HyperekplexiaNCT01476514
Effects of Mutations of the Glycine Gene Associated With Hyperekplexia on Central Pain Processing
A study of Hyperekplexia, run by Insel Gruppe AG, University Hospital Bern at 1 site in Switzerland.
Trial summary
Mutations in genes affecting pain transmission start to be known, the investigators are investigating a mutation in a glycine channel, which has an influence on pain modulation. Pain modulation is the ability of the central nervous system to enhance or diminish the sensation of pain. Read more about this study
- Who is it for?
- Ages 7 years and olderHealthy volunteers can take part
- Conditions the study is for
- Hyperekplexia
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 9 participants
- Where
- 1 siteSwitzerland
- Study dates
- Oct 2011to Dec 2012
- Phase
- Interventional
- 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 7 years and older
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
Who may be able to join
- Hyperekplexia
- GLRA1
- GLRB
- SCLA5
- GPHN
- Gephyrin
- ARHGEF9
Who cannot join
- Age below 7 years
- Pregnancy
- Breast feeding
- Ongoing medication
- Cognitive impairment
Trial locations and contacts
1 site in 1 country.
Switzerland1 site
Dep. of Anesthesia and Pain medicine, Bern University Hospital
Bern, Canton of Bern, 3010
About this study
Mutations in genes affecting pain transmission start to be known, the investigators are investigating a mutation in a glycine channel, which has an influence on pain modulation. Pain modulation is the ability of the central nervous system to enhance or diminish the sensation of pain. The investigators therefore will test patients and healthy volunteers with quantitative sensory tests, basically determining the point at which a stimulation just starts to induce pain. These tests are reliable and permit a direct comparison between healthy volunteers and patients with the affected glycine gene.
Read the detailed description
Background
Hyperekplexia, also known as hereditary startle disease or stiff baby syndrome, is a rare neurogenetic non-epileptic disorder characterized by exaggerated persistent startle response and neonatal hypertonia to unexpected auditory, somatosensory and visual stimuli. Startle responses and generalized muscle stiffness both gradually subside during the first months of life. Pathological startle responses can remain throughout adulthood resulting in unprotected falls and injury.
Hereditary hyperekplexia has been identified in 70 pedigrees, most of them being characterized by the major form. Some occasional occurrence of the minor form was described in rare families, but its presence may remain clinically undetected.
The clinical diagnosis of the major form of hyperekplexia needs three mandatory features:
- Generalized stiffness after birth normalizing during the first years of life
- Excessive startling to an unexpected stimulus, particularly auditory, present from birth and remaining throughout life
- Generalized stiffness after a startle reflex that lasts a few seconds Five genes are associated with hyperekplexia, the disease being caused by mutations in the genes encoding different subunits of the inhibitory postsynaptic glycine receptor GLRA1 and GLRB. Additionally defects in the presynaptic glycine transporter gene (SLC6A5) have been recently identified in human hyperekplexia. GPHN, encoding the glycinergic clustering molecule gephyrin, and ARHGEF9, an X-linked gene encoding collybistin, are each associated with one known case of hyperekplexia.
The glycine receptor is a member of the pentameric ligand-gated ion channel family. The receptor is a membrane-embedded protein that contains an integral Cl- -selective pore. The glycine receptor is the major determinant of inhibitory neurotransmission in the retina, spinal cord and brainstem.
Inhibitory synaptic transmission in the spinal cord dorsal horn use GABA and glycine as their principle fast neurotransmitters. Both of them open the Cl- -channels, which induce postsynaptic hyperpolarisation and impairs the propagation of excitatory potentials on dendrites of neurons. Immunofluorescence studies have revealed abundant glycinergic innervations in the dorsal horn, site attributed to the long standing gate control theory of pain. According to this model, inhibitory GABAergic and glycinergic interneurons in the superficial spinal dorsal horn are key components in the control of pain transmission from the periphery to the brain. The model states that a non-painful stimulation is felt as non painful as long as the synaptic GABAergic and glycinergic inhibition remains intact.
