Short communication Weird Laughing in Hyperekplexia: A new phenotype associated with a novel mutation in the GLRA1 gene? Zhi Huang, Yajun Lian*, Hongliang Xu, Haifeng Zhang Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, 450052, People's Republic of China A R T I C L E I N F O Article history: Received 11 November 2017 Received in revised form 17 February 2018 Accepted 16 March 2018 Keywords: Hyperekplexia GLRA1 Weird laughing Epilepsy A B S T R A C T Hyperekplexia (HPX) or startle disease is a rare hereditary neurological disorder characterized by generalizedstiffness,excessive startle reflex to unexpected stimuli anda 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. © 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. 1. Introduction 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. The pathogenesis involves glycinergic neurotransmission disorders, associates with the gene mutations of GLRA1 , GLRB, GPHN, ARHGEF9 and SLC6A5, and has a good response to clonazepam. The clinical manifestations are complex and varied [1], but the symptom of weird laughing hasn’t been reported. We describe an 11-year-old girl with excessive startle reflex, weird laughing, epilepsy and a novel heterozygous variant in GLRA1 . The weird laughing, mostly triggered by unexpected stimuli, was controlled with clonazepam. 2. Case study The patient was an 11-year-old girl born of non-consanguineous parents, who presented with epileptic seizures and weird laughing. She was delivered vaginally at term, without anoxia suffocation. She appeared to be timid, with excessive startle reactions to unexpected stimuli in early infancy. The umbilical hernia occurred two months after birth. Since four months of age, she exhibited intermittent weird laughing without loss of consciousness, snicker, and discontinuous breath holding, which was mostly triggered by unexpected stimuli, occurring several times a week and lasting approximately one minute. At nine months old, she suffered from intermittent nodding with the arms flung out and the body bent forward, lasting a second but occurred close together in a series, about 10 times per day. The electroencephalogram (EEG) examination showed hypsarrhytmia (Fig. 1A). She was diagnosed with infantile spasms, and treated with prednisone and topiramate for three years. The infantile spasms did not occur after withdrawing antiepileptic drugs, but the intermittent weird laughing continued. Generalized tonic- clonic seizures started by the age of 10 with a frequency of six to seven times per day. Epilepsy was considered and topiramate was used (100 mg/d). However, there was no improvement. Finally, 300 mg oxcarbazepine and 750 mg levetiracetam daily were added to treatment, and she became seizure-free. The weird laughing was still present during antiepileptic drug treatment, occurring at a frequency of five to six times a day. The laughing was triggered by unexpected stimuli, especially an audio stimulus, or when she was blamed, and felt a sense of shame. In response, she usually covered her mouth or hid in an effort to avoid being ridiculed. Brain Abbreviations: EEG, electroencephalogram; MRI, magnetic resonance imaging. * Corresponding author at: Department of Neurology, The First Affiliated Hospital of Zhengzhou University, 1 Jian she East Road, Zhengzhou, Henan Province, 450052, People's Republic of China. E-mail address: [email protected] (Y. Lian). https://doi.org/10.1016/j.seizure.2018.03.017 1059-1311/© 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. Seizure 58 (2018) 6–8 Contents lists available at ScienceDirect Seizure journal homepage: www.else vie r.com/locat e/y seiz
Weird Laughing in Hyperekplexia: A new phenotype associated with a novel mutation in the GLRA1 gene?
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Weird Laughing in Hyperekplexia: A new phenotype associated with a novel mutation in the GLRA1 gene?Short communication
Weird Laughing in Hyperekplexia: A new phenotype associated with a novel mutation in the GLRA1 gene?
Zhi Huang, Yajun Lian*, Hongliang Xu, Haifeng Zhang Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, 450052, People's Republic of China
A R T I C L E I N F O
Article history: Received 11 November 2017 Received in revised form 17 February 2018 Accepted 16 March 2018
Keywords: Hyperekplexia GLRA1 Weird laughing Epilepsy
A B S T R A C T
Hyperekplexia (HPX) or startle disease is a rare hereditary neurological disorder characterized by generalizedstiffness,excessive startlereflex tounexpectedstimulianda shortperiod ofgeneralizedstiffness 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.
© 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Contents lists available at ScienceDirect
Seizure
1. Introduction
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. The pathogenesis involves glycinergic neurotransmission disorders, associates with the gene mutations of GLRA1, GLRB, GPHN, ARHGEF9 and SLC6A5, and has a good response to clonazepam. The clinical manifestations are complex and varied [1], but the symptom of weird laughing hasn’t been reported. We describe an 11-year-old girl with excessive startle reflex, weird laughing, epilepsy and a novel heterozygous variant in GLRA1. The weird laughing, mostly triggered by unexpected stimuli, was controlled with clonazepam.
