile seizure is defined as a short (<15 min) generalized seizure, not repeat within 24 h, that occurs during a febrile illness not resulting from an acute disease of the nervous system in a child aged between 6 months and 5 years, with no neurologic deficits and no previous afebrile seizures. Complex febrile seizures are a focal, or generalized and prolonged seizure, of a duration of greater than 15 min, recurring more than once in 24 h, and/or associated with postictal neurologic abnormalities, more frequently a postictal palsy (Todd's palsy), or with previous neurologic deficits.
The etiology of FN is still the subject of numerous studies and it is known that it can depend on genetic predisposition.
Animal studies have shown that mice without the KCC2 gene have frequent generalized seizures, while those with heterozygous deletion of the KCC2 gene have a reduced threshold for seizure onset. In the human population, mutations of this gene have been reported in children with FN as well as in children with epilepsy. There is no examined an association between polymorphism rs2297201 KCC2 gene and FS.
Studies have shown an association between TRPV1 genes and the appearance of FS in experimental models, however, similar studies in the human population have not been done so far. Studies Moria et al. 2012 showed that polymorphism rs222797 TRPV1 gene involve the regulation of human cortical excitability, glutamate transmission and increased neuronal excitability. The C allele this polymorphism is associated with a greater maximal response to the caspaicin and anadamine agonists. All of this indicate that changes TRPV1 gene that lead to increased channel function may suggest a predisposition for FS.
Since FS are genetically controlled, we want to determine the association of TRPV1 and KCC2 gene polymorphisms with the occurrence of FN.
- Conditions
- Febrile Seizure
- Being tested
- Isolated DNA, Real Time PCR
- Keywords
- gene polymorphisms, febrile seizure, KCC2 gene, TRPV1 gene
- Medical subject headings
- Seizures, Febrile
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Isolated DNA, Real Time PCRGenetic
We are isolated DNA from the blood sample. To determine the genotypes of the analyzed polymorphisms use real-time PCR using TaqMan essays.
When analyzing the KCC2 polymorphisms, the VIC dye gene corresponded to the C allele, and the FAM dye corresponded to the T allele, while at the TRPV1 gene polymorphism, the VIC dye corresponded to the C allele and the FAM dye to the G allele.
| Study group | Role | What they receive |
|---|---|---|
| FS: Febrile Seizures | Involved patient with diagnosed Febrile Seizures which were hospitalized or recieved ambulatory treatment in University Children´s Hospital in Belgrade. Ages 1-14 years Receives: Genetic: Isolated DNA, Real Time PCR | |
| CN: Control group | The control group was made of healthy children older than 5 years of age, which have never had any neurological disorders in their anamnesis and who were patients in preschool or school dispensaries in the city of Belgrade Receives: Genetic: Isolated DNA, Real Time PCR | |
| SFS : group of individuals with simple FS | Simplex febrile seizures (SFS) last shorter than 15 minutes and their type is tonic-clonic. Also, they did not show signs of recidivism during the first 24 hours and were diagnosed at the patients aged from 6th months to 5th year Receives: Genetic: Isolated DNA, Real Time PCR | |
| CFS : group of individuals with complex FS | Complex febrile seizures (CFS) were diagnosed at those patients that had focal seizure or epileptic status or seizure having the body temperature lower than 38 degree, which occurred outside of the typical age group and finally which repeated in the first 24 hours again Receives: Genetic: Isolated DNA, Real Time PCR | |
| WFS: group of individuals with FS and without epilepsia | group of children with Febrile Seizure and not developed Epilepsia Receives: Genetic: Isolated DNA, Real Time PCR | |
| EFS: group of individuals with Epilepsia and Febrile Seizures | Group of children with Febrile Seizures, who have developed Epilepsy Receives: Genetic: Isolated DNA, Real Time PCR |
What is being measured
The primary outcome is the main question the study is designed to answer.
Detection of the polymorphism in the TRPV1 gene polymorphisms
The detection of the polymorphism in the TRPV1 gene will be done by the PCR Real time method: During PCR ampification, in addition to primers, an allele of specific oligonucleotide probes is used, which at the 5 'end is labeled with specific fluorescent dye (Reporter dye, eg VIC and FAM), while at the 3' position there is a quencher, which is the role of blocking fluorescence emissions.The fluorescence intensity increases during each cycle and allows us to monitor dynamic reactions in real time.After the final PCR reaction, increasing the fluorescence of the dyes is displayed on the heterozygosity of the test allele. Fluorescence coupling of only one color indicates a homozygous state.VIC dye corresponds to allele C, and FAM dye to allele G.
