Hyperekplexia (literally meaning exaggerated surprise) is classically characterised by pronounced startle responses to tactile or acoustic stimuli, hypertonia (stiffness) and episodic neonatal apnoea (a form of breath-holding attack). In classic hyperekplexia the symptoms start from birth and are worse in the first year of life. The hypertonia may be mostly in the abdomen, not so noticable in sleep and less prominent after a year of age.

Although primarily seen as a neurogenetic syndrome with both familial and sporadic cases, acquired hyperekplexia is also recognised. Inheritance is often misreported as solely autosomal dominant, but this represents a bias of early reports: autosomal recessive inheritance is seen and is important in certain ethnic groups.

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 hypertonia in infants. The disease may have been responsible for sudden infant deaths in very rare cases.

Clinical signs

The most prevalent feature of hyperekplexia is an exaggerated startle response consisting of forced closure of the eyes and an extension of the extremities followed by a period of generalised stiffness similar to paralysis and possibly resulting in uncontrolled falling. It can be mistaken for startle seizures which are epileptic and cataplexy attacks (provoked by high emotion seen only in narcolepsy).

Some people with hyperekplexia display an exaggerated startle response without the generalised stiffness. The symptoms usually subside within the first year of life although it is not unknown for some symptoms to proceed into adulthood.

Genetic cause

In 1993 mutations in the alpha one subunit of the human glycine receptor (GLRA1) were shown to be a major cause of hyperekplexia. Inhibitory glycine receptors are ligand-gated chloride channels that facilitate fast responses in the brainstem and spinal-cord.

Hyperekplexia however also exhibits considerable genetic heterogeneity: symptomatic mutations in the beta subunit of the glycine receptor, the receptor clustering protein gephryn and collybisitin all cause classic symptoms. Mutations in the presynaptic glycine trasporter 2 (GlyT2) have also been shown to be an important cause of hyperekplexia. The SLC6A5 gene encodes GlyT2, which is involved in the re-uptake of glycine from the synaptic cleft of glycinergic neurones and maintains the pool of glycine molecules for presynaptic vesicular replenishment. Similar phenotypes in mice and cattle have been described in association with similar glycinergic mutations.

The glycine receptors can become up to 400 times less sensitive to glycine resulting in a decrease of spinal inhibition. Therefore the patients experience an exaggerated response to stimuli.

Research into the genetic causes of hyperkplexia is underway at Swansea University, Wales. Professor Mark Rees has the largest database of clinical information and new mutations causing hyperekplexia and is always keen to hear from physicians or patients regarding potential cases. The work is offered as a research tool only at present.

Treatment

Most patients receive symptomatic benefit from clonazepam; appearing to offer more relief from exaggerated startle reflexes, than from hypertonia. When clonazepam is ineffective or intolerable due to sedation, alternative benzodiazepines or antiepileptics are used with patchy or partial success. Physical activity (for hypertonia) and patient education should form part of a treatment regime for anyone with hyperekplexia.