Hyperekplexia: Treatment of a Severe Phenotype and Review of the Literature

Abstract

Hyperekplexia is a syndrome of exaggerated startle response to tactile, auditory, or other stimuli. 1 Patients can present early in the neonatal period with episodes of stiffening that can be so severe as to cause apnea and death, 2-9 a phenotype often referred to as "stiff-baby syndrome." 5 With time, the life-threatening manifestations of hyperekplexia are replaced by startle responses that are characterized by stiffening and falls. 2,5,8,10 Less severely affected patients experience excessive startle without significant stiffening. 11 Onset of symptoms can occur after the neonatal period and can be into adulthood. 12,13 Hyperekplexia is understood to be a monogenic, though heterogeneous, disorder. Autosomal dominant, autosomal recessive, and apparently sporadic forms (that are more likely the result of de novo mutations) have been recognized. 14 Mutations responsible for hyperekplexia have been found in the alpha 1 subunit of the glycine receptor gene (GLRA1), 15 the beta glycine receptor subunit gene (GLRB), 16 the presynaptic sodiumand chloride-dependent glycine transporter 2 gene ABSTRACT: Hyperekplexia is a rare disorder caused by autosomal dominant or recessive modes of inheritance and characterized by episodes of exaggerated startle. Five causative genes have been identified to date. The syndrome has been recognized for decades and due to its rarity, the literature contains mostly descriptive reports, many early studies lacking molecular genetic diagnoses. A spectrum of clinical severity exists. Severe cases can lead to neonatal cardiac arrest and death during an episode, an outcome prevented by early diagnosis and clinical vigilance. Large treatment studies are not feasible, so therapeutic measures continue to be empiric. A marked response to clonazepam is often reported but refractory cases exist. Herein we report the clinical course and treatment response of a severely affected infant homozygous for an SLC6A5 nonsense mutation and review the literature summarizing the history and genetic understanding of the disease as well as the described comorbidities and treatment options. RÉSUMÉ: Hyperekplexie : traitement d'un phénotype sévère et revue de la littérature. L'hyperekplexie est une maladie caractérisés par des épisodes de réaction exagérée de sursaut et dont le mode d'hérédité peut être dominant ou récessif. À ce jour, cinq gènes différents ont été identifiés. Le syndrome est connu depuis plusieurs dizaines d'années et, à cause de sa rareté, la littérature fait état surtout de descriptions de cas dont plusieurs, surtout les premières, ne comportent pas de diagnostic moléculaire. La sévérité clinique est très variable et, chez les cas sévères, la maladie peut entraîner un arrêt cardiaque dans la période néonatale et le décès, ce qui peut être prévenu par un diagnostic précoce et une surveillance clinique. Son traitement demeure empirique parce qu'il n'est pas possible d'effectuer de grandes études sur ce sujet. Bien qu'une excellente réponse au clonazépam soit souvent rapportée, il existe des cas ré...

Clobazam-Clonazepam Combination Effective for Stimulus-Induced Falling in Hyperekplexia

“…This child’s clinical syndrome has previously been described. 2 Hyperekplexia frequently is genetically based 3 but no genetic mutation was detected in this child. The falls were unpredictable and daily and occurred from the time that he initially started to walk.…”

“…Many of the medication trials have focused on improving the infantile stiffness and apnea, which often resolves after infancy. 2,3,[9][10][11][12] Fewer reports address the stimulus-induced falls, which can persist into the adult years. [4][5]7 Clobazam has been reported to be effective in the treatment of the stiffness, apnea, and startles, 9,10 although not all reports have noted efficacy.…”

“…Combination benzodiazepine therapy has been previously reported to be an effective treatment of symptoms of hyperekplexia when monotherapy with a benzodiazepine was either ineffective or not tolerated. 3,13 Recent long-term studies have demonstrated the efficacy and safety of clobazam in doses up to 2 mg/kg/d, 14 suggesting that further attempts at monotherapy with clobazam are possible. Combination benzodiazepine therapy should be considered in the treatment of stimulus-induced falling preventing ambulation in patients with hyperekplexia.…”

Nonepileptic paroxysmal event in newborn: A case report

“…Hastalarda görülen katılık hâli ve apneik nöbetler 1 yaşından sonra azalarak kaybolmakla birlikte, irkilme atakları erişkin yaşlarda da görülebilmektedir. İrkilme nöbetleri ve istemli hareketlerin yapılamadığı katılık hâli, bebeklik döneminde beslenme zorluğu, aspirasyon pnömonisi, apne, ani bebek ölümüne, ilerleyen yaşlarda ise ani düşmelere ve yaralanmalara yol açabilir (2,(10)(11)(12)(13) . Bu nedenle hastaların yakın takibi ve tedavisi gereklidir.…”

Presynaptic control of inhibitory neurotransmitter content in VIAAT containing synaptic vesicles

“…Disease symptoms subside in some patients as they age, presumably because GABAergic systems are eventually able to adapt and compensate for the deficiencies in glycine transmission. The most effective drug treatment for children born with hyperekplexia is benzodiazepines, which enhance existing GABAergic transmission (Dreissen and Tijssen, 2012;McAbee, 2015;Mineyko et al, 2011). Together these observations indicate that the circuits that are deficient in glycine also release GABA and have GABA receptors present but, like in GlyT2 knock-out animals, endogenous neonatal GABA systems are unable to compensate for a chronic loss of glycine signaling.…”