Pharmacological blockade of GABAergic and/or glycinergic neurotransmission in the dorsal horn mimics many symptoms of inflammatory and neuropathic pain. Additionally, a loss of synaptic inhibition in the dorsal horn occurs in animal models of experimental pain. This is difficult to prove experimentally in humans, although studies on nociceptive long term potentiation suggest that loss of inhibitory interneurons in the dorsal horn may have a role in the development of chronic pain in patients.
Objective
The aim of this study is to evaluate for the first time in humans whether symptomatic mutations in the glycinergic system affect central pain processing. Positive results would be suggestive for an important role of the glycinergic system in pain modulation and would therefore stimulate further developments for the pharmacological modulation of human pain syndromes.
Methods
Design Assessment of pain thresholds in consecutive hyperekplexia patients and a group of sex and age-matched healthy volunteers.
Subjects We will test consecutive patients with one of the five mutations cited in the introduction. Patients will receive a compensation of 150 Swiss Francs for their participation, plus reimbursement of travel costs.
23 hyperekplexia patients will be recruited. Once the testing of these patients is completed, 45 healthy age and sex-matched controls will be enrolled.
Treatment with a GABA-agonist (mainly clonazepam) will not be discontinued for safety reasons .
Pain tests:
Pressure pain detection threshold (primary outcome) Electric pain detection threshold to single cutaneous and temporal summation to repeated electrical stimulation Heat and cold pain detection, conditioned pain modulation
- Conditions
- Hyperekplexia
- Being tested
- No intervention
- Keywords
- Hyperekplexia, Pain modulation, Glycine receptors, Hyperalgesia, Spinal inhibitory interneurons
- Medical subject headings
- Hyperekplexia, Hyperalgesia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
No interventionOther
The testing will be the same for healthy volunteers and patients with a mutations in the glycine channel.
| Study group | Role | What they receive |
|---|---|---|
| 1 | Experimental | In the setting of comparing patients with a genetic mutation and healthy volunteers blinding of the PI would demand a substantial increase in co-workers (i.e. recruitment, selection of age-and sex matched volunteers), reason why no blinding was chosen.
Affected patients will be compared to age and sex matched volunteers, recruited after completion of testing 23 hyperekplexia patients. Receives: Other: No intervention |
What is being measured
The primary outcome is the main question the study is designed to answer.
Pressure pain detection threshold measured in kPA, measured with electronic pressure algometer applied at the centre of the pulp of the 2nd toe
Pain detection thresholds will be measured with an electronic pressure algometer applied at the center of the pulp of the 2nd toe. The probe has a surface area of 1 cm2. The pressure is increased from 0 at a rate of 30kPa/s to a maximum pressure of 1000kPa. Pain detection threshold is defined as the point at which the pressure sensation turns to pain. The subjects are instructed to press a button when these points are reached. The algometer displays the pressure intensity at which the button is pressed.
Measured: Within 0 to 33 seconds after the beginning of the stimulation
Secondary outcomes (4)
Electric pain reflex, as measured with electromyography from the biceps femoris and the rectus femoris muscles
Electromyographic (EMG) reflex responses to electrical stimulation will be recorded from the middle of the biceps femoris and the rectus femoris muscles (Ag/AgCl-electrodes). A 25 ms, train-of-five, 1 ms, square-wave impulse (perceived as a single stimulus), will be delivered. The current intensity will be increased from 1 mA in steps of 1 mA until: 1) a biceps femoris reflex with an amplitude exceeding 20 mV for at least 10 ms in the 50-150 ms post-stimulation interval will be detected (single stimulus reflex threshold); and 2) a pain sensation will be evoked (single stimulus pain threshold).
Measured: Within 50 to 150 ms after the beginning of stimulation
Heat and cold pain detection thresholds, as measured with a thermode in degrees Celsius
A thermode will be applied to the skin. The temperature of the thermode will be continuously increased from 30 ºC to a maximum of 50.5 ºC at a rate of 1.5 ºC/s. Pain detection threshold is defined as for pressure stimulation. The subjects are instructed to press a button when this point is reached. For cold stimulation, the temperature of the thermode will be continuously decreased from 30 ºC to a minimum of 0 ºC at a rate of 1.5 ºC/sec. Pain detection threshold is defined as for pressure stimulation. The subjects are instructed to press a button when this point is reached.
