Hyperekplexia (; "exaggerated surprise") is a neurological disorder characterized by a pronounced startle response to tactile or acoustic stimuli and an ensuing period of hypertonia. The hypertonia may be predominantly Torso, attenuated during sleep, or less prominent after one year of age.
Classic hyperekplexia is caused by in a number of different genes, 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;
Signs and symptoms
The three main signs of hyperekplexia are generalized stiffness, excessive startle response beginning at birth, and nocturnal
myoclonus.
Affected individuals are 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 and uncontrolled falling at times.
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.
Genetic evidence has only been found for the major form of the condition.
Other signs and symptoms of hyperekplexia may include episodic neonatal apnea, excessive movement during sleep and the head-retraction reflex. The link to some cases of sudden infant death remains controversial.
Genetics
Hyperekplexia is known to be caused by a variety of genes, encoding both pre- and postsynaptic proteins. The symptoms displayed, as well as the types of inheritance, vary, based on the affected gene, as discussed in detail below.
GLRA1
The first gene linked conclusively to hyperekplexia was GLRA1.
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.
glycine receptors are thus presumed to be
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 the pentamer, causing the ion-channel to open. Although autosomal dominant
GLRB
The
GLRB 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.
SLC6A5
The SLC6A5 gene encodes the GlyT2 transporter, a neuronal pre-synaptic glycine re-uptake transporter. In comparison to the GlyT1 transporter, found mostly in
, 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 inheritance pattern.
Defects within this gene are hypothesized either to affect the incorporation of the transporter into the cellular membrane or to affect 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.
GPHN and ARHGEF9 are often included in lists of genetic causes of hyperekplexia - but, in fact, they produce a much more complex phenotype, very distinct from classical hyperekplexia. As such they are no longer considered to be causative genes.
GPHN
Gephyrin, 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 one sporadic case of hyperekplexia, though experimental data is inconclusive as to whether the mutation itself is, in fact, 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 receptor at synapses and molybdenum cofactor synthesis.
Because of gephyrin's multi-functional nature, in mutated form it is not presumed to be a common genetic source of hyperekplexia.
ARHGEF9
A defect within the gene coding for
collybistin, ARHGEF9, has been shown to cause hyperekplexia occurring 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 a lack of glycine and GABA receptors at the synaptic cleft.
Diagnosis
There are three signs used to diagnose if an infant has hereditary hyperekplexia: if the child's body is stiff all over as soon as they are born, if they overreact to noises and other stimuli, and if the reaction to stimuli is followed by an overall stiffness where the child is unable to make any voluntary movements.
A combination of electroencephalogram and an
Electromyography may help diagnose this condition in patients who have not displayed symptoms as children. The electroencephalogram will not show abnormal activity other than a spike in wakefulness or alertness, while the electromyogram will show rapid muscular responses and
hyperreflexia. Otherwise,
genetic testing is the only definitive diagnosis.
MRIs and
CT scan will be normal unless other conditions are present.
Treatment
The most commonly used effective treatment is
clonazepam, which leads to the increased efficacy of another inhibitory neurotransmitter,
GABA.
There are
of the use of
levetiracetam in genetic and acquired hyperekplexia.
During attacks of
hypertonia and
apnea, the limbs and head may be forcibly manipulated towards the trunk in order to resolve the symptoms. This is referred to as the "Vigevano maneuver'.
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, which initially presented as
hypertonia in infants.
Genetic analysis within this large Dutch pedigree revealed a mutation within the GLRA1 gene, the first gene to be implicated in hyperekplexia.
See also
External links
