Hereditary hyperekplexia

Hereditary hyperekplexia, also known as startle disease or hyperekplexia, is a rare neurological disorder characterized by an exaggerated startle reflex in response to unexpected stimuli, particularly sudden noises or touch. The condition primarily affects the nervous system, specifically the glycinergic inhibitory neurotransmission pathways in the brainstem and spinal cord. It is caused by mutations in genes encoding components of the glycine receptor or glycine transporter, most commonly the GLRA1 gene (encoding the glycine receptor alpha-1 subunit), but also GLRB, SLC6A5, GPHN, and ARHGEF9. The hallmark features of hereditary hyperekplexia typically present in the neonatal period and include excessive startle responses to unexpected stimuli, neonatal hypertonia (generalized stiffness that is particularly prominent in the trunk and limbs), and episodic neonatal apnea, which can be life-threatening if not promptly managed. The hypertonia is often most pronounced shortly after birth and tends to diminish during the first year of life, though an exaggerated startle reflex usually persists into adulthood. Affected neonates may exhibit a characteristic nose-tap response, where tapping the bridge of the nose elicits a pronounced, non-habituating startle. Episodes of stiffness triggered by startle can cause falls and injuries in older children and adults. Treatment for hereditary hyperekplexia is primarily symptomatic. Clonazepam, a benzodiazepine that enhances GABAergic inhibition, is the most widely used and effective medication, significantly reducing both the startle response and hypertonia in most patients. In neonates experiencing acute episodes of stiffness and apnea, the Vigevano maneuver — forceful flexion of the head and limbs toward the trunk — can be a life-saving intervention. Other medications such as clobazam, valproate, carbamazepine, and levetiracetam have been used with variable success. Early diagnosis and treatment are essential to prevent potentially fatal apneic episodes in infancy and to reduce the risk of injury from startle-induced falls later in life. Genetic counseling is recommended for affected families.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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