Hyperekplexia Research Articles

Molecular mechanisms of inherited startle syndromes

Molecular mechanisms of inherited startle syndromes

Does a mutation of the glycine receptor modify GABA metabolism in startle disease?

Does a mutation of the glycine receptor modify GABA metabolism in startle disease?

Mutation of an arginine residue in the human glycine receptor transforms β-alanine and taurine from agonists into competitive antagonists

Agonist binding to the inhibitory glycine receptor (GlyR) initiates the opening of a chloride-selective channel that modulates the neuronal membrane potential. Point mutations of the GlyR, substituting Arg-271 with either Leu or Gln, have been shown to underlie the inherited neurological disorder startle disease (hyperekplexia). We show that these substitutions result in the redistribution of GlyR single-channel conductances to lower conductance levels. Additionally, the binding of the glycinergic agonists beta-alanine and taurine to mutated GlyRs does not initiate a chloride current, but instead competitively antagonizes currents activated by glycine. These findings are consistent with mutations of Arg-271 resulting in the uncoupling of the agonist binding process from the channel activation mechanism of the receptor.

Startle disease mutations reduce the agonist sensitivity of the human inhibitory glycine receptor.

The receptor for the inhibitory neurotransmitter glycine is a member of the ligand-gated ion channel receptor superfamily. Point mutations in the gene encoding the alpha 1 subunit of the glycine receptor-channel complex (GlyR) have recently been identified in pedigrees with the autosomal dominant neurological disorder, startle disease (hyperekplexia). These mutations result in the substitution of leucine or glutamine for arginine 271. This charged residue is located near the ion channel region and is predicted to affect chloride permeation through the GlyR. We found little evidence for this role from the anion/cation selectivity and lack of pronounced rectification of currents flowing through recombinant human alpha 1 subunit GlyRs containing the startle disease mutations. We reveal, however, that the startle disease mutations profoundly disrupt GlyR function by causing 230-410-fold decreases in the sensitivity of receptor currents activated by the agonist glycine. Additionally, we report corresponding 56- and 120-fold reductions in the apparent binding affinity (Ki) of glycine to the mutant GlyRs, but no change in the binding affinity of the competitive antagonist, strychnine. Thus, startle disease reduces the efficacy of glycinergic inhibitory neurotransmission by producing GlyRs with diminished agonist responsiveness. Our results show that startle disease mutations define a novel receptor activation site.

Hyperekplexia Associated With Apnea and Sudden Infant Death Syndrome

Stiff-baby syndrome or hyperekplexia (also known as startle disease) is an unusual familial neurologic disorder that may be associated with fatal apnea or an apparent life-threatening event in infancy. While the neonatal clinical features of increased muscle tone, pathologic startle response, and occasional myoclonic jerks have been reported,¹the association of hyperekplexia with apnea and feeding difficulties has not been emphasized in the pediatric literature. The purpose of this report is to document further the association of sudden infant death syndrome (SIDS) and recurrent apnea of infancy with hyperekplexia, to describe possible common pathogenic mechanisms, and to summarize the response to myorelaxing therapy. In addition, we provide further evidence for assignment of the hyperekplexia gene to chromosome 5q. <b>Patient Report</b>. A white male infant (propositus) was born after an uncomplicated pregnancy and weighed 2683 g at birth. His Apgar score was 7/9 at 1 and 5 minutes. At birth,

Evidence for recessive as well as dominant forms of startle disease (hyperekplexia) caused by mutations in the alpha 1 subunit of the inhibitory glycine receptor.

Startle disease, or hyperekplexia, is characterized by an exaggerated startle reflex and neonatal hypertonia. An autosomal dominant form of the disorder is associated with mutations in the same codon of the alpha 1 subunit of the inhibitory glycine receptor (GLRA 1) resulting in the substitution of an uncharged amino acid for Arg271 in the mature protein. However, recessive transmission is seen in the mouse mutant spasmodic which resembles startle disease phenotypically and is also associated with mutations in Glra 1. We have confirmed the finding of Arg271 mutations in individuals with startle disease in a UK family showing autosomal dominant transmission. In addition we describe an apparently sporadic case, the offspring of a consanguineous mating, who is homozygous for a novel mutation (T1112A) in GLRA 1, which results in the substitution of asparagine for isoleucine at position 244 of the mature protein. This suggests that human startle disease can display recessive as well as dominant inheritance resulting from different mutations in GLRA 1.

