Effects of Mutations of the Glycine Gene Associated With Hyperekplexia on Central Pain Processing

Effects of Mutations of the Glycine Gene Associated With Hyperekplexia on Central Pain Processing


Lead Sponsor: University Hospital Inselspital, Berne

Source University Hospital Inselspital, Berne
Brief 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. 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: 1. Generalized stiffness after birth normalizing during the first years of life 2. Excessive startling to an unexpected stimulus, particularly auditory, present from birth and remaining throughout life 3. 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

Overall Status Terminated
Start Date October 2011
Completion Date December 2012
Primary Completion Date December 2012
Phase N/A
Study Type Interventional
Primary Outcome
Measure Time Frame
Pressure pain detection threshold measured in kPA, measured with electronic pressure algometer applied at the centre of the pulp of the 2nd toe Within 0 to 33 seconds after the beginning of the stimulation
Secondary Outcome
Measure Time Frame
Electric pain reflex, as measured with electromyography from the biceps femoris and the rectus femoris muscles Within 50 to 150 ms after the beginning of stimulation
Heat and cold pain detection thresholds, as measured with a thermode in degrees Celsius 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 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 At the end of the experiment, expected to be after 30 minutes on average
Enrollment 9

Intervention Type: Other

Intervention Name: No intervention

Description: The testing will be the same for healthy volunteers and patients with a mutations in the glycine channel.

Arm Group Label: 1



Inclusion Criteria: - Hyperekplexia - GLRA1 - GLRB - SCLA5 - GPHN - Gephyrin - ARHGEF9 Exclusion Criteria - Age below 7 years - Pregnancy - Breast feeding - Ongoing medication - Cognitive impairment

Gender: All

Minimum Age: 7 Years

Maximum Age: N/A

Healthy Volunteers: Accepts Healthy Volunteers

Overall Official
Last Name Role Affiliation
Michele Curatolo, Prof. Study Chair Dep. of Anesthesia and Pain medicine, Bern University Hospital
Facility: Dep. of Anesthesia and Pain medicine, Bern University Hospital
Location Countries


Verification Date

September 2014

Responsible Party

Name Title: Pascal H. Vuilleumier, MD

Organization: University Hospital Bern, Switzerland

Has Expanded Access No
Condition Browse
Number Of Arms 1
Arm Group

Label: 1

Type: Experimental

Description: 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.

Study Design Info

Intervention Model: Parallel Assignment

Primary Purpose: Basic Science

Masking: None (Open Label)

Source: ClinicalTrials.gov