Abnormal neurodevelopment outcome in case of neonatal hyperekplexia secondary to missense mutation in GLRB gene.

Hyperekplexia is an exaggerated startle to external stimuli associated with a generalised increase in tone seen in neonates with both sporadic and genetic predisposition. This is an uncommon neurological entity that is misdiagnosed as seizure. A 28-days-old infant was admitted to us with characteristic intermittent generalised tonic spasm being treated as a seizure disorder. The infant had characteristic stiffening episode, exaggerated startle and non-habituation on tapping the nose. Hyperekplexia was suspected and confirmed by genetic testing (mutation in the ß subunit of glycine was found). Initial improvement was seen with the use of clonazepam, which was not sustained. At the age of 4.5 years, the child is still having neurobehavioural issues like hyperactivity and sensory hyper-responsiveness. Usually, hyperekplexia is benign in nature. We report a case of hyperekplexia with non-sense mutation in the ß subunit of GlyR gene having abnormal neurodevelopmental findings at 4.5 years.

Impaired glycinergic transmission in hyperekplexia: a model of parasomnia overlap disorder.

We report sleep phenotypes and polysomnographic findings in two siblings with a novel homozygous variant of the GLRA1 gene causing hereditary hyperekplexia (HH). Both sisters had startles during wakefulness and sleep, sleep terrors, and one had symptoms of REM sleep behavior disorder (RBD). Frequent startles were found in NREM sleep associated with NREM parasomnias in deep sleep. In REM sleep, both had motor behaviors and increased phasic/tonic muscle activities confirming RBD. Clonazepam improved startles, motor behaviors, and muscle activities in REM sleep. Impaired glycinergic transmission in human HH could be involved in the pathophysiology of RBD and NREM parasomnias.

Neonatal tremor episodes and hyperekplexia-like presentation at onset in a child with SCN8A developmental and epileptic encephalopathy.

SCN8A encephalopathy is a newly defined epileptic encephalopathy caused by de novo mutations of the SCN8A gene. We report herein a four-year-old boy presenting with severe non-epileptic abnormal movements, of possibly antenatal onset, progressively associated with pharmacoresistant epilepsy and regression, associated with a de novo heterozygous missense mutation of SCN8A. This case shows that paroxysmal non-epileptic episodes of severe tremor and hyperekplexia-like startles and a striking vegetative component can be the first early symptoms of severe SCN8A developmental and epileptic encephalopathy. Clinicians should be aware of these symptoms in order to avoid misdiagnosis and ensure early appropriate therapeutic management. [Published with video sequences on www.epilepticdisorders.com].

Weird Laughing in Hyperekplexia: A new phenotype associated with a novel mutation in the GLRA1 gene?

Hyperekplexia (HPX) or startle disease is a rare hereditary neurological disorder characterized by generalized stiffness, excessive startle reflex to unexpected stimuli and a short period of generalized stiffness following the startle response, and can be complicated by umbilical or inguinal hernia, developmental delay and apnea spell. HPX is caused mainly by mutations in the GLRA1 gene, and has a good response to clonazepam. In this short communication we describe an 11-year-old girl with excessive startle reflex, weird laughing and developmental delay since early infancy. She also suffered from infantile spasms and generalized tonic-clonic seizures, and became seizure-free with antiepileptic drugs treatment. However, the weird laughing was still present during the treatment. Her mother also appeared excessive startle reflex during early infancy. A novel mutation in GLRA1 was detected in the girl and her mother. Consequently, she was diagnosed with HPX, and clonazepam was added. The weird laughing was dramatic improved, which hasn't been reported in HPX. This is the first report of weird laughing in a hyperekplexia patient carrying a novel GLRA1 mutation, and expanded the phenotype spectrum of HPX.

CACNA1A-related early-onset encephalopathy with myoclonic epilepsy: A case report.

We report a one-year-old boy with early-onset myoclonic epilepsy, developmental arrest, and hyperekplexia during early infancy. He presented with refractory myoclonic/tonic seizures since birth. Electroencephalography revealed multifocal spikes, and rhythmic activities that occurred simultaneous with aggravation of myoclonus accompanied by tonic upper limb elevation. Brain magnetic resonance imaging revealed progressive cerebral atrophy with periventricular signal change and thin corpus callosum at one year of age. A de novo heterozygous missense mutation in the CACNA1A gene was confirmed. This patient was the most severe phenotype of CACNA1A-related early-onset encephalopathy among previous reports.

