Hyperekplexia
Encyclopedia
Hyperekplexia is a neurologic disorder classically characterised by pronounced startle responses to tactile or acoustic stimuli and hypertonia
. The hypertonia may be predominantly truncal, attenuated during sleep and less prominent after a year of age. Hyperekplexia has been linked to genetic defects in a number of different gene families, all of which play an important role in glycine
neurotransmission
. Glycine is used by the central nervous system
as an inhibitory neurotransmitter. Hyperekplexia is generally classified as a genetic disease, but some brain traumas can produce similar signs and symptoms.
and possibly resulting in uncontrolled falling. Initially, the disease was classified into a "major" and a "minor" form, with the minor form being characterized by an excessive startle reflex, but lacking stiffness. Only the major form was found to be hereditary.
Other signs and symptoms of hyperekplexia may include episodic neonatal apnea
, excessive movement during sleep, brain damage, epilepsy
, a head-retraction reflex and possibly some rare cases of Sudden Infant Death.
. The GLRA1 gene encodes the glycine receptor alpha-1 subunit, which, together with the glycine receptor beta subunit, forms synaptic glycine receptors. Inhibitory glycine receptors are ligand-gated chloride channels that facilitate fast responses in the brainstem and spinal-cord. Homomeric
glycine receptors composed exclusively of alpha-1 subunits exhibit normal ion channel electrophysiology
, but are not sequestered at the synaptic junction. Native glycine receptors are thus supposed to be heteromer
s of the alpha-1 and beta subunits, in either a 3:2 or 2:3 ratio.
Within these heteromers, it is believed that the alpha-1 subunits bind glycine and undergo a conformational change, inducing a conformational change in neighboring beta subunits, causing the ion-channel to open. Due to the nature of these interactions, inheritance of GLRA1 mutations is often characterized as autosomal dominant, though a few pathogenic alleles display autosomal recessive inheritance. Thus far, the general rule is that mutations causing structurally normal proteins that cannot bind glycine or cannot properly undergo a required conformational change will result in a dominant form of the disease, while mutations that result in truncated or wildly malformed subunits that cannot be integrated into a receptor protein will result in a recessive form of the disease.
gene encodes the beta subunit of the glycine receptor. Homomeric glycine receptors composed of beta subunits do not open in response to glycine stimulation, however the beta subunit is essential for proper receptor localization through its interactions with gephyrin, which results in receptor clustering at the synaptic cleft. As such, the defects within the GLRB gene show autosomal recessive inheritance.
, an integral membrane protein believed to coordinate glycine receptors, is coded by the gene GPHN. A heterozygous mutation in this gene has been identified in a sporadic case of hyperekplexia, though experimental data is inconclusive as to whether the mutation is pathogenic. Gephyrin is essential for glycine receptor clustering at synaptic junctions through its action of binding both the glycine receptor beta subunit and internal cellular microtubule
structures. Gephyrin also assists in clustering GABA
receptors at synpases and molybdenum cofactor synthesis. Because of its multi-functional nature, it is not presumed to be a common genetic source of hyperekplexia.
gene encodes the GlyT2 transporter, a neuronal pre-synaptic glycine re-uptake transporter. In comparison to the GlyT1 transporter, found mostly in glial cell
s, GlyT2 helps maintain a high concentration of glycine within the axon terminal
of glycinergic neurons. Mutations of the SLC6A5 gene have been associated with hyperekplexia in an autosomal recessive manner. Defects within this gene are hypothesized either to effect the incorporation of the transporter into the cellular membrane or to its affinity for the molecules it transports: sodium ions, chloride ions and glycine. Any of these actions would drastically reduce the pre-synaptic cell's ability to produce the high vesicular concentrations of glycine necessary for proper glycine neurotransmission.
(ARHGEF9) has also been shown to cause hyperekplexia in concert with epilepsy. Since the ARHGEF9 gene is on the X chromosome, this gene displays X-linked recessive heritance. The collybistin protein is responsible for proper gephyrin targeting, which is crucial for the proper localization of glycine and GABA receptors. Deficiencies in collybistin function would result in an artificial lack of glycine and GABA receptors at the synaptic cleft.
, which leads to the increased efficacy of another inhibitory neurotransmitter, GABA. Levetiracetam has been used to some success with an acquired case of hyperekplexia. During attacks of hypertonia and apnea, the limbs and head may be flexed towards the trunk in order to dissipate the symptoms. This is named the Vigevano maneuver after the doctor who invented it.
in infants. Genetic analysis within this large Duch pedigree was later found to carry a mutation within the GLRA1 gene, which was the first gene implicated in hyperekplexia.