Measured: Within 0 to 14 seconds after the beginning of the stimulation
Ice water pain threshold of the hand as measured in seconds the hand was left in the water, measured with ice water container
The device consists of a container separated into an outer and an inner part by a mesh screen. The mesh screen prevents direct contact between the ice (placed in the outer part) and the hand of the subject (placed in the inner part). The water is regularly mixed to maintain the temperature in the inner part near to 0°C. The subject places his hand, wide open and to the wrist, into the inner part of the container. He is asked to keep it in the water until he feels an intolerable sensation of pain and is forced to remove his hand from the container, in any case for a maximum time of 2 min.
Measured: Within 0 to 2 minutes after the beginning of the stimulation
Pressure pain detection threshold measured in kPA, measured with electronic pressure algometer applied at the centre of the pulp of the 2nd toe
Pain detection thresholds will be measured with an electronic pressure algometer applied at the center of the pulp of the 2nd toe. The probe has a surface area of 1 cm2. The pressure is increased from 0 at a rate of 30kPa/s to a maximum pressure of 1000kPa. Pain detection threshold is defined as the point at which the pressure sensation turns to pain. The subjects are instructed to press a button when these points are reached. The algometer displays the pressure intensity at which the button is pressed.
Measured: At the end of the experiment, expected to be after 30 minutes on average
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Nov 2011 (estimated)
- Study startOct 2011
- Primary completionDec 2012
- Study completionDec 2012
Why it stopped: Recruitment problems
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for HyperekplexiaStudies of the same condition, open and under way.
- More trials run by Insel Gruppe AG, University Hospital BernThe 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
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 9 participants (actual)
Sponsor and investigators
- Lead sponsor
- Insel Gruppe AG, University Hospital Bern
- Sponsor type
- University, hospital or other
- Investigators
- Michele Curatolo, Prof., Study chair, Dep. of Anesthesia and Pain medicine, Bern University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01476514
- Sponsor's protocol ID
- 131/11
- Other IDs
- SPUM no. 33CM30_124117
- Status last verified
- Sep 2014
- First submitted
- 2 Nov 2011
- Last updated
- 4 Sep 2014
- Results posted
- No
- Data monitoring committee
- No
Publications
Zhou L, Chillag KL, Nigro MA. Hyperekplexia: a treatable neurogenetic disease. Brain Dev. 2002 Oct;24(7):669-74. doi: 10.1016/s0387-7604(02)00095-5.
PubMed 12427512Andermann F, Keene DL, Andermann E, Quesney LF. Startle disease or hyperekplexia: further delineation of the syndrome. Brain. 1980 Dec;103(4):985-97. doi: 10.1093/brain/103.4.985.
PubMed 6777025Praveen V, Patole SK, Whitehall JS. Hyperekplexia in neonates. Postgrad Med J. 2001 Sep;77(911):570-2. doi: 10.1136/pmj.77.911.570.
PubMed 11524514Muller F, Heinke B, Sandkuhler J. Reduction of glycine receptor-mediated miniature inhibitory postsynaptic currents in rat spinal lamina I neurons after peripheral inflammation. Neuroscience. 2003;122(3):799-805. doi: 10.1016/j.neuroscience.2003.07.009.
PubMed 14622922
Study at a glance
From the registry record, last updated by the sponsor on 4 Sep 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effects of Mutations of the Glycine Gene Associated With Hyperekplexia on Central Pain Processing
- ClinicalTrials.gov ID
- NCT01476514
- Acronym / sponsor ID
- 131/11
- Conditions
- Hyperekplexia
- Keywords
- Hyperekplexia, Pain modulation, Glycine receptors, Hyperalgesia, Spinal inhibitory interneurons
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Recruitment problems
- Enrolment
- 9 participants (actual)
- Lead sponsor
- Insel Gruppe AG, University Hospital BernUniversity, hospital or other
- Study start
- Oct 2011
- Primary completion
- Dec 2012 (actual)
- Study completion
- Dec 2012 (actual)
- First posted
- 22 Nov 2011 (estimated)
- 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.
