Journal Identification = EPD Article Identification = 0986 Date: August 7, 2018 Time: 2:22 pm

Clinical commentary

Epileptic Disord 2018; 20 (4): 279-82 A child with hyperekplexia and epileptic

Lara Wadi 1, Yasser Medlej 2, Makram Obeid 2,3 1 Faculty of Medicine, American University of Beirut, Beirut 2 Department of Anatomy, Cell biology and Physiological Sciences, American University of Beirut, Beirut 3 Division of Child Neurology, Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon

Received October 25, 2017; Accepted April 24, 2018

ABSTRACT – Hyperekplexia is a rare neurogenetic disorder character- ized by startle. Accurate diagnosis of this notorious mimicker of epilepsy is important to prevent life-threatening apnoea. We report a novel case of concomitant GLRA1-related hyperkeplexia and myoclonic epilepsy. A toddler with daily paroxysms of head drops and falls presented with epileptic myoclonus on EEG, however, whole-exome sequencing revealed hyperekplexia-related GLRA1 mutation. The boy eventually developed spells induced by noise and surprise. All his spells remitted upon treat- ment with . Paediatricians and paediatric neurologists should be aware of this possible mixed presentation in order to appropriately tailor medication regimens and treatment goals. [Published with video sequence on www.epilepticdisorders.com]. Key words: epilepsy, genetic, myoclonus, hyperekplexia,

Hyperekplexia or human star- tic seizures. Prompt diagnosis and tle disease is a rare hereditary treatment should not be delayed as character- infants are at risk of life-threatening ized by neonatal-onset generalized apnoea (Cross, 2013). While distin- stiffness, associated with life- guishing between hyperekplexia threatening apnoea, swallowing and epileptic seizures is a known difficulties, umbilical or inguinal challenge, here we present an even hernias, hypnagogic myoclonus, more challenging case of a boy and hip dislocation. Stiffness with hyperekplexia and pathologi- improves after the first year of life cal startle, along with EEG-proven VIDEO ONLINE and the hallmark of the condi- and treatment-resistant epileptic tion becomes excessive startle myoclonus. Correspondence: reflex, which can be triggered Makram Obeid Division of Child Neurology, by visual or auditory stimuli, sur- Case study Department of Pediatrics and Adolescent, prise, sudden awakening, or bathing American University of Beirut, (Dreissen and Tijssen, 2012). Parox- We report a 14-month-old Syr- Medical Center, P.O. Box 11-0236 Riad EI ysms of excessive startle can lead ian boy who was brought to the Solh, Beirut 1107 2020, Lebanon to generalized stiffness lasting a child neurology clinic with a one- few seconds, mimicking epilep- month history of recurrent and doi:10.1684/epd.2018.0986