Hypertonia
Hypertonia a condition marked by an abnormal increase in muscle tension and a reduced ability of a muscle to stretch. It is caused by lesions to upper motor neurons in the central nervous system, which carry information from the central nervous system to the muscles and control posture, muscle...
. The hypertonia may be predominantly truncal, attenuated during sleep and less prominent after a year of age. Hyperekplexia has been linked to genetic defects in a number of different gene families, all of which play an important role in glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
neurotransmission
Neurotransmission
Neurotransmission , also called synaptic transmission, is the process by which signaling molecules called neurotransmitters are released by a neuron , and bind to and activate the receptors of another neuron...
. Glycine is used by the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
as an inhibitory neurotransmitter. Hyperekplexia is generally classified as a genetic disease, but some brain traumas can produce similar signs and symptoms.
Signs and symptoms
The main three classical signs of hyperekplexia are generalized stiffness, excessive startle reflex beginning at birth and a short period of generalized stiffness following the startle reflex. Affected individuals are generally fully conscious during episodes of stiffness, which consist of forced closure of the eyes and an extension of the extremities followed by a period of generalised stiffness similar to paralysisParalysis
Paralysis is loss of muscle function for one or more muscles. Paralysis can be accompanied by a loss of feeling in the affected area if there is sensory damage as well as motor. A study conducted by the Christopher & Dana Reeve Foundation, suggests that about 1 in 50 people have been diagnosed...
and possibly resulting in uncontrolled falling. Initially, the disease was classified into a "major" and a "minor" form, with the minor form being characterized by an excessive startle reflex, but lacking stiffness. Only the major form was found to be hereditary.
Other signs and symptoms of hyperekplexia may include episodic neonatal apnea
Apnea
Apnea, apnoea, or apnœa is a term for suspension of external breathing. During apnea there is no movement of the muscles of respiration and the volume of the lungs initially remains unchanged...
, excessive movement during sleep, brain damage, epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
, a head-retraction reflex and possibly some rare cases of Sudden Infant Death.
Genetics
Hyperekplexia is currently known to be caused by a variety of different genes, encoding both pre- and postsynaptic proteins. The symptoms displayed, as well as the forms of heritance, vary based on which gene is affected.GLRA1
The first gene linked conclusively to hyperekplexia was GLRA1GLRA1
Glycine receptor subunit alpha-1 is a protein that in humans is encoded by the GLRA1 gene.-Further reading:...
. The GLRA1 gene encodes the glycine receptor alpha-1 subunit, which, together with the glycine receptor beta subunit, forms synaptic glycine receptors. Inhibitory glycine receptors are ligand-gated chloride channels that facilitate fast responses in the brainstem and spinal-cord. Homomeric
Homomeric
A homomeric substance is one which is made out of any number of identical products or molecules.e.g. A homomeric peptide = glutathione A peptide which is made up of only a single type of amino acid subunit; e.g., alanylalanylalanine.ALA-ALA-ALA...
glycine receptors composed exclusively of alpha-1 subunits exhibit normal ion channel electrophysiology
Electrophysiology
Electrophysiology is the study of the electrical properties of biological cells and tissues. It involves measurements of voltage change or electric current on a wide variety of scales from single ion channel proteins to whole organs like the heart...
, but are not sequestered at the synaptic junction. Native glycine receptors are thus supposed to be heteromer
Heteromer
-Pharmacology:* Ligand-gated ion channels such as the nicotinic acetylcholine receptor and GABAA receptor are composed of five subunits arranged around a central pore that opens to allow ions to pass through. There are a large number of different subunits available, which can come together in a...
s of the alpha-1 and beta subunits, in either a 3:2 or 2:3 ratio.
Within these heteromers, it is believed that the alpha-1 subunits bind glycine and undergo a conformational change, inducing a conformational change in neighboring beta subunits, causing the ion-channel to open. Due to the nature of these interactions, inheritance of GLRA1 mutations is often characterized as autosomal dominant, though a few pathogenic alleles display autosomal recessive inheritance. Thus far, the general rule is that mutations causing structurally normal proteins that cannot bind glycine or cannot properly undergo a required conformational change will result in a dominant form of the disease, while mutations that result in truncated or wildly malformed subunits that cannot be integrated into a receptor protein will result in a recessive form of the disease.
GLRB
The GLRBGLRB
Glycine receptor subunit beta is a protein that in humans is encoded by the GLRB gene.-Further reading:...
gene encodes the beta subunit of the glycine receptor. Homomeric glycine receptors composed of beta subunits do not open in response to glycine stimulation, however the beta subunit is essential for proper receptor localization through its interactions with gephyrin, which results in receptor clustering at the synaptic cleft. As such, the defects within the GLRB gene show autosomal recessive inheritance.