A frameshift mutation in the mouse alpha 1 glycine receptor gene (Glra1) results in progressive neurological symptoms and juvenile death.

The neurologic mutant mouse, oscillator, is characterized by a fine motor tremor and muscle spasms that begin at 2 weeks of age and progressively worsen, resulting in death by 3 weeks of age. We report the localization of the oscillator mutation to the central region of mouse Chr 11, and demonstrate its allelism with spasmodic, a recessive viable neurological mutation which displays excessive startle. Oscillator is caused by a microdeletion in the gene coding for the alpha 1 subunit of the adult glycine receptor (Glra1). Glra1 assembles into a pentameric complex with the beta subunit of the glycine receptor (3 alpha (1)2 beta 5) to form a glycine-gated chloride channel. This receptor is the major adult glycine receptor, and the site of action of the poison strychnine. The oscillator deletion causes a frameshift resulting in loss of the highly conserved third cytoplasmic loop and fourth transmembrane domain of the protein. Membranes isolated from oscillator homozygote spinal cords display a 90% reduction in glycine-displaceable strychnine binding. This lack of ligand binding function confirms that oscillator is a complete loss of function allele. The oscillator mutation provides evidence that although at least four different alpha subunits exist for the glycine receptor, none of the other subunits can compensate for the loss of alpha 1 function. Mutations which impair GLRA1 function in humans have been shown to cause dominant familial startle disease. The identification of the oscillator mutation suggests that severe loss of function alleles in humans would result in prenatal or neonatal lethality.

Mutations in the alpha 1 subunit of the inhibitory glycine receptor cause the dominant neurologic disorder, hyperekplexia.

Hereditary hyperekplexia, or familial startle disease (STHE), is an autosomal dominant neurologic disorder characterized by marked muscle rigidity of central nervous system origin and an exaggerated startle response to unexpected acoustic or tactile stimuli. Linkage analyses in several large families provided evidence for locus homogeneity and showed the disease gene was linked to DNA markers on the long arm of chromosome 5. Here we describe the identification of point mutations in the gene encoding the alpha 1 subunit of the glycine receptor (GLRA1) in STHE patients from four different families. All mutations occur in the same base pair of exon 6 and result in the substitution of an uncharged amino acid (leucine or glutamine) for Arg271 in the mature protein.

Inhibition and over-reaction

Familial startle disease is among the oddest of disorders. The demonstration of a mutation in the inhibitory glycine receptor points towards a cause of this and similar perturbations.

Startle disease

Startle disease

Genetic Mapping and Evaluation of Candidate Genes for Spasmodic, a Neurological Mouse Mutation with Abnormal Startle Response

Spasmodic (spd) is a recessive mouse mutation characterized by a prolonged righting reflex, fine motor tremor, leg clasping, and stiffness. Using an intersubspecific backcross that segregates spd, we placed spd on Chr 11 with the following gene order: Adra-1-3.8 ± 2.1 cM-Pad-1-6.3 ± 2.7-(spd, Anx-6, Csfgm, Glr-1, Il-3, Il-4, Il-5, Sparc)-9.1 ± 2.4-D11 Mit5-2.2 ± 1.5-Asgr-1. This localization eliminated the α1-adrenergic receptor (Adra-1) and the α1 and γ2 subunits of the GABAA receptor as candidate genes. Two other promising candidate genes, annexin VI (Anx-6) and a glutamate receptor (Glr-1), were mapped to within 2.1 cM of the spd locus. Although no recombination was observed between spd and Anx-6 or Glr-1, no evidence was obtained for a lesion in either gene. The presence of normal Anx-6 and Glr-1 mRNA transcripts was confirmed by Northern blot analysis, in situ hybridization, and DNA sequence analysis. The localization of Anx-6 and Glr-1 extends the known synteny homology between human chromosome 5q21-q31 and mouse Chr 11 and reveals the probable chromosomal location of the human counterpart to spd. Synteny homology and phenotypic similarities suggest that spasmodic mice may be a genetic model for the inherited human startle disease, hyperekplexia (STHE).