A novel compound mutation in GLRA1 cause hyperekplexia in a Chinese boy- a case report and review of the literature.

BACKGROUND: The pathogenesis of hereditary hyperekplexia is thought to involve abnormalities in the glycinergic neurotransmission system, the most of mutations reported in GLRA1. This gene encodes the glycine receptor α1 subunit, which has an extracellular domain (ECD) and a transmembrane domain (TMD) with 4 α-helices (TM1-TM4). CASE PRESENTATION: We investigated the genetic cause of hyperekplexia in a Chinese family with one affected member. Whole-exome sequencing of the 5 candidate genes was performed on the proband patient, and direct sequencing was performed to validate and confirm the detected mutation in other family members. We also review and analyse all reported GLRA1 mutations. The proband had a compound heterozygous GLRA1 mutation that comprised 2 novel GLRA1 missense mutations, C.569C > T (p.T190 M) from the mother and C.1270G > A (p.D424N) from the father. SIFT, Polyphen-2 and MutationTaster analysis identified the mutations as disease-causing, but the parents had no signs of hyperekplexia. The p.T190 M mutation is located in the ECD, while p.D424N is located in TM4. CONCLUSIONS: Our findings contribute to a growing list GLRA1 mutations associated with hyperekplexia and provide new insights into correlations between phenotype and GLRA1 mutations. Some recessive mutations can induce hyperekplexia in combination with other recessive GLRA1 mutations. Mutations in the ECD, TM1, TM1-TM2 loop, TM3, TM3-TM4 loop and TM4 are more often recessive and part of a compound mutation, while those in TM2 and the TM2-TM3 loop are more likely to be dominant hereditary mutations.

[Myoclonus as a movement disorder]. / Myoklonien als Bewegungsstörung.

Myoclonus is often a diagnostic and therapeutic challenge due to its broad phenomenological variability and limited therapeutic options. This article gives a short survey and characterizes in detail two common types of myoclonus, cortical myoclonus and reticular reflex myoclonus. Clinical testing and electrophysiological investigations provide relevant local diagnostic indications for the generating structure(s). Such indications would influence not only the strategies of neuroimaging and laboratory investigations aimed at clarifying the underlying cause but also the selection of drugs to suppress myoclonus.

Hyperekplexia: Report on phenotype and genotype of 16 Jordanian patients.

BACKGROUND: Hyperekplexia, is a rare disorder characterized by excessive startle response to acoustic, visual, or other stimuli. It is inherited in autosomal recessive and dominant pattern. OBJECTIVE: To describe the clinical and genetic features of hyperekplexia in Jordanian patients. METHODS: This retrospective study includes all patients with proved genetic diagnosis of hyperekplexia who presented to our clinic at the Jordan University Hospital from January 2001 through July 2015. RESULTS: A total of 16 children from 12 families were included. The total follow up period ranged from one to eleven years. The majority of the patients (13/16=81.3%) were initially misdiagnosed as epilepsy. All patients had excessive startle response since birth. Tonic-apneic spells occurred in 15/16=93.8% patients. Fourteen patients (45/16=87.5%) received clonazepam. Stopping clonazepam by three years of age failed in 11/14 (78.6%) due to reappearance of tonic-apneic spells (8/14=57.1%), recurrent falling (10/14=71.4%) or due to both reasons (5/14=35.7%). Delayed motor development occurred in 7/16 (43.8%), speech delay in 4/16 (25.0%), global developmental delay in 1/16 (6.3%), and autism spectrum disorder in 1/16 (6.3%) patient. The mode of inheritance is autosomal recessive in all 12/12 (100%) families. Mutations in GLRA1 gene was present in 9/16 (56.3%); the most common mutation was in p.G254D (4/9; 44.5%). Mutations in the GLRB gene was present in 4/16 (25.0%) patients and the SLC6A5 gene in 3/16 (18.8%) patients. CONCLUSION: The clinical presentation of hyperekplexia in Jordanian patients is manifested by tonic-apneic spells in all homozygous patients. The persistence of apneic spells and recurrent falls throughout childhood necessitate continuous treatment and surveillance.

Investigating the Mechanism by Which Gain-of-function Mutations to the α1 Glycine Receptor Cause Hyperekplexia.

Hyperekplexia is a rare human neuromotor disorder caused by mutations that impair the efficacy of glycinergic inhibitory neurotransmission. Loss-of-function mutations in the GLRA1 or GLRB genes, which encode the α1 and ß glycine receptor (GlyR) subunits, are the major cause. Paradoxically, gain-of-function GLRA1 mutations also cause hyperekplexia, although the mechanism is unknown. Here we identify two new gain-of-function mutations (I43F and W170S) and characterize these along with known gain-of-function mutations (Q226E, V280M, and R414H) to identify how they cause hyperekplexia. Using artificial synapses, we show that all mutations prolong the decay of inhibitory postsynaptic currents (IPSCs) and induce spontaneous GlyR activation. As these effects may deplete the chloride electrochemical gradient, hyperekplexia could potentially result from reduced glycinergic inhibitory efficacy. However, we consider this unlikely as the depleted chloride gradient should also lead to pain sensitization and to a hyperekplexia phenotype that correlates with mutation severity, neither of which is observed in patients with GLRA1 hyperekplexia mutations. We also rule out small increases in IPSC decay times (as caused by W170S and R414H) as a possible mechanism given that the clinically important drug, tropisetron, significantly increases glycinergic IPSC decay times without causing motor side effects. A recent study on cultured spinal neurons concluded that an elevated intracellular chloride concentration late during development ablates α1ß glycinergic synapses but spares GABAergic synapses. As this mechanism satisfies all our considerations, we propose it is primarily responsible for the hyperekplexia phenotype.

Murine startle mutant Nmf11 affects the structural stability of the glycine receptor and increases deactivation.

KEY POINTS: Hyperekplexia or startle disease is a serious neurological condition affecting newborn children and usually involves dysfunctional glycinergic neurotransmission. Glycine receptors (GlyRs) are major mediators of inhibition in the spinal cord and brainstem. A missense mutation, replacing asparagine (N) with lysine (K), at position 46 in the GlyR α1 subunit induced hyperekplexia following a reduction in the potency of the transmitter glycine; this resulted from a rapid deactivation of the agonist current at mutant GlyRs. These effects of N46K were rescued by mutating a juxtaposed residue, N61 on binding Loop D, suggesting these two asparagines may interact. Asparagine 46 is considered to be important for the structural stability of the subunit interface and glycine binding site, and its mutation represents a new mechanism by which GlyR dysfunction induces startle disease. ABSTRACT: Dysfunctional glycinergic inhibitory transmission underlies the debilitating neurological condition, hyperekplexia, which is characterised by exaggerated startle reflexes, muscle hypertonia and apnoea. Here we investigated the N46K missense mutation in the GlyR α1 subunit gene found in the ethylnitrosourea (ENU) murine mutant, Nmf11, which causes reduced body size, evoked tremor, seizures, muscle stiffness, and morbidity by postnatal day 21. Introducing the N46K mutation into recombinant GlyR α1 homomeric receptors, expressed in HEK cells, reduced the potencies of glycine, ß-alanine and taurine by 9-, 6- and 3-fold respectively, and that of the competitive antagonist strychnine by 15-fold. Replacing N46 with hydrophobic, charged or polar residues revealed that the amide moiety of asparagine was crucial for GlyR activation. Co-mutating N61, located on a neighbouring ß loop to N46, rescued the wild-type phenotype depending on the amino acid charge. Single-channel recording identified that burst length for the N46K mutant was reduced and fast agonist application revealed faster glycine deactivation times for the N46K mutant compared with the WT receptor. Overall, these data are consistent with N46 ensuring correct alignment of the α1 subunit interface by interaction with juxtaposed residues to preserve the structural integrity of the glycine binding site. This represents a new mechanism by which GlyR dysfunction induces startle disease.