GPHN
GephyrinGephyrin
Gephyrin is a protein that is a component of the postsynaptic protein network of inhibitory synapses. Positive antibody staining for gephyrin at a synapse is consistent with the presence of glycine and/or GABA-A receptors. Gephyrin displaces GABA receptors from the GABARAP/P130 complex, then brings...
, an integral membrane protein believed to coordinate glycine receptors, is coded by the gene GPHN. A heterozygous mutation in this gene has been identified in a sporadic case of hyperekplexia, though experimental data is inconclusive as to whether the mutation is pathogenic. Gephyrin is essential for glycine receptor clustering at synaptic junctions through its action of binding both the glycine receptor beta subunit and internal cellular microtubule
Microtubule
Microtubules are a component of the cytoskeleton. These rope-like polymers of tubulin can grow as long as 25 micrometers and are highly dynamic. The outer diameter of microtubule is about 25 nm. Microtubules are important for maintaining cell structure, providing platforms for intracellular...
structures. Gephyrin also assists in clustering GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
receptors at synpases and molybdenum cofactor synthesis. Because of its multi-functional nature, it is not presumed to be a common genetic source of hyperekplexia.
SLC6A5
The SLC6A5SLC6A5
Glycine transporter 2 also known as the sodium- and chloride-dependent glycine transporter 2 or solute carrier family 6 member 5 is a protein that in humans is encoded by the SLC6A5 gene....
gene encodes the GlyT2 transporter, a neuronal pre-synaptic glycine re-uptake transporter. In comparison to the GlyT1 transporter, found mostly in glial cell
Glial cell
Glial cells, sometimes called neuroglia or simply glia , are non-neuronal cells that maintain homeostasis, form myelin, and provide support and protection for neurons in the brain, and for neurons in other parts of the nervous system such as in the autonomous nervous system...
s, GlyT2 helps maintain a high concentration of glycine within the axon terminal
Axon terminal
Axon terminals are distal terminations of the branches of an axon. An axon nerve fiber is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body, or soma, in order to transmit those impulses to other neurons.Neurons are...
of glycinergic neurons. Mutations of the SLC6A5 gene have been associated with hyperekplexia in an autosomal recessive manner. Defects within this gene are hypothesized either to effect the incorporation of the transporter into the cellular membrane or to its affinity for the molecules it transports: sodium ions, chloride ions and glycine. Any of these actions would drastically reduce the pre-synaptic cell's ability to produce the high vesicular concentrations of glycine necessary for proper glycine neurotransmission.
ARHGEF9
A defect within the gene coding for collybistinCollybistin
Collybistin is a protein much like gephyrin which is thought to aid the formation of submembrane gephyrin aggregates that accumulate hetero-oligomeric glycine receptors. Data from Nature Neuroscience 2000 suggests that the expression of collybistin regulates the membrane disposition of gephyrin by...
(ARHGEF9) has also been shown to cause hyperekplexia in concert with epilepsy. Since the ARHGEF9 gene is on the X chromosome, this gene displays X-linked recessive heritance. The collybistin protein is responsible for proper gephyrin targeting, which is crucial for the proper localization of glycine and GABA receptors. Deficiencies in collybistin function would result in an artificial lack of glycine and GABA receptors at the synaptic cleft.
Treatment
The most commonly effective treatment is clonazepamClonazepam
Clonazepamis a benzodiazepine drug having anxiolytic, anticonvulsant, muscle relaxant, and hypnotic properties. It is marketed by Roche under the trade name Klonopin in the United States and Rivotril in Australia, Brazil, Canada and Europe...
, which leads to the increased efficacy of another inhibitory neurotransmitter, GABA. Levetiracetam has been used to some success with an acquired case of hyperekplexia. During attacks of hypertonia and apnea, the limbs and head may be flexed towards the trunk in order to dissipate the symptoms. This is named the Vigevano maneuver after the doctor who invented it.
History
The disorder was first described in 1958 by Kirstein and Silfverskiold, who reported a family with 'drop seizures'. In 1962 Drs. Kok and Bruyn reported an unidentified hereditary syndrome, initially started as hypertoniaHypertonia
Hypertonia a condition marked by an abnormal increase in muscle tension and a reduced ability of a muscle to stretch. It is caused by lesions to upper motor neurons in the central nervous system, which carry information from the central nervous system to the muscles and control posture, muscle...
in infants. Genetic analysis within this large Duch pedigree was later found to carry a mutation within the GLRA1 gene, which was the first gene implicated in hyperekplexia.