Advances in hyperekplexia and other startle syndromes

Zhan, Feixia; Wang, Shi-Ge; Cao, Li

doi:10.1007/s10072-021-05493-8

Cited by 13 publications

(18 citation statements)

References 79 publications

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“…Human hyperekplexia is characterized by generalized hypertonia and an exaggerated startle response that often can be induced by external stimuli (auditory, visual and tactile) starting early after birth (Zhan et al 2021). However, there is some phenotypic variation of hyperekplexia, most likely caused by the large variety of genetic defects involving ve genes related to the glycinergic neurotransmission system (Harvey et al 2008; Bode and Lynch 2014; Zhan et al 2021). Therefore, humans might only experience mild clinical signs with sporadic hypertonic jerks or may suffer from more severe clinical phenotypes with permanent generalized stiffness.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, clinical symptoms were rapidly progressive without responding to any of the medication given, including clonazepam, resulting in an inability to ambulate within a few weeks. However, it is di cult to compare clinical signs of one single variant in the canine family presented here with the wide spectrum of phenotypical expressions in humans, considering the large variety of genetic defects involving ve different genes related to the glycinergic neurotransmission system in humans (Harvey et al 2008; Bode and Lynch 2014; Zhan et al 2021). The canine GLRA1 variant described in this study is predicted to result in a loss of protein function and, consequently, likely to have a severe outcome.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, there are common features of hyperekplexia in humans and in the dogs described here, although there are also differences. Human hyperekplexia is characterized by generalized hypertonia and an exaggerated startle response that often can be induced by external stimuli (auditory, visual and tactile) starting early after birth (Zhan et al 2021). However, there is some phenotypic variation of hyperekplexia, most likely caused by the large variety of genetic defects involving ve genes related to the glycinergic neurotransmission system (Harvey et al 2008; Bode and Lynch 2014; Zhan et al 2021).…”

Section: Discussionmentioning

confidence: 99%

“…The isolated hereditary hyperekplexia is caused by defective inhibitory glycinergic neurotransmission and has been associated with genes encoding glycine receptor (GlyR) subunits alpha and beta (GLRA1, GLRB) and solute carrier family 6 member 5 (SLC6A5), of which the variants in glycine receptor alpha 1 (GLRA1) constitute the vast majority (80%) of cases. Nearly 80 variants have been described in GLRA1 so far, causing the disease either through dominant or recessive inheritance (Zhan et al 2021).…”

Section: Introductionmentioning

confidence: 99%

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A loss-of-function variant in canine GLRA1 associates with a neurological disorder resembling human hyperekplexia

Heinonen

Flegel

Müller³

et al. 2023

Preprint

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Hereditary hyperekplexia is a rare neuronal disorder characterized by an exaggerated startle response to sudden tactile or acoustic stimuli. In this study, we present a Miniature Australian Shepherd family showing clinical signs which have genetic and phenotypic similarities with human hereditary hyperekplexia: episodes of muscle stiffness that could occasionally be triggered by acoustic stimuli. Whole genome sequence data analysis of two affected dogs revealed a 36-bp deletion spanning the exon-intron boundary in the glycine receptor alpha 1 (GLRA1) gene. Further validation in pedigree samples and an additional cohort of 45 Miniature American Shepherds and 74 Australian Shepherds demonstrated complete segregation of the variant with the disease, according to an autosomal recessive inheritance pattern. The protein encoded by GLRA1 is a subunit of the glycine receptor, which mediates postsynaptic inhibition in the brain stem and spinal cord. The canine GLRA1 deletion is located in the signal peptide and is predicted to cause exon skipping and subsequent premature stop codon resulting in a significant defect in glycine signaling. Variants in GLRA1 are known to cause hereditary hyperekplexia in humans; however, this is the first study to associate a variant in canine GLRA1 with the disorder, establishing a spontaneous large animal disease model for the human condition.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A loss-of-function variant in canine GLRA1 associates with a neurological disorder resembling human hyperekplexia

Heinonen

Flegel

Müller³

et al. 2023

Preprint

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“…These events are misdiagnosed as seizures and treated with anti-seizure medications [4]. It is caused by mutations in different genes such as GLRA1, SLC6A5, GLRB, GPHN, and ARHGEF9 [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Hyperekplexia: A Treatable Seizure Mimicker in Infants

Dudipala¹,

Reddy²,

Shankar³

2023

Cureus

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Hyperekplexia (HK) or startle disease is an uncommon, early infantile onset, potentially treatable neurogenetic disorder. It is characterized by an exaggerated startle reflex in response to tactile or acoustic or visual stimuli followed by generalized hypertonia. It is caused by genetic mutations in a number of different genes such as GLRA1, SLC6A5, GLRB, GPHN, and ARHGEF9. HK is frequently misdiagnosed as a form of epilepsy and is advised for prolonged antiseizure medications. Here, we report a two-month-old female child with HK, who was treated for epilepsy. Next-generation sequencing revealed a pathogenic homozygous missense mutation of variant c.1259C>A in exon 9 of the GLRA1 gene that was compatible with the diagnosis of hyperekplexia-1.

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A loss-of-function variant in canine GLRA1 associates with a neurological disorder resembling human hyperekplexia

Heinonen

Flegel

Müller³

et al. 2023

Hum. Genet.

View full text Add to dashboard Cite

Hereditary hyperekplexia is a rare neuronal disorder characterized by an exaggerated startle response to sudden tactile or acoustic stimuli. In this study, we present a Miniature Australian Shepherd family showing clinical signs, which have genetic and phenotypic similarities with human hereditary hyperekplexia: episodes of muscle stiffness that could occasionally be triggered by acoustic stimuli. Whole genome sequence data analysis of two affected dogs revealed a 36-bp deletion spanning the exon–intron boundary in the glycine receptor alpha 1 (GLRA1) gene. Further validation in pedigree samples and an additional cohort of 127 Miniature Australian Shepherds, 45 Miniature American Shepherds and 74 Australian Shepherds demonstrated complete segregation of the variant with the disease, according to an autosomal recessive inheritance pattern. The protein encoded by GLRA1 is a subunit of the glycine receptor, which mediates postsynaptic inhibition in the brain stem and spinal cord. The canine GLRA1 deletion is located in the signal peptide and is predicted to cause exon skipping and subsequent premature stop codon resulting in a significant defect in glycine signaling. Variants in GLRA1 are known to cause hereditary hyperekplexia in humans; however, this is the first study to associate a variant in canine GLRA1 with the disorder, establishing a spontaneous large animal disease model for the human condition.

show abstract

Advances in hyperekplexia and other startle syndromes

Cited by 13 publications

References 79 publications

A loss-of-function variant in canine GLRA1 associates with a neurological disorder resembling human hyperekplexia

A loss-of-function variant in canine GLRA1 associates with a neurological disorder resembling human hyperekplexia

Hyperekplexia: A Treatable Seizure Mimicker in Infants

A loss-of-function variant in canine GLRA1 associates with a neurological disorder resembling human hyperekplexia

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