Hyperekplexia

The most striking feature is an exaggerated startle response (typically eye blinking and a flexor spasm of the trunk) to unexpected, innocuous, particularly auditory stimuli, present from birth or occasionally noted prenatally in the last trimester. Generalised stiffness is apparent immediately after birth, increases with handling, and disappears during sleep; held horizontally, the affected newborn appears rigid. Episodes of tonic neonatal apnoea may occur and are associated with sudden infant death, underlining the importance of early recognition. Generalised stiffness usually normalises within the first years of life (by age 2 years; range 0.7-5 years), while startle-induced stiffness and an increased risk of falls and injury may persist into adulthood. Epilepsy is reported in 7-12% of affected individuals.

The exact prevalence of hereditary hyperekplexia is unknown. In the United States, an estimated prevalence of approximately 1 in 40,000 individuals is reported.

Hyperekplexia is caused by germline pathogenic variants in GLRA1 (~62%), SLC6A5 (~25%) and GLRB (~13%), accounting for the majority of molecularly confirmed cases. These genes encode the α1 and β subunits of the post-synaptic glycine receptor and the pre-synaptic glycine transporter GlyT2, respectively; loss-of-function variants disrupt glycinergic inhibitory neurotransmission and reduce the inhibitory tone that normally restrains startle reflexes in brainstem and spinal cord circuits.

GLRA1– and GLRB-related hereditary hyperekplexia can be inherited in an autosomal recessive or, less commonly, an autosomal dominant manner. SLC6A5-HPX is inherited in an autosomal recessive manner (autosomal dominant inheritance of SLC6A5-HPX has been reported in one family). For families with a child affected by autosomal recessive hyperekplexia, the recurrence risk for each subsequent pregnancy is 25%. Most patients diagnosed with autosomal dominant HPX have an affected parent. Carrier testing of at-risk relatives is possible once the familial pathogenic variants have been identified. Prenatal molecular testing is technically possible once the familial pathogenic variants have been identified.

Diagnosis is established primarily by molecular genetic testing in individuals with consistent clinical features; no established clinical diagnostic criteria, biochemical markers, or specific imaging findings are currently available.

Main differential diagnoses include:

• GLYT1 encephalopathy (SLC6A9-related): hypotonia evolving to hypertonicity, arthrogryposis, respiratory failure, dysmorphic features and encephalopathy distinguish it from isolated startle disease; SLC6A9
• Early-infantile epileptic encephalopathy 42 (CACNA1A-related): epileptic encephalopathy with myoclonic seizures provoked by tactile stimuli and reflex seizures to noise and touch (true seizures rather than non-epileptic startle); CACNA1A
• Early-infantile epileptic encephalopathy 8 (ARHGEF9-related): X-linked severe intellectual disability with intractable focal or febrile seizures and dysmorphic features rather than isolated congenital stiffness; ARHGEF9

• Establishing the diagnosis: molecular confirmation distinguishes the condition from clinically overlapping disorders and ends the diagnostic odyssey for affected individuals and families.
• Specific and individualised clinical management: molecular confirmation is a prerequisite for targeted medical care; the choice of supportive measures and multidisciplinary follow-up is made by the treating physicians in consultation with the affected individual.
• Family member testing: once the familial pathogenic variants have been identified, predictive and carrier testing of at-risk relatives becomes possible, supporting informed reproductive decisions and clarification of recurrence risk.

• Balint B, Thomas R. Hereditary hyperekplexia overview. 2019 Dec 19. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: PMID:20301437.
• Schaefer N, Harvey RJ, Villmann C. Startle disease: new molecular insights into an old neurological disorder. Neuroscientist. 2023;29(6):767-81. doi:10.1177/10738584221104724. PMID:; PMCID: PMC10623600.
• Lim TT, Por CY, Beh YY, Schee JP, Tan AH. Treatment of startle and related disorders. Clin Park Relat Disord. 2023;9:100218. doi:10.1016/j.prdoa.2023.100218. PMID:; PMCID: PMC10556813.
• Cleveland Clinic. Hyperekplexia: what it is, causes, symptoms & treatment [Internet]. Cleveland: Cleveland Clinic; c2024. Available from: