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

Eligibility Criteria:
Inclusion Criteria:

* Hyperekplexia
* GLRA1
* GLRB
* SCLA5
* GPHN
* Gephyrin
* ARHGEF9

Exclusion Criteria

* Age below 7 years
* Pregnancy
* Breast feeding
* Ongoing medication
* Cognitive impairment