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daily uncontrollable head drops, occurring up to 10 that is thought to be related to is also an times per day. There was no identifiable clustering pat- early feature of this condition. The diagnosis of hyper- tern. The child was sitting and pulling to stand, but not ekplexia was confirmed by whole-exome sequencing walking yet. This was attributed to developmental dys- which revealed a known causative mutation in plasia of the right hip that was corrected between the GLRA1. In addition to GLRA1-related hyperekplexia, ages of four and eight months. Otherwise, his language the boy had EEG-proven concomitant myoclonic and social interactions were age-appropriate and no epilepsy. other neurodevelopmental abnormalities could be Hyperekplexia is a genetic disease caused by dis- detected. There were no perinatal complications. The turbances in glycine homeostasis, mainly due to a parents were non-consanguineous and there was no dysfunction in ligand-gated chloride channels. The family history of epilepsy or developmental delays. On glycine receptor chloride channel (GlyR) is located physical examination, his head circumference was at in the postsynaptic membranes of inhibitory neu- the ninetieth percentile for age, and he had slightly rons, predominantly at the level of the spinal cord decreased lower extremity muscle tone. A prolonged and brain stem, and mutations in its ␣1 and ␤ sub- one-hour EEG revealed five generalized electroclini- units (GLRA1 and GLRB genes) are the most common cal myoclonic seizures manifesting with whole-body culprits in this condition. To date, three other cul- myoclonic jerks, the ictal signature of which con- prit genes have been identified in the GlyR signalling sisted of one-second bursts of irregular generalized, complex and these include the anchoring proteins, frontally predominant spike-and-slow-wave comple- (GPHN) and collybistin (ARHGEF9), and xes (figure 1 and video sequence). MRI of the brain a glycine transporter (SLC6A5) (James et al., 2013; was normal. Despite sequential trials of levetiracetam Harvey et al., 2008). Hyperekplexia is induced by (up to 100 mg/kg/day) and topiramate (10 mg/kg/day), impaired glycinergic and conse- his seizures kept increasing in frequency with around quent excessive neuronal excitability at the level of the 20 spells of head drops per day. As he started walk- brainstem and spinal cord. The maturational changes ing at the age of 15 months, these paroxysms resulted in the developmentally-regulated inhibitory channels, in daily falls. His mother also noted around that time, including the glycine receptor, as well as emerging that some of the spells were triggered by noise or just compensatory mechanisms, are reflected clinically by the element of surprise. These spells were character- the evolution from stiffness in the infantile period to ized by eye closure, and neck and trunk flexion, with only paroxysmal stiffness in the form of startle later abduction at the shoulder and flexion at the elbow. In in life. Autosomal dominant, recessive, and sporadic addition, a prominent clustering of whole-body jerk- forms of hyperekplexia have been reported (Dreissen ing occurred upon falling asleep (later considered as et al., 2012). In parallel to genetic studies, other tests spells of hypnagogic myoclonus). The boy was then such as brain MRI and EEG are performed to rule out started on clonazepam (0.03 mg/kg/day) with only mod- structural and epilepsy disorders. The EEG is normal est improvements. He also failed a pyridoxine trial but because this condition is a notorious mimicker (30 mg/kg/day). Since non-lesional refractory epilepsy of epilepsy, an EEG is usually performed to differen- is suspected to be genetic in origin, genetic studies tiate hyperekplexia-related pathological startle from were performed in order to identify a possible treat- epileptic myoclonus and tonic seizures. Our patient able metabolic aetiology. Whole-exome sequencing is unique in that he had both hyperekplexia-related (WES) revealed a heterozygous mutation in GLRA1, startle and epileptic myoclonus. c.994G>A p. (Val332Ile), which is known to be asso- An association between hyperekplexia and epilepsy ciated with hyperekplexia. The mutation was not has been previously described in the literature. Refrac- detected in either parents and thus considered a de tory seizures culminating in death in two Ashkenazi novo dominant mutation. There were no detected Jew siblings with hyperekplexia was reported by mutations known to be associated with myoclonic Lerman-Sagie et al. (2004). It was speculated that an epilepsy. We therefore initiated incremental increases autosomal recessive gamma-aminobutyric acid recep- in clonazepam. All the spells remitted at a clonazepam tor (GABARs) channelopathy, affecting both the brain dose of 0.15 mg/kg/day. and the spinal cord, may have been the underlying cause of the unusual presentation (Lerman-Sagie et al., 2004). Harvey et al. (2004) also reported a patient Discussion with clinical symptoms of both hyperekplexia and early infantile epileptic encephalopathy. The child was The boy described here experienced hypnagogic found to have an ARHGEF9 mutation leading to a myoclonus and pathological startle induced by sur- malfunctioning collybistin protein, and a likely sec- prise and auditory stimuli; the clinical hallmark of ondary disturbance in anchoring GABARs and glycine hyperekplexia. The congenital right hip dislocation receptors to the postsynaptic membrane (Harvey et al.,

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Figure 1. Illustrative EEG of one of the patient’s myoclonic epileptic seizures. Shown are two bursts of irregular, frontally predominant, generalized spike-and-wave complexes in a longitudinal bipolar montage (A) and average referential montage (B). One of the bursts was associated with a myoclonic seizure (white arrow in both panels). The myoclonus occurred during the slow-wave component of the burst, as shown on the EMG (electromyography) lead in this image.

