Review articleHyperekplexia: a treatable neurogenetic disease
Introduction
Hyperekplexia, also known as hereditary startle disease, is a rare neurogenetic disorder characterized by exaggerated startle response and neonatal hypertonia [1], [2]. It was first reported in 1958 by Kirstein and Silfverskiold as ‘emotionally precipitated drop seizure’ [3]. It was subsequently reported by Suhren et al. in 1966 using the Greek term ‘hyperexplexia’ [4] and was corrected to ‘hyperekplexia’ a year later by Gastaut and Villeneuve [5]. The other terms used in the past to report the same disease included ‘congenital stiff-man syndrome’ [6] and ‘hereditary stiff-baby syndrome’ [7]. In this article, we review the clinical features, genetic causes, animal models, pathophysiology, and treatment of hyperekplexia.
Section snippets
Clinical features
Hyperekplexia is predominantly an autosomal dominant disease with much fewer autosomal recessive and sporadic cases reported. The disease is rare and the prevalence remains unknown. It mainly affects northern European descendants, although two Japanese families have been reported as well [8].
Newborns with hyperekplexia manifest diffuse hypertonia, hyperreflexia, and exaggerated startle response to noise and handling shortly after birth [3], [9]. The startle attack can be easily elicited by nose
Genetic causes
In 1992, the hyperekplexia gene was linked to the long arm of chromosome 5 (5q33-35) by a linkage study in a large kindred with autosomal dominant hyperekplexia [20]. This locus contains several neurotransmitter receptor genes, including two GABA receptor subunit (GABRA1 and GABRG2) genes, a glutamate receptor gene and an α-adrenergic receptor gene. Radiation hybrid mapping in four unrelated hyperekplexia families, including one family we had been following, further localized the gene to the
Animal models
Three hyperekplexia mouse models have been identified resulting from spontaneous mutations. Unlike human hyperekplexia that mainly is an autosomal dominant disease, all three mouse models display autosomal recessive inheritance [21], [48], [49], indicating that they harbor loss of function mutations.
Spasmoid mouse (spd) harbors Ala52Ser mutation at N-terminal of GLRA1, the gene being mapped to mouse chromosome 11 [21]. The mechanism by which spd mutation affects the receptor is unknown. The
Pathophysiology
Hyperekplexia does not appear to have gross or microscopic pathology in the nervous system. No histopathological abnormalities have been identified in hyperekplexia mouse model [48]. Likewise, head computerized tomography (CT) of human patients is unremarkable [1].
Extensive electrophysiological studies have been performed in patients and in the mouse models to characterize the physiological abnormalities. Electromyographic (EMG) reflex studies, recording the response of head and limb muscles to
Treatment
Fortunately, hyperekplexia is a highly treatable disease as opposed to the majority of neurogenetic disorders. Clonazepam is the drug of choice that dramatically diminishes exaggerated startle response and consequently reduces morbidities and mortalities associated with the disease. However, it does not reduce infantile hypertonicity to the same degree. Patients usually require high doses (0.1–0.2 mg/kg/day) of clonazepam and tolerate it very well without losing effectiveness with time [1], [2],
Conclusions
Hyperekplexia is a treatable neurogenetic disease and clonazepam is the treatment of choice. It is characterized by exaggerated startle reflex and infantile hypertonicity due to increased excitability in pontomedullary reticular neurons and abnormal spinal reciprocal inhibition. This disease is caused by mutations in GLRA1. It can also be caused by mutation in GLRB in the mouse model. Recognition of the disease is essential for appropriate treatment and genetic counseling.
References (63)
- et al.
Hyperexplexia. A hereditary startle syndrome
J Neurol Sci
(1966) - et al.
The startle disease of hyperekplexia. Pathological surprise reaction
J Neurol Sci
(1967) - et al.
Hyperekplexia and sudden neonatal death
Pediatr Neurol
(1992) - et al.
Localization of the glycine receptor alpha 1 subunit gene (GLRA1) to chromosome 5q32 by FISH
Genomics
(1994) - et al.
The human glycine receptor beta subunit gene (GLRB): structure, refined chromosomal localization, and population polymorphism
Genomics
(1998) - et al.
Startle disease mutations reduce the agonist sensitivity of the human inhibitory glycine receptor
J Biol Chem
(1994) - et al.
The frameshift mutation oscillator (Glra1(spd-ot)) produces a complete loss of glycine receptor alpha1-polypeptide in mouse central nervous system
Neuroscience
(1997) - et al.
Human startle reflex: technique and criteria for abnormal response
Electroenceph clin Neurophysiol
(1992) - et al.
Giant somatosensory evoked potentials and pathophysiology of hyperekplexia. Neurophysiological study of one patient
Neurophysiol Clin
(1994) - et al.
The effects of clonazepam and vigabatrin in hyperekplexia
J Neurol Sci
(1997)
Startle disease or hyperekplexia: adolescent onset and response to valproate
Pediatr Neurol
Neonatal sporadic hyperekplexia: a rare and often unrecognized entity
Brain Dev
Startle disease or hyperekplexia: future delineation of the syndrome
Brain
Hyperekplexia in neonates
Postgrad Med J
A family with emotionally precipitated ‘drop seizure’
Acta Psychiatr Neurol Scand
Congenital stiff-man syndrome
Ann Neurol
Hereditary stiff baby syndrome
Am J Dis Child
Hyperekplexia: pedigree studies in two families
Am J Med Genet
Hyperekplexia associated with apnea and sudden infant death syndrome
Arch Pediatr Adolesc Med
Hyperekplexia, a cause of neonatal apnea: a case report
Brain Dev
Molecular genetic reevaluation of the Dutch hyperekplexia family
Arch Neurol
Startle responses in hereditary hyperekplexia
Arch Neurol
Patients with the major and minor form of hyperekplexia differ with regards to disynaptic reciprocal inhibition between ankle flexor and extensor muscles
Exp Brain Res
Mutational analysis of familial and sporadic hyperekplexia
Ann Neurol
Hyperekplexia relieved by surgical decompression of the cervicomedullary region
Neurosurgery
Hyperekplexia and trismus due to brainstem encephalopathy
J Neurol Neurosurg Psychiatry
Hypertension, hyperekplexia, and pyramidal paresis due to vascular compression of the medulla
Neurology
Symptomatic hyperekplexia occurring as a result of pontine infarction
Mov Disord
Startle disease, or hyperekplexia: response to clonazepam and assignment of the gene (STHE) to chromosome 5q by linkage analysis
Ann Neurol
A missense mutation in the gene encoding the alpha 1 subunit of the inhibitory glycine receptor in the spasmodic mouse
Nat Genet
Glycine receptors: a startling connection
Nat Genet
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2020, Journal of the Neurological SciencesThe synthetic cannabinoid dehydroxylcannabidiol restores the function of a major GABA<inf>A</inf> receptor isoform in a cell model of hyperekplexia
2020, Journal of Biological ChemistryCitation Excerpt :Another possible reason is that, although CBD and DH-CBD are very similar in structure, the subtle structural differences between them still lead to differences in their direct action on GABAAR. To illustrate the therapeutic effects of DH-CBD on hyperekplexia disease, the R271Q site mutation was selected as for this study because, of all reported GlyRα1 gene mutations, R271Q is the most common mutation causing hyperekplexia disease (21–23). In addition to R271Q mutant GlyRα1, GlyRα1 carrying many other mutations, such as R218Q, P250T, V260M, S270T, and K276E, is also responsive to DH-CBD (25).