A Physical Map of 15 Loci on Human Chromosome 5q23-q33 by Two-Color Fluorescence in Situ Hybridization

The q23-q33 region of human chromosome 5 encodes a large number of growth factors, growth factor receptors, and hormone/neurotransmitter receptors. This is also the general region into which several disease genes have been mapped, including diastrophic dysplasia, Treacher Collins syndrome, hereditary startle disease, the myeloid disorders that are associated with the 5q-syndrome, autosomal-dominant forms of hereditary deafness, and limb girdle muscular dystrophy. We have developed a framework physical map of this region using cosmid clones isolated from the Los Alamos arrayed chromosome 5-specific library. Entry points into this library included 14 probes to genes within this interval and one anonymous polymorphic marker locus. A physical map has been constructed using fluorescence in situ hybridization of these cosmids on metaphase and interphase chromosomes, and this is in good agreement with the radiation hybrid map of the region. The derived order of loci across the region is cen-IL4-IL5-IRF1-IL3-IL9-EGR1-CD14-FGFA-GRL-D5S207-ADRB2-SPARC-RPS14-CSF1R-ADRA1, and the total distance spanned by these loci is approximately 15 Mb. The framework map, genomic clones, and contig expansion within 5q23-q33 should provide valuable resources for the eventual isolation of the clinically relevant loci that reside in this region.

Hyperekplexia; Response to Clonazepam

Sixteen patients, including 1 neonate, in a large 5 generation family with hyperekplexia (startle disease or congenital stiff-man syndrome) were treated with clonazepam at the University of Texas Health Science Center, San Antonio, TX.

Low cerebrospinal fluid concentration of free gamma-aminobutyric acid in startle disease

The pathophysiology of startle disease (hyperekplexia) is unknown. Hyperactivity of the brainstem reticular formation has been suggested as a cause. We report a newborn infant with classic features of startle disease in whom cerebrospinal fluid (CSF) concentrations of gamma-aminobutyric acid (GABA) were substantially lower than normal during the first weeks of life. She improved greatly on clonazepam treatment. We suggest that the signs of this disorder may be due to a genetic defect or to delayed maturation resulting in low CSF GABA.

Startle disease (hyperekplexia): a hereditary disorder with abnormal startle, falling spells, and attacks of spontaneous clonus

Startle disease (hyperekplexia): a hereditary disorder with abnormal startle, falling spells, and attacks of spontaneous clonus

Exaggerated startle reflexes in an elderly woman

A 76-year-old woman with a 5-year history of excessive startle is reported. Electrophysiological recordings were made of muscle activation after acoustic and proprioceptive stimulation. The findings are discussed in relation to current knowledge of the startle reflex and classification of startle syndromes. It is concluded that this patient is best regarded as having a pathological exaggeration of the normal startle reflex rather than other causes of stimulus-sensitive muscle jerks.

Startle-induced seizures and their relationship to epilepsy: Three case reports

Three cases of startle-induced seizures are presented. Well-established concepts of classification of startle-induced seizures (“reflex epilepsy,” “startle epilepsy,” “startle disease/hyperexplexia”) are reviewed. Difficulty in classifying the presented cases is pointed out. In two patients, seizures could be provoked during video/EEG monitoring. In both cases, there were no epileptiform discharges during the seizures, suggesting startle disease. Nevertheless, one of the patients had a history of generalized tonic-clonic seizures; in the other, generalized seizures developed after slow withdrawal of medication, indicating startle epilepsy. The third patient, by history, had reflex epilepsy. Unfortunately, provocation of seizures under controlled conditions was not possible, rendering further classification of seizures into subtypes impossible.

Startle disease or hyperekplexia: Adolescent onset and response to valproate

We report a boy with rigidity and hyperekplexia or startle disease which began in adolescence. His symptoms completely resolved with valproic acid therapy. Two relatives have the minor form of this disorder, suggesting autosomal dominant