Abstract
Hyperekplexia is a rare neurological disorder characterized by neonatal hypertonia, exaggerated startle responses to unexpected stimuli and a variable incidence of apnoea, intellectual disability and delays in speech acquisition. The majority of motor defects are successfully treated by clonazepam. Hyperekplexia is caused by hereditary mutations that disrupt the functioning of inhibitory glycinergic synapses in neuromotor pathways of the spinal cord and brainstem. The human glycine receptor α1 and β subunits, which predominate at these synapses, are the major targets of mutations. International genetic screening programs, that together have analysed several hundred probands, have recently generated a clear picture of genotype-phenotype correlations and the prevalence of different categories of hyperekplexia mutations. Focusing largely on this new information, this review seeks to summarise the effects of mutations on glycine receptor structure and function and how these functional alterations lead to hyperekplexia.
Highlights
Hyperekplexia is a rare neurological disorder characterized by neonatal hypertonia, exaggerated startle responses to unexpected stimuli and a variable incidence of apnoea, intellectual disability and delays in speech acquisition
We know that hyperekplexia is a rare neurological disorder characterized by 1) episodic and generalized stiffness after birth which gradually subsides during the first years of life, 2) an increased likelihood of apnoea attacks, delayed speech acquisition and/or intellectual disability, 3) excessive startle reflexes to unexpected stimuli, auditory or tactile, that persist throughout life, and 4) a transient generalized stiffness after startle reflexes that can result in injurious falls [3,4,5,6]
Shiang and colleagues were first to show that hyperekplexia is caused by hereditary mutations in the GLRA1 gene that encodes the α1 subunit of the inhibitory human glycine receptor chloride channel [7]
Summary
Efficacy of glycinergic neurotransmission or even a chronic depolarization that could lead to an increased action potential firing rate. The autosomal dominant mutation Q266H [61] in the TM2 domain reduces glycine sensitivity and single channel open times indicating that it disrupts receptor gating efficacy [88]. HGlyRs containing the truncated subunit exhibited low cell surface expression and reduced glycine sensitivity As this truncation occurs upstream of the naturally occurring premature stop codon in the human GLRA4 gene, it suggests that a review of the presumed pseudogene status of GLRA4 [24,36] and of other classified pLGIC genes may be warranted. The GLRA1 V170S mutation was shown to produce an autosomal dominant form of hyperekplexia [56] When these mutant receptors were recombinantly expressed in a mammalian cell line, V170S was found to have no effect on glycine sensitivity it completely eliminated zinc potentiation [98]. Most of the remaining mutations (P169L, M177R, G229D, △S262, W310C, R450X, Y470C) either reduce cell surface expression of functional heteromeric hGlyRs
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