2004). In addition, hyperekplexia has been associated seizures were identified on WES. Since a disruption with developmental delay, neurodegeneration, spas- in glycine homeostasis in diseases such as non-ketotic tic paraparesis, and intellectual disability (Vergouwe hyperglycinaemia (Kure et al., 1997) and autoimmune et al., 1997; Baxter et al., 1996). Brain imaging and clin- GlyR antibody-related disorders (Chan et al., 2017) is ical history did not reveal an acquired aetiology for known to cause epileptic seizures, we hypothesize the child’s epileptic syndrome, and no potential cul- that the child’s myoclonic epilepsy is also sec- prit genes known to be associated with myoclonic ondary to hyperekplexia-related impaired glycinergic

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neurotransmission. More cases and mechanistic stud- References ies will be needed, however, to explore this possible causality between GLRA1 mutation and epileptic Baxter P, Connolly S, Curtis A, et al. Co-dominant inheritance myoclonic seizures. of hyperekplexia and spastic paraparesis. Dev Med Child This case illustrates the importance of thorough Neurol 1996; 38: 739-43. history-taking and workup to distinguish epileptic Chan DWS, Thomas T, Lim M, Ling S, Woodhall M, Vin- seizures from epilepsy mimickers such as hyperke- cent A. Focal status epilepticus and progressive dyskinesia: plexia. More importantly, it highlights the fact that a novel phenotype for glycine receptor antibody-mediated epileptic seizures, including myoclonic seizures, and neurological disease in children. Eur J Paediatr Neurol hyperklexia can coexist, which has implications on 2017; 21: 414-7. treatment of potentially life-threatening symptoms. Cross JH. Differential diagnosis of epileptic seizures in Stiffness and startle may be difficult to completely infancy including the neonatal period. Semin Fetal Neonatal treat, and are best approached with clonazepam or Med 2013; 18: 192-5. clobazam (Stewart et al., 2002). In addition to ben- Dreissen YE, Tijssen MA. The startle syndromes: physiology zodiazepines, epileptic myoclonus is also treated and treatment. Epilepsia 2012; 53: 3-11. with valproate and levetiracetam (McAbee, 2015). In Dreissen YE, Bakker MJ, Koelman JH, Tijssen MA. Exaggerated our patient, levetiracetam failed, but high-dose clon- startle reactions. Clin Neurophysiol 2012; 123: 34-44. azepam was effective in completely suppressing the child’s spells. Diagnosticians should be aware of the Harvey K, Duguid IC, Alldred MJ, et al. The GDP-GTP exchange factor collybistin: an essential determinant of neu- possibility of concomitant epileptic myoclonus along ronal gephyrin clustering. J Neurosci 2004; 24: 5816-26. with hyperekplexia in order to tailor treatment choices and targets.  Harvey RJ, Topf M, Harvey K, Rees MI. The genetics of hyper- ekplexia: more than startle! Trends Genet 2008; 24: 439-47. Disclosures. James VM, Bode A, Chung SK, et al. Novel missense muta- None of the authors have any conflict of interest to declare. tions in the glycine receptor ␤ subunit gene (GLRB) in startle disease. Neurobiol Dis 2013; 52: 137-49. Legend for video sequence Kure S, Tada K, Narisawa K. Nonketotic hyperglycinemia: bio- chemical, molecular, and neurological aspects. J Hum Genet EEG segment synchronized with video. A burst of 1997; 42: 13-22. an irregular frontal predominant generalized spike- Lerman-Sagie T, Watemberg N, Vinkler N, Fishhof J, and-wave complex is accompanied by a behavioural Leshinsky-Silver E, Lev D. Familial hyperekplexia and refrac- correlate, consisting of a whole-body jerk. This is tory status epilepticus: a new autosomal recessive syndrome. an epileptic myoclonic seizure that occurred during J Child Neurol 2004; 19: 522-5. the slow-wave component of the generalized spike- McAbee GN. Clobazam-clonazepam combination effective and-wave complex. for stimulus-induced falling in hyperekplexia. J Child Neurol Key words for video research on 2015; 30: 91-2. www.epilepticdisorders.com Stewart WA, Wood EP, Gordon KE, Camfield PR. Successful treatment of severe infantile hyperekplexia with low-dose Phenomenology: myoclonic seizure clobazam. J Child Neurol 2002; 17: 154-6. Localization: generalized Syndrome: epilepsy not classified Vergouwe MN, Tijssen MAJ, Shiang R, Van Dijk JG, et al. Aetiology: unknown, genetic Hyperekplexia-like syndromes without mutations in the GLRA1 gene. Clin Neurol Neurosurg 1997; 99: 172-8.

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