Measured: 2 weeks
Detection of the polymorphism in the KCC2 gene polymorphisms
The detection of the polymorphism in the KCC2 gene will be done by the PCR Real time method: During PCR ampification, in addition to primers, an allele of specific oligonucleotide probes is used, which at the 5 'end is labeled with specific fluorescent dye (Reporter dye, eg VIC and FAM), while at the 3' position there is a quencher, which is the role of blocking fluorescence emissions.The fluorescence intensity increases during each cycle and allows us to monitor dynamic reactions in real time.After the final PCR reaction, increasing the fluorescence of the dyes is displayed on the heterozygosity of the test allele. Fluorescence coupling of only one color indicates a homozygous state. VIC dye corresponds to allele C, and FAM dye to allele T.
Measured: 2 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Apr 2020
- Study start31 Mar 2015
- Primary completion15 May 2019
- Study completionAug 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for Febrile SeizureStudies of the same condition, open and under way.
- 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
- Case-control
- Time perspective
- Cross-sectional
- Enrolment
- 121 participants (actual)
- Target duration
- 2 Years
Sponsor and investigators
- Lead sponsor
- Institut za Rehabilitaciju Sokobanjska Beograd
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Tamara Filipovic, Institut za Rehabilitaciju Sokobanjska Beograd
- Investigators
- Sanja Dimitrijevic, PhD, Principal investigator, Specila hospital for cerebral palsy and developmental neurology
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04368936
- Sponsor's protocol ID
- SBCPRN2
- Status last verified
- Oct 2021
- First submitted
- 24 Apr 2020
- Last updated
- 19 Oct 2021
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: All of individual participant data collected during the trial, after deindetification.
Publications
Leung AK, Hon KL, Leung TN. Febrile seizures: an overview. Drugs Context. 2018 Jul 16;7:212536. doi: 10.7573/dic.212536. eCollection 2018.
PubMed 30038660Dimitrijevic S, Cvjeticanin S, Pusica A, Jekic B, Filipovic T, Nikolic D. Anthropogenetic Variability in the Group of Individuals with Febrile Seizures: Population-Genetic Study. Biomed Res Int. 2018 Jul 5;2018:7845904. doi: 10.1155/2018/7845904. eCollection 2018.
PubMed 30069480Reid AY, Riazi K, Campbell Teskey G, Pittman QJ. Increased excitability and molecular changes in adult rats after a febrile seizure. Epilepsia. 2013 Apr;54(4):e45-8. doi: 10.1111/epi.12061. Epub 2013 Jan 7.
PubMed 23293960Puskarjov M, Seja P, Heron SE, Williams TC, Ahmad F, Iona X, Oliver KL, Grinton BE, Vutskits L, Scheffer IE, Petrou S, Blaesse P, Dibbens LM, Berkovic SF, Kaila K. A variant of KCC2 from patients with febrile seizures impairs neuronal Cl- extrusion and dendritic spine formation. EMBO Rep. 2014 Jun;15(6):723-9. doi: 10.1002/embr.201438749. Epub 2014 Mar 24.
PubMed 24668262Huang WX, Yu F, Sanchez RM, Liu YQ, Min JW, Hu JJ, Bsoul NB, Han S, Yin J, Liu WH, He XH, Peng BW. TRPV1 promotes repetitive febrile seizures by pro-inflammatory cytokines in immature brain. Brain Behav Immun. 2015 Aug;48:68-77. doi: 10.1016/j.bbi.2015.01.017. Epub 2015 Mar 20.
PubMed 25801060Xu H, Tian W, Fu Y, Oyama TT, Anderson S, Cohen DM. Functional effects of nonsynonymous polymorphisms in the human TRPV1 gene. Am J Physiol Renal Physiol. 2007 Dec;293(6):F1865-76. doi: 10.1152/ajprenal.00347.2007. Epub 2007 Oct 3.
PubMed 17913835
Study at a glance
From the registry record, last updated by the sponsor on 19 Oct 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Relationship Between Polymorphisms of TRPV1 and KCC2 Gene in Children With Febrile Seizures
- ClinicalTrials.gov ID
- NCT04368936
- Acronym / sponsor ID
- SBCPRN2
- Conditions
- Febrile Seizure
- Keywords
- gene polymorphisms, febrile seizure, KCC2 gene, TRPV1 gene
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 121 participants (actual)
- Lead sponsor
- Institut za Rehabilitaciju Sokobanjska BeogradUniversity, hospital or other
- Study start
- 31 Mar 2015 (actual)
- Primary completion
- 15 May 2019 (actual)
- Study completion
- Aug 2021 (actual)
- First posted
- 30 Apr 2020 (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.
Febrile seizures (FS) are the most common neurological disorder in chilhood. The etiology of FN is still the subject of numerous studies and it is known that it can depend on genetic predisposition.