2. Case study
The patient was an 11-year-old girl born of non-consanguineous parents, who presented with epileptic seizures and weird
Abbreviations: EEG, electroencephalogram; MRI, magnetic resonance imaging. * Corresponding author at: Department of Neurology, The First Affiliated Hospital
of Zhengzhou University, 1 Jianshe East Road, Zhengzhou, Henan Province, 450052, People's Republic of China.
E-mail address: [email protected] (Y. Lian).
https://doi.org/10.1016/j.seizure.2018.03.017 1059-1311/© 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights res
laughing. She was delivered vaginally at term, without anoxia suffocation. She appeared to be timid, with excessive startle reactions to unexpected stimuli in early infancy. The umbilical hernia occurred two months after birth. Since four months of age, she exhibited intermittent weird laughing without loss of consciousness, snicker, and discontinuous breath holding, which was mostly triggered by unexpected stimuli, occurring several times a week and lasting approximately one minute. At nine months old, she suffered from intermittent nodding with the arms flung out and the body bent forward, lasting a second but occurred close together in a series, about 10 times per day. The electroencephalogram (EEG) examination showed hypsarrhytmia (Fig. 1A). She was diagnosed with infantile spasms, and treated with prednisone and topiramate for three years. The infantile spasms did not occur after withdrawing antiepileptic drugs, but the intermittent weird laughing continued. Generalized tonic- clonic seizures started by the age of 10 with a frequency of six to seven times per day. Epilepsy was considered and topiramate was used (100 mg/d). However, there was no improvement. Finally, 300 mg oxcarbazepine and 750 mg levetiracetam daily were added to treatment, and she became seizure-free. The weird laughing was still present during antiepileptic drug treatment, occurring at a frequency of five to six times a day. The laughing was triggered by unexpected stimuli, especially an audio stimulus, or when she was blamed, and felt a sense of shame. In response, she usually covered her mouth or hid in an effort to avoid being ridiculed. Brain
erved.
Z. Huang et al. / Seizure 58 (2018) 6–8 7
magnetic resonance imaging (MRI) was normal (Fig. 2C), and the weird laughing was not accompanied by ictal activity on the EEG (Fig. 1B).
She started talking by one year of age and could walk by two and a half years old, which indicated she had delayed in gross motor. Although she ultimately caught up on her delayed motor skills, she still had difficulties in studies. She went to a special school, and could only calculate the addition and subtraction within 10 by this time. Her mother also appeared to be timid, afraid of sudden sound stimulation, with excessive startle reactions during early infancy. Her mother had no developmental delay and the startled reflex gradually subsided after 10 years old.
Gene analysis revealed a novel heterozygous missense variant c.1286T > A (p.I429N) in the GLRA1 gene, which had not been previously reported and was absent from the 1000GP, GO-ESP, and ExAC databases. The mutation was predicted to be possibly damaging by PolyPhen-2, disease causing by Mutation Taster and deleterious by PROVEN. No mutations were found in GLRB, SLC6A5, GPHN and ARHGEF9 gene. This variant was further confirmed by Sanger sequencing and detected in her mother (Fig. 2B).
According to the clinical manifestations and genetic test, the girl was diagnosed with HPX. Clonazepam (2 mg/d) was added to current treatment. A dramatic improvement in the frequency of
laughing episodes was observed. The frequency of laughing decreased to less than four to five times in the first week and decreased to three to four times per month in the following three months.
3. Discussion
Hyperekplexia could be split up into two clinical forms: the major and the minor form. The major form had three typical clinical features: generalized stiffness after birth; excessive startle reflex to an unexpected stimulus and generalized stiffness after a startle reflex, while the minor form was only characterized by excessive startle [2]. The GLRA1 mutations could be detected in both two clinical forms, between which there was no genotype- phenotype correlation [3].
The clinical manifestations were varied, including apnea spell, developmental delay, umbilical hernia, inguinal hernia, hip dislocation, cautious gait, and club foot [1]. The developmental delay and learning difficulties were consistent with previous reports. Previous studies showed that individuals carrying the same mutation in a family can have different symptoms. Variations in phenotype between the proband and her mother were most likely caused by the differences in genetic penetrance of the
Fig. 2. A: the Pedigree chart. Arrow: proband; square: male; circle: female, solid symbol: affected; B: Sanger sequencing of the family members, red circle: mutation site; C: the proband's MRI was normal. Median sagittal section (left), transverse section (right). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
8 Z. Huang et al. / Seizure 58 (2018) 6–8
GLRA1I429N allele. As triggered by unexpected stimuli, weird laughing was potentially caused by throat and facial muscles spasms or contractions.