Mutations in genes affecting pain transmission start to be known, the investigators are investigating a mutation in a glycine channel, which has an influence on pain modulation. Pain modulation is the ability of the central nervous system to enhance or diminish the sensation of pain. The investigators therefore will test patients and healthy volunteers with quantitative sensory tests, basically determining the point at which a stimulation just starts to induce pain. These tests are reliable and permit a direct comparison between healthy volunteers and patients with the affected glycine gene.
Detailed description
Background
Hyperekplexia, also known as hereditary startle disease or stiff baby syndrome, is a rare neurogenetic non-epileptic disorder characterized by exaggerated persistent startle response and neonatal hypertonia to unexpected auditory, somatosensory and visual stimuli. Startle responses and generalized muscle stiffness both gradually subside during the first months of life. Pathological startle responses can remain throughout adulthood resulting in unprotected falls and injury.
Hereditary hyperekplexia has been identified in 70 pedigrees, most of them being characterized by the major form. Some occasional occurrence of the minor form was described in rare families, but its presence may remain clinically undetected.
The clinical diagnosis of the major form of hyperekplexia needs three mandatory features:
- Generalized stiffness after birth normalizing during the first years of life
- Excessive startling to an unexpected stimulus, particularly auditory, present from birth and remaining throughout life
- Generalized stiffness after a startle reflex that lasts a few seconds Five genes are associated with hyperekplexia, the disease being caused by mutations in the genes encoding different subunits of the inhibitory postsynaptic glycine receptor GLRA1 and GLRB. Additionally defects in the presynaptic glycine transporter gene (SLC6A5) have been recently identified in human hyperekplexia. GPHN, encoding the glycinergic clustering molecule gephyrin, and ARHGEF9, an X-linked gene encoding collybistin, are each associated with one known case of hyperekplexia.
The glycine receptor is a member of the pentameric ligand-gated ion channel family. The receptor is a membrane-embedded protein that contains an integral Cl- -selective pore. The glycine receptor is the major determinant of inhibitory neurotransmission in the retina, spinal cord and brainstem.
Inhibitory synaptic transmission in the spinal cord dorsal horn use GABA and glycine as their principle fast neurotransmitters. Both of them open the Cl- -channels, which induce postsynaptic hyperpolarisation and impairs the propagation of excitatory potentials on dendrites of neurons. Immunofluorescence studies have revealed abundant glycinergic innervations in the dorsal horn, site attributed to the long standing gate control theory of pain. According to this model, inhibitory GABAergic and glycinergic interneurons in the superficial spinal dorsal horn are key components in the control of pain transmission from the periphery to the brain. The model states that a non-painful stimulation is felt as non painful as long as the synaptic GABAergic and glycinergic inhibition remains intact.
Pharmacological blockade of GABAergic and/or glycinergic neurotransmission in the dorsal horn mimics many symptoms of inflammatory and neuropathic pain. Additionally, a loss of synaptic inhibition in the dorsal horn occurs in animal models of experimental pain. This is difficult to prove experimentally in humans, although studies on nociceptive long term potentiation suggest that loss of inhibitory interneurons in the dorsal horn may have a role in the development of chronic pain in patients.
Objective
The aim of this study is to evaluate for the first time in humans whether symptomatic mutations in the glycinergic system affect central pain processing. Positive results would be suggestive for an important role of the glycinergic system in pain modulation and would therefore stimulate further developments for the pharmacological modulation of human pain syndromes.
Methods
Design Assessment of pain thresholds in consecutive hyperekplexia patients and a group of sex and age-matched healthy volunteers.
Subjects We will test consecutive patients with one of the five mutations cited in the introduction. Patients will receive a compensation of 150 Swiss Francs for their participation, plus reimbursement of travel costs.
23 hyperekplexia patients will be recruited. Once the testing of these patients is completed, 45 healthy age and sex-matched controls will be enrolled.
Treatment with a GABA-agonist (mainly clonazepam) will not be discontinued for safety reasons .