Detailed description
Febrile seizures (FS) are the most common neurological disorder in chilhood. It is precisely because of the high incidence of the disease, the age that includes the tendency of repetition, represent a particular challenge in pediatric practice.
FS, as defined by the American Academy of Pediatrics (AAP), are " seizure occurring in febrile children between the ages of 6 and 60 months who do not have an intracranial infection, metabolic disturbance, or history of afebrile seizures ".
Simple febrile seizure is defined as a short (<15 min) generalized seizure, not repeat within 24 h, that occurs during a febrile illness not resulting from an acute disease of the nervous system in a child aged between 6 months and 5 years, with no neurologic deficits and no previous afebrile seizures. Complex febrile seizures are a focal, or generalized and prolonged seizure, of a duration of greater than 15 min, recurring more than once in 24 h, and/or associated with postictal neurologic abnormalities, more frequently a postictal palsy (Todd's palsy), or with previous neurologic deficits.
The etiology of FN is still the subject of numerous studies and it is known that it can depend on genetic predisposition.
Animal studies have shown that mice without the KCC2 gene have frequent generalized seizures, while those with heterozygous deletion of the KCC2 gene have a reduced threshold for seizure onset. In the human population, mutations of this gene have been reported in children with FN as well as in children with epilepsy. There is no examined an association between polymorphism rs2297201 KCC2 gene and FS.
Studies have shown an association between TRPV1 genes and the appearance of FS in experimental models, however, similar studies in the human population have not been done so far. Studies Moria et al. 2012 showed that polymorphism rs222797 TRPV1 gene involve the regulation of human cortical excitability, glutamate transmission and increased neuronal excitability. The C allele this polymorphism is associated with a greater maximal response to the caspaicin and anadamine agonists. All of this indicate that changes TRPV1 gene that lead to increased channel function may suggest a predisposition for FS.
Since FS are genetically controlled, we want to determine the association of TRPV1 and KCC2 gene polymorphisms with the occurrence of FN.
Study design
- Observational model
- Case-control
- Time perspective
- Cross-sectional
- Target follow-up
- 2 Years
- Number of arms
- 6
| Arm | Type | Receives |
|---|---|---|
| FS: Febrile Seizures | – | Genetic: Isolated DNA, Real Time PCRInvolved patient with diagnosed Febrile Seizures which were hospitalized or recieved ambulatory treatment in University Children´s Hospital in Belgrade. Ages 1-14 years |
| CN: Control group | – | Genetic: Isolated DNA, Real Time PCRThe control group was made of healthy children older than 5 years of age, which have never had any neurological disorders in their anamnesis and who were patients in preschool or school dispensaries in the city of Belgrade |
| SFS : group of individuals with simple FS | – | Genetic: Isolated DNA, Real Time PCRSimplex febrile seizures (SFS) last shorter than 15 minutes and their type is tonic-clonic. Also, they did not show signs of recidivism during the first 24 hours and were diagnosed at the patients aged from 6th months to 5th year |
| CFS : group of individuals with complex FS | – | Genetic: Isolated DNA, Real Time PCRComplex febrile seizures (CFS) were diagnosed at those patients that had focal seizure or epileptic status or seizure having the body temperature lower than 38 degree, which occurred outside of the typical age group and finally which repeated in the first 24 hours again |
| WFS: group of individuals with FS and without epilepsia | – | Genetic: Isolated DNA, Real Time PCRgroup of children with Febrile Seizure and not developed Epilepsia |
| EFS: group of individuals with Epilepsia and Febrile Seizures | – | Genetic: Isolated DNA, Real Time PCRGroup of children with Febrile Seizures, who have developed Epilepsy |
Who may qualify
- Ages
- 1 year to 14 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child
- Study population
- The Febrile Seizure affected children as well as the individuals from the control group were members of the same population (Serbian).
Key inclusion criteria (3 listed)
- Our research involve patient with diagnosed Febrile Seizure which were hospitalized or recieved ambulatory treatment in University Children´s Hospital in Belgrade
- For each patient, a diagnosis of FS was made based on the ILAE definition (International Leage
- The main criterion for inclusion in the study was enhanced FS without prior occurrence of afebrile seizure.