Having similar manifestations to epilepsy, HPX was usually misdiagnosed as epileptic seizures. There has been reported more than 200 patients suffering from HPX caused by the mutation of CLRA1, and three of those patients were accompanied by epileptic seizures as follows: generalized tonic-clonic epileptic seizures, epileptic seizures at night, and infantile spasms [4]. The mutations were EX1-7del, c.921delT and c.801G > C, leading to truncation of the protein or loss of extracellular domain. But none of the others in the four pedigrees had epileptic seizures, which indicate it may be just a coincidence.
In conclusion, this is the first report of weird laughing in a hyperekplexia patient carrying a novel GLRA1 mutation, which has a good response to clonazepam and expanded the phenotype spectrum of Hyperekplexia.
Funding
This work was supported by the National Natural Science Foundation of China [Grant No. 81371438].
Conflict of interest
Acknowledgements
I would like to express my gratitude to the patient and her parents, especially for their thoughtful cooperation. This has been a truly collaborative work that would never have been possible without the ongoing support of the talented and dedicated team members.
References
[1] Lee Y., Kim NY, Hong S, Chung SJ, Jeong SH, Lee PH, et al. Familiar hyperekplexia, a potential cause of cautious gait: a new Korean case and a systematic review of phenotypes. J Mov Disord 2017;10:53–8.
[2] Tijssen MA, Vergouwe MN, van Dijk JG, Rees M, Frants RR, Brown P. Major and minor form of hereditary hyperekplexia. Mov Disord 2002;17:826–30.
[3] Bakker MJ, van Dijk JG, van den Maagdenberg AM, Tijssen MA. Startle syndromes. Lancet Neurol 2006;5:513–24.
[4] Gilbert SL, Ozdag F, Ulas UH, Dobyns WB, Lahn BT. Hereditary hyperekplexia caused by novel mutations of GLRA1 in Turkish families. Mol Diagn 2004;8:151– 5.
1 Introduction
Weird Laughing in Hyperekplexia: A new phenotype associated with a novel mutation in the GLRA1 gene?
Zhi Huang, Yajun Lian*, Hongliang Xu, Haifeng Zhang Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, 450052, People's Republic of China
A R T I C L E I N F O
Article history: Received 11 November 2017 Received in revised form 17 February 2018 Accepted 16 March 2018
Keywords: Hyperekplexia GLRA1 Weird laughing Epilepsy
A B S T R A C T
Hyperekplexia (HPX) or startle disease is a rare hereditary neurological disorder characterized by generalizedstiffness,excessive startlereflex tounexpectedstimulianda shortperiod ofgeneralizedstiffness 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.
© 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Contents lists available at ScienceDirect
Seizure
1. Introduction
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. The pathogenesis involves glycinergic neurotransmission disorders, associates with the gene mutations of GLRA1, GLRB, GPHN, ARHGEF9 and SLC6A5, and has a good response to clonazepam. The clinical manifestations are complex and varied [1], but the symptom of weird laughing hasn’t been reported. We describe an 11-year-old girl with excessive startle reflex, weird laughing, epilepsy and a novel heterozygous variant in GLRA1. The weird laughing, mostly triggered by unexpected stimuli, was controlled with clonazepam.
2. Case study
The patient was an 11-year-old girl born of non-consanguineous parents, who presented with epileptic seizures and weird
Abbreviations: EEG, electroencephalogram; MRI, magnetic resonance imaging. * Corresponding author at: Department of Neurology, The First Affiliated Hospital
of Zhengzhou University, 1 Jianshe East Road, Zhengzhou, Henan Province, 450052, People's Republic of China.
E-mail address: [email protected] (Y. Lian).
https://doi.org/10.1016/j.seizure.2018.03.017 1059-1311/© 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights res
laughing. She was delivered vaginally at term, without anoxia suffocation. She appeared to be timid, with excessive startle reactions to unexpected stimuli in early infancy. The umbilical hernia occurred two months after birth. Since four months of age, she exhibited intermittent weird laughing without loss of consciousness, snicker, and discontinuous breath holding, which was mostly triggered by unexpected stimuli, occurring several times a week and lasting approximately one minute. At nine months old, she suffered from intermittent nodding with the arms flung out and the body bent forward, lasting a second but occurred close together in a series, about 10 times per day. The electroencephalogram (EEG) examination showed hypsarrhytmia (Fig. 1A). She was diagnosed with infantile spasms, and treated with prednisone and topiramate for three years. The infantile spasms did not occur after withdrawing antiepileptic drugs, but the intermittent weird laughing continued. Generalized tonic- clonic seizures started by the age of 10 with a frequency of six to seven times per day. Epilepsy was considered and topiramate was used (100 mg/d). However, there was no improvement. Finally, 300 mg oxcarbazepine and 750 mg levetiracetam daily were added to treatment, and she became seizure-free. The weird laughing was still present during antiepileptic drug treatment, occurring at a frequency of five to six times a day. The laughing was triggered by unexpected stimuli, especially an audio stimulus, or when she was blamed, and felt a sense of shame. In response, she usually covered her mouth or hid in an effort to avoid being ridiculed. Brain
erved.
