Hyperekplexia Clinical Trial
Official title:
Effects of Mutations of the Glycine Gene Associated With Hyperekplexia on Central Pain Processing
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.
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
;
Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Basic Science
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Completed |
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| Recruiting |
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