Key exclusion criteria (2 listed)
- Patients with evidence of intracranial infections and metabolic disbalance
- Patients with incomplited medical documentation
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 |
|---|---|---|
| Isolated DNA, Real Time PCRWe are isolated DNA from the blood sample. To determine the genotypes of the analyzed polymorphisms use real-time PCR using TaqMan essays. When analyzing the KCC2 polymorphisms, the VIC dye gene corresponded to the C allele, and the FAM dye corresponded to the T allele, while at the TRPV1 gene polymorphism, the VIC dye corresponded to the C allele and the FAM dye to the G allele. | Genetic | CFS : group of individuals with complex FS, CN: Control group, EFS: group of individuals with Epilepsia and Febrile Seizures, FS: Febrile Seizures, SFS : group of individuals with simple FS, WFS: group of individuals with FS and without epilepsia |
Primary outcome
Detection of the polymorphism in the TRPV1 gene polymorphisms
Time frame: 2 weeks
The detection of the polymorphism in the TRPV1 gene will be done by the PCR Real time method: During PCR ampification, in addition to primers, an allele of specific oligonucleotide probes is used, which at the 5 'end is labeled with specific fluorescent dye (Reporter dye, eg VIC and FAM), while at the 3' position there is a quencher, which is the role of blocking fluorescence emissions.The fluorescence intensity increases during each cycle and allows us to monitor dynamic reactions in real time.After the final PCR reaction, increasing the fluorescence of the dyes is displayed on the heterozygosity of the test allele. Fluorescence coupling of only one color indicates a homozygous state.VIC dye corresponds to allele C, and FAM dye to allele G.
Detection of the polymorphism in the KCC2 gene polymorphisms
Time frame: 2 weeks
The detection of the polymorphism in the KCC2 gene will be done by the PCR Real time method: During PCR ampification, in addition to primers, an allele of specific oligonucleotide probes is used, which at the 5 'end is labeled with specific fluorescent dye (Reporter dye, eg VIC and FAM), while at the 3' position there is a quencher, which is the role of blocking fluorescence emissions.The fluorescence intensity increases during each cycle and allows us to monitor dynamic reactions in real time.After the final PCR reaction, increasing the fluorescence of the dyes is displayed on the heterozygosity of the test allele. Fluorescence coupling of only one color indicates a homozygous state. VIC dye corresponds to allele C, and FAM dye to allele T.
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 19 Oct 2021.
- Background: PubMed 30038660Leung AK, Hon KL, Leung TN. Febrile seizures: an overview. Drugs Context. 2018 Jul 16;7:212536. doi: 10.7573/dic.212536. eCollection 2018.
- Background: PubMed 30069480Dimitrijevic S, Cvjeticanin S, Pusica A, Jekic B, Filipovic T, Nikolic D. Anthropogenetic Variability in the Group of Individuals with Febrile Seizures: Population-Genetic Study. Biomed Res Int. 2018 Jul 5;2018:7845904. doi: 10.1155/2018/7845904. eCollection 2018.
- Background: PubMed 23293960Reid AY, Riazi K, Campbell Teskey G, Pittman QJ. Increased excitability and molecular changes in adult rats after a febrile seizure. Epilepsia. 2013 Apr;54(4):e45-8. doi: 10.1111/epi.12061. Epub 2013 Jan 7.
- Background: PubMed 24668262Puskarjov M, Seja P, Heron SE, Williams TC, Ahmad F, Iona X, Oliver KL, Grinton BE, Vutskits L, Scheffer IE, Petrou S, Blaesse P, Dibbens LM, Berkovic SF, Kaila K. A variant of KCC2 from patients with febrile seizures impairs neuronal Cl- extrusion and dendritic spine formation. EMBO Rep. 2014 Jun;15(6):723-9. doi: 10.1002/embr.201438749. Epub 2014 Mar 24.
- Background: PubMed 25801060Huang WX, Yu F, Sanchez RM, Liu YQ, Min JW, Hu JJ, Bsoul NB, Han S, Yin J, Liu WH, He XH, Peng BW. TRPV1 promotes repetitive febrile seizures by pro-inflammatory cytokines in immature brain. Brain Behav Immun. 2015 Aug;48:68-77. doi: 10.1016/j.bbi.2015.01.017. Epub 2015 Mar 20.
- Background: PubMed 17913835Xu H, Tian W, Fu Y, Oyama TT, Anderson S, Cohen DM. Functional effects of nonsynonymous polymorphisms in the human TRPV1 gene. Am J Physiol Renal Physiol. 2007 Dec;293(6):F1865-76. doi: 10.1152/ajprenal.00347.2007. Epub 2007 Oct 3.
- Individual participant dataSharing planned: Yes. All of individual participant data collected during the trial, after deindetification.
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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.
Sanja Dimitrijevic, PhD principal investigator
Specila hospital for cerebral palsy and developmental neurology
Questions about this trial
What is this clinical trial studying?
An observational study of Febrile Seizure, run by Institut za Rehabilitaciju Sokobanjska Beograd.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 2 exclusion criteria. 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 19 Oct 2021. Status can change between updates, so confirm with the study contact before making plans.
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?
Detection of the polymorphism in the TRPV1 gene polymorphisms (time frame: 2 weeks). The study lists 2 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 NCT04368936, which also lists 6 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 19 Oct 2021.