Pain tests:
Pressure pain detection threshold (primary outcome) Electric pain detection threshold to single cutaneous and temporal summation to repeated electrical stimulation Heat and cold pain detection, conditioned pain modulation
Study design
- Primary purpose
- Basic science
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| 1 | Experimental | Other: No interventionIn the setting of comparing patients with a genetic mutation and healthy volunteers blinding of the PI would demand a substantial increase in co-workers (i.e. recruitment, selection of age-and sex matched volunteers), reason why no blinding was chosen. Affected patients will be compared to age and sex matched volunteers, recruited after completion of testing 23 hyperekplexia patients. |
Who may qualify
- Ages
- 7 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (7 listed)
- Hyperekplexia
- GLRA1
- GLRB
- SCLA5
- GPHN
Key exclusion criteria (5 listed)
- Age below 7 years
- Pregnancy
- Breast feeding
- Ongoing medication
- Cognitive impairment
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 |
|---|---|---|
| No interventionThe testing will be the same for healthy volunteers and patients with a mutations in the glycine channel. | Other | 1 |
Primary outcome
Pressure pain detection threshold measured in kPA, measured with electronic pressure algometer applied at the centre of the pulp of the 2nd toe
Time frame: Within 0 to 33 seconds after the beginning of the stimulation
Pain detection thresholds will be measured with an electronic pressure algometer applied at the center of the pulp of the 2nd toe. The probe has a surface area of 1 cm2. The pressure is increased from 0 at a rate of 30kPa/s to a maximum pressure of 1000kPa. Pain detection threshold is defined as the point at which the pressure sensation turns to pain. The subjects are instructed to press a button when these points are reached. The algometer displays the pressure intensity at which the button is pressed.
4 secondary outcomes
Electric pain reflex, as measured with electromyography from the biceps femoris and the rectus femoris muscles
Time frame: Within 50 to 150 ms after the beginning of stimulation
Heat and cold pain detection thresholds, as measured with a thermode in degrees Celsius
Time frame: Within 0 to 14 seconds after the beginning of the stimulation
Ice water pain threshold of the hand as measured in seconds the hand was left in the water, measured with ice water container
Time frame: Within 0 to 2 minutes after the beginning of the stimulation
Pressure pain detection threshold measured in kPA, measured with electronic pressure algometer applied at the centre of the pulp of the 2nd toe
Time frame: At the end of the experiment, expected to be after 30 minutes on average
Results and safety
The study was stopped early (reason given: Recruitment problems). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Sep 2014.
- Background: PubMed 12427512Zhou L, Chillag KL, Nigro MA. Hyperekplexia: a treatable neurogenetic disease. Brain Dev. 2002 Oct;24(7):669-74. doi: 10.1016/s0387-7604(02)00095-5.
- Background: PubMed 6777025Andermann F, Keene DL, Andermann E, Quesney LF. Startle disease or hyperekplexia: further delineation of the syndrome. Brain. 1980 Dec;103(4):985-97. doi: 10.1093/brain/103.4.985.
- Background: PubMed 11524514Praveen V, Patole SK, Whitehall JS. Hyperekplexia in neonates. Postgrad Med J. 2001 Sep;77(911):570-2. doi: 10.1136/pmj.77.911.570.
- Background: PubMed 14622922Muller F, Heinke B, Sandkuhler J. Reduction of glycine receptor-mediated miniature inhibitory postsynaptic currents in rat spinal lamina I neurons after peripheral inflammation. Neuroscience. 2003;122(3):799-805. doi: 10.1016/j.neuroscience.2003.07.009.
Related trials for Hyperekplexia
RecruitingObservational study
Hyperekplexia : Adaptative Skills and Neurodevelopmental Trajectory
Hyperekplexia
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.
Michele Curatolo, Prof. study chair
Dep. of Anesthesia and Pain medicine, Bern University Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study of Hyperekplexia, run by Insel Gruppe AG, University Hospital Bern at 1 site in Switzerland.
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 7 inclusion and 5 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: stopped early, as of the sponsor's last update on 4 Sep 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Switzerland. 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 was stopped early (reason given: Recruitment problems). Results are not available in the source record.
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?
Pressure pain detection threshold measured in kPA, measured with electronic pressure algometer applied at the centre of the pulp of the 2nd toe (time frame: Within 0 to 33 seconds after the beginning of the stimulation). 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 NCT01476514, which also lists 4 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 4 Sep 2014.