Z. Huang et al. / Seizure 58 (2018) 6–8 7
magnetic resonance imaging (MRI) was normal (Fig. 2C), and the weird laughing was not accompanied by ictal activity on the EEG (Fig. 1B).
She started talking by one year of age and could walk by two and a half years old, which indicated she had delayed in gross motor. Although she ultimately caught up on her delayed motor skills, she still had difficulties in studies. She went to a special school, and could only calculate the addition and subtraction within 10 by this time. Her mother also appeared to be timid, afraid of sudden sound stimulation, with excessive startle reactions during early infancy. Her mother had no developmental delay and the startled reflex gradually subsided after 10 years old.
Gene analysis revealed a novel heterozygous missense variant c.1286T > A (p.I429N) in the GLRA1 gene, which had not been previously reported and was absent from the 1000GP, GO-ESP, and ExAC databases. The mutation was predicted to be possibly damaging by PolyPhen-2, disease causing by Mutation Taster and deleterious by PROVEN. No mutations were found in GLRB, SLC6A5, GPHN and ARHGEF9 gene. This variant was further confirmed by Sanger sequencing and detected in her mother (Fig. 2B).
According to the clinical manifestations and genetic test, the girl was diagnosed with HPX. Clonazepam (2 mg/d) was added to current treatment. A dramatic improvement in the frequency of
laughing episodes was observed. The frequency of laughing decreased to less than four to five times in the first week and decreased to three to four times per month in the following three months.
3. Discussion
Hyperekplexia could be split up into two clinical forms: the major and the minor form. The major form had three typical clinical features: generalized stiffness after birth; excessive startle reflex to an unexpected stimulus and generalized stiffness after a startle reflex, while the minor form was only characterized by excessive startle [2]. The GLRA1 mutations could be detected in both two clinical forms, between which there was no genotype- phenotype correlation [3].
The clinical manifestations were varied, including apnea spell, developmental delay, umbilical hernia, inguinal hernia, hip dislocation, cautious gait, and club foot [1]. The developmental delay and learning difficulties were consistent with previous reports. Previous studies showed that individuals carrying the same mutation in a family can have different symptoms. Variations in phenotype between the proband and her mother were most likely caused by the differences in genetic penetrance of the
Fig. 2. A: the Pedigree chart. Arrow: proband; square: male; circle: female, solid symbol: affected; B: Sanger sequencing of the family members, red circle: mutation site; C: the proband's MRI was normal. Median sagittal section (left), transverse section (right). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
8 Z. Huang et al. / Seizure 58 (2018) 6–8
GLRA1I429N allele. As triggered by unexpected stimuli, weird laughing was potentially caused by throat and facial muscles spasms or contractions.
Having similar manifestations to epilepsy, HPX was usually misdiagnosed as epileptic seizures. There has been reported more than 200 patients suffering from HPX caused by the mutation of CLRA1, and three of those patients were accompanied by epileptic seizures as follows: generalized tonic-clonic epileptic seizures, epileptic seizures at night, and infantile spasms [4]. The mutations were EX1-7del, c.921delT and c.801G > C, leading to truncation of the protein or loss of extracellular domain. But none of the others in the four pedigrees had epileptic seizures, which indicate it may be just a coincidence.
In conclusion, this is the first report of weird laughing in a hyperekplexia patient carrying a novel GLRA1 mutation, which has a good response to clonazepam and expanded the phenotype spectrum of Hyperekplexia.
Funding
This work was supported by the National Natural Science Foundation of China [Grant No. 81371438].
Conflict of interest
Acknowledgements
I would like to express my gratitude to the patient and her parents, especially for their thoughtful cooperation. This has been a truly collaborative work that would never have been possible without the ongoing support of the talented and dedicated team members.
References
[1] Lee Y., Kim NY, Hong S, Chung SJ, Jeong SH, Lee PH, et al. Familiar hyperekplexia, a potential cause of cautious gait: a new Korean case and a systematic review of phenotypes. J Mov Disord 2017;10:53–8.
[2] Tijssen MA, Vergouwe MN, van Dijk JG, Rees M, Frants RR, Brown P. Major and minor form of hereditary hyperekplexia. Mov Disord 2002;17:826–30.
[3] Bakker MJ, van Dijk JG, van den Maagdenberg AM, Tijssen MA. Startle syndromes. Lancet Neurol 2006;5:513–24.
[4] Gilbert SL, Ozdag F, Ulas UH, Dobyns WB, Lahn BT. Hereditary hyperekplexia caused by novel mutations of GLRA1 in Turkish families. Mol Diagn 2004;8:151– 5.
1 Introduction
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