Elsevier

Brain and Development

Volume 24, Issue 7, October 2002, Pages 669-674
Brain and Development

Review article
Hyperekplexia: a treatable neurogenetic disease

https://doi.org/10.1016/S0387-7604(02)00095-5Get rights and content

Abstract

Hyperekplexia is primarily an autosomal dominant disease characterized by exaggerated startle reflex and neonatal hypertonia. It can be associated with, if untreated, sudden infant death from apnea or aspiration pneumonia and serious injuries and loss of ambulation from frequent falls. Different mutations in the α1 subunit of inhibitory glycine receptor (GLRA1) gene have been identified in many affected families. The most common mutation is Arg271 reported in at least 12 independent families. These mutations uncouple the ligand binding and chloride channel function of inhibitory glycine receptor and result in increased excitability in pontomedullary reticular neurons and abnormal spinal reciprocal inhibition. Three mouse models from spontaneous mutations in GLRA1 and β subunit of inhibitory glycine receptor (GLRB) genes and two transgenic mouse models are valuable for the study of the pathophysiology and the genotype–phenotype correlation of the disease. The disease caused by mutation in GLRB in mice supports the notion that human hyperekplexia with no detectable mutations in GLRA1 may harbor mutations in GLRB. Clonazepam, a gamma aminobutyric acid (GABA) receptor agonist, is highly effective and is the drug of choice. It enhances the GABA-gated chloride channel function and presumably compensates for the defective glycine-gated chloride channel in hyperekplexia. Recognition of the disease will lead to appropriate treatment and genetic counseling.

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.

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      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).

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