Neonatal hyperekplexia with homozygous p.R392H mutation in <i>GLRA1</i>

Hmami, F.; Wood, Sian-Elin; Chaouki, S.; Oulmaati, Abdellah; Hida, M.; Rees, Mark I.; Chung, Seo‐Kyung; Bouharrou, A.

doi:10.1684/epd.2014.0663

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Epileptic Disorders

2014

DOI: 10.1684/epd.2014.0663

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Neonatal hyperekplexia with homozygous p.R392H mutation in GLRA1

F. Hmami

Sian-Elin Wood

S. Chaouki

et al.

Abstract: Hyperekplexia is a rare neurogenetic disorder, frequently misdiagnosed in neonates with a risk of apnoea, asphyxia, and sudden infant death. We present video sequences of a male newborn, admitted on the second day of life to the neonatal intensive care unit, due to tonic-clonic movements. Following clinical and paraclinical investigations, a final diagnosis of hyperekplexia was made. Genetic analysis revealed a homozygous mutation in GLRA1 resulting in a R392H amino acid substitution and altered receptor dynam… Show more

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Cited by 2 publications

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A Missense Mutation A384P Associated with Human Hyperekplexia Reveals a Desensitization Site of Glycine Receptors

Wang

Hernández

et al. 2018

J. Neurosci.

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Hyperekplexia, an inherited neuronal disorder characterized by exaggerated startle responses with unexpected sensory stimuli, is caused by dysfunction of glycinergic inhibitory transmission. From analysis of newly identified human hyperekplexia mutations in the glycine receptor (GlyR) α1 subunit, we found that an alanine-to-proline missense mutation (A384P) resulted in substantially higher desensitization level and lower agonist sensitivity of homomeric α1 GlyRs when expressed in HEK cells. The incorporation of the β subunit fully reversed the reduction in agonist sensitivity and partially reversed the desensitization of α1 The heteromeric α1β GlyRs showed enhanced desensitization but unchanged agonist-induced maximum responses, surface expression, main channel conductance, and voltage dependence compared with that of the wild-type α1β (α1β) GlyRs. Coexpression of the R392H and A384P mutant α1 subunits, which mimic the expression of the compound heterozygous mutation in a hyperekplexia patient, resulted in channel properties similar to those with α1 subunit expression alone. In comparison, another human hyperekplexia mutation α1, which was previously reported to enhance desensitization, caused a strong reduction in maximum currents in addition to the altered desensitization. These results were further confirmed by overexpression of α1 or α1 subunits in cultured neurons isolated from SD rats of either sex. Moreover, the IPSC-like responses of cells expressing α1β induced by repeated glycine pulses showed a stronger frequency-dependent reduction than those expressing α1β. Together, our findings demonstrate that A384 is associated with the desensitization site of the α1 subunit and its proline mutation produced enhanced desensitization of GlyRs, which contributes to the pathogenesis of human hyperekplexia. Human startle disease is caused by impaired synaptic inhibition in the brainstem and spinal cord, which is due to either direct loss of GlyR channel function or reduced number of synaptic GlyRs. Considering that fast decay kinetics of GlyR-mediated inhibitory synaptic responses, the question was raised whether altered desensitization of GlyRs will cause dysfunction of glycine transmission and disease phenotypes. Here, we found that the α1 subunit mutation A384P, identified from startle disease patients, results in enhanced desensitization and leads to rapidly decreasing responses in the mutant GlyRs when they are activated repeatedly by the synaptic-like simulation. These observations suggest that the enhanced desensitization of postsynaptic GlyRs could be the primary pathogenic mechanism of human startle disease.

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A Missense Mutation A384P Associated with Human Hyperekplexia Reveals a Desensitization Site of Glycine Receptors

Wang

Hernández

et al. 2018

J. Neurosci.

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Hyperekplexiа. Clinical observation

et al. 2021

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The differential diagnosis of paroxysmal conditions, as well as disorders of muscle tone (hypertension) in the neonatal period and in young children is quite complicated. Various states of the nervous system in newborns are transient and permanent, optimal and suboptimal, normal and pathological. Among them, we can mention non-epileptic paroxysmal states of early childhood. In some cases, non-epileptic paroxysmal states of early childhood is accompanied by motor disorders, manifested by an excessive increase in limb tone in newborns. This pathological condition of muscle tone in the English-language literature is referred to by the term stiffness baby (the syndrome of a rigid or fettered baby). Neonatal pathological muscle hypertonicity, unlike physiological hypertonicity of muscles of a newborn, is a rather rare condition. The article presents literature data and a description of the clinical observation of a patient with hyperekplexia. Hyperekplexia is a rare paroxysmal movement disorder in young children. The main clinical variants of the disease, methods of diagnosis and correction, the main mutations associated with this condition are considered. The article describes the own clinical observation of an early-age patient with hyperekplexia, its clinical picture, features of paroxysmal states and therapy, neuroimaging data, electroencephalographic phenomena recorded in the patient and genetic testing that confirmed the diagnosis of non-epileptic paroxysmal disorders. The child has a mutation in the ATAD1 gene associated with type 4 Hyperekplexia (618011).

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Neonatal hyperekplexia with homozygous p.R392H mutation in GLRA1

Cited by 2 publications

References 15 publications

A Missense Mutation A384P Associated with Human Hyperekplexia Reveals a Desensitization Site of Glycine Receptors

A Missense Mutation A384P Associated with Human Hyperekplexia Reveals a Desensitization Site of Glycine Receptors

Hyperekplexiа. Clinical observation

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