Hyperekplexia: A Frequent Near Miss in Infants and Young Children.

Hyperekplexia, an underdiagnosed motor paroxysm of infancy, mimics epilepsy closely. It is hallmarked by episodic and excessive startle response, brief episodes of intense, generalized hypertonia, or stiffness in response to unexpected auditory and/or tactile stimuli right from birth. Though a seemingly benign entity with an excellent prognosis, hyperekplexia has been occasionally associated with recurrent apneas, feeding difficulties, and sudden infant death syndrome (SIDS). We describe three unrelated children with hyperekplexia (two SLC6A5; one GLRA1). All three children had the onset of motor paroxysms from the neonatal period and were initially labeled as drug-resistant epilepsy leading to a variable diagnostic delay, the longest being 2.5 years. An excellent response to oral clonazepam with a good neurodevelopmental outcome was observed. The lack of habituation on the nose-tapping test is a simple clinical clue to the diagnosis. Early differentiation from epilepsy minimizes treatment cost, allays caregiver anxiety, and empowers them with abortive measures.

Teaching Video NeuroImage: Hereditary Hyperekplexia Mimicking Tonic Seizures in an Infant.

Hereditary hyperekplexia is a rare neurologic disorder characterized by an exaggerated startle response with profound muscle stiffness.1,2 Given the nature of the spells, this condition is often misdiagnosed as epilepsy. Mutations in glycine receptors and transporters are the primary cause of this syndrome.1 We present an example of stimulus-induced hyperekplexia captured on video EEG in a 7-week-old girl with compound heterozygous variants in the presynaptic glycine transporter gene SLC6A5.

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.

Approach to exaggerated startle reflex: a case of hyperekplexia minor.

A broad set of conditions may present with an exaggerated startle reflex in clinics. This, combined with the overall rarity of these disorders, may pose diagnostic uncertainty in the mind of the treating physician. Herein, we report a case of a patient who presented to us with the complaint of exaggerated startle reflex and outline a simple approach towards characterisation of these disorders.

Clinical features and genetic analysis of two siblings with startle disease in an Italian family: a case report.

BACKGROUND: Hyperekplexia also known as Startle disease is a rare neuromotor hereditary disorder characterized by exaggerated startle responses to unexpected auditory, tactile, and visual stimuli and generalized muscle stiffness, which both gradually subside during the first months of life. Although the diagnosis of Hyperekplexia is based on clinical findings, pathogenic variants in five genes have been reported to cause Hyperekplexia, of which GLRA1 accounts for about 80% of cases. Dominant and recessive mutations have been identified in GLRA1 gene as pathogenic variants in many individuals with the familial form of Hyperekplexia and occasionally in simplex cases. CASE PRESENTATION: In the present study, we describe clinical and genetic features of two Italian siblings, one with the major and one with the minor form of the disease. DNA samples from the probands and their parents were performed by NGS approach and validated by Sanger sequencing. The analysis of the GLRA1 gene revealed, in both probands, compound heterozygous mutations: c.895C > T or p.R299X inherited from the mother and c.587C > A or p.D98E inherited from the father. CONCLUSIONS: Until now, these two identified mutations in GLRA1 have not been reported before as compound mutations. What clearly emerges within our study is the clinical heterogeneity in the same family. In fact, even though in the same pedigree, the affected mother showed only mild startle responses to unexpected noise stimuli, which might be explained by variable expressivity, while the father, showed no clear signs of symptomatology, which might be explained by non-penetrance. Finally, the two brothers have different form of the disease, even if the compound heterozygous mutations in GLRA1 are the same, showing that the same mutation in GLRA1 could have different phenotypic expressions and suggesting an underling mechanism of variable expressivity.

[Non-epileptic paroxysmal disorder in neonates]. / Trastornos paroxísticos no epilépticos neonatales.

Non-epileptic paroxysmal disorders are frequent events in the neonate, generally transient. However, due to their intensity they can be confused as true epileptic seizures. The objective of this review is to update the concepts in relation to tremors, neonatal benign sleep myoclonus (MNBS) and hyperekplexia. The tremors are very frequent, once identified it must be determined if they belong to a hyperexcitability syndrome related to maternal or perinatal factors, in idiopathic cases a good prognosis is expected. MNBS are often confused with epileptic seizures. They are characterized by the fact that myoclonus is brief and occurs only in sleep, children are normal, and the EEG is also normal. Hyperekplexia is a rare, genetically determined disorder characterized by hypertonia and exaggerated startle reactions to a banal stimulus, which can be improved with clonazepam.

Trastornos paroxísticos no epilépticos neonatales / Non-epileptic paroxysmal disorder in neonates

Los trastornos paroxísticos no epilépticos son eventos frecuentes en el neonato, generalmente transitorios. Sin embargo, por su intensidad pueden ser confundidos como verdaderas crisis epilépticas. El objetivo de esta revisión es actualizar los conceptos en relación a los temblores, mioclonías neonatales benignas del sueño (MNBS) e hiperecplexia. Los temblores son muy frecuentes, una vez identificados debe determinarse si pertenecen a un síndrome de hiperexcitabilidad relacionado con factores maternos o perinatales, en casos idiopáticos se espera buen pronóstico. Las MNBS con frecuencia se confunden con crisis epilépticas, se caracterizan porque las mioclonías son breves y solo se presentan en el sueño, los niños son normales y el EEG también es normal. La hiperecplexia es un trastorno raro, genéticamente determinado, caracterizado por hipertonía y reacciones de sobresalto exagerado ante un estímulo banal, que pueden mejorar con clonazepam.

Non-epileptic paroxysmal disorders are frequent events in the neonate, generally transient. However, due to their intensity they can be confused as true epileptic seizures. The objective of this review is to update the concepts in relation to tremors, neonatal benign sleep myoclonus (MNBS) and hyperekplexia. The tremors are very frequent, once identified it must be determined if they belong to a hyperexcitability syndrome related to maternal or perinatal factors, in idiopathic cases a good prognosis is expected. MNBS are often confused with epileptic seizures. They are characterized by the fact that myoclonus is brief and occurs only in sleep, children are normal, and the EEG is also normal. Hyperekplexia is a rare, genetically determined disorder characterized by hypertonia and exaggerated startle reactions to a banal stimulus, which can be improved with clonazepam.

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].

A child with hyperekplexia and epileptic myoclonus.

Hyperekplexia is a rare neurogenetic disorder characterized 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 treatment with clonazepam. 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].

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.

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.

[Clinical and genetic analysis of hyperekplexia in a Chinese child and literature review].

Objective: To investigate the clinical and genetic features of a Chinese child with hyperekplexia and review the related literature. Method: The clinical and genetic data of one patient with hyperekplexia, who had visited the department of Pediatrics, Peking University First Hospital in July 2012, were analyzed. "Hyperekplexia" "startle disease" "GLRB" were used as key words to search at CNKI, Wanfang and PubMed from the database from creation to August 2016. Result: The one-year-old female patient showed exaggerated startle reflexes and generalized stiffness in response to external sudden, unexpected stimuli at 2 hours after birth, which existed every day. Her younger twin sister died of severe apnea due to a continuous generalized stiffness at the age of 7 months. Physical examination exhibited the positive nose-tapping reflex. There were no obvious abnormalities in laboratory tests, electroencephalogram (EEG) and neuroimaging tests. The patient was revealed to have compound heterozygous mutations in GLRB gene, c. 298-1G>A (or IVS4-1G>A) inherited from the father and c. 347T>C (p. L116P) inherited from the mother. The mutation L116P in GLRB gene was not reported before. During the follow-up until 5 years old, the girl's symptoms of startle reflexes and generalized stiffness were controlled with clonazepam treatment. Her mental development was normal, but she walked very carefully as wide-based gait to avoid of external sudden stimuli. Literature retrieval obtained 8 reports (all in English) with 39 GLRB-related cases. Combined analysis of the data of the 39 foreign cases and our case showed that the onset age of all 40 cases was in neonatal or in utero, and all presented exaggerated startle reflexes and generalized stiffness in response to external stimuli. Other symptoms included neonatal apneas (83%, 20/24), falls (56%, 15/27) and squint (42%, 10/24) etc. EEG (13/13) and brain imaging (90%, 28/31) were normal, or unrelated/nonspecific to hyperekplexia. In the total 17 mutations of GLRB gene found in 28 cases, the most frequent mutations were GLRB gene M177R (9 cases) and IVS5+ 5G>A (5 cases). Most cases (82%, 32/39) had received the treatment of clonazepam. The symptoms of hyperekplexia all could be improved in different degree after treatment, and 84% (32/38) of the cases were completely controlled or only existed exaggerated startle reflexes. The psychomotor development could be normal (13 cases) or retarded (25 cases). Conclusion: The patient presented typical clinical manifestations of hyperekplexia and had a good response to clonazepam. The patient carried GLRB gene mutations found by genetic analysis, and was finally diagnosed with hyperekplexia. The younger twin sister died due to lack of timely diagnosis and treatment, suggesting the significance of early detection and proper treatment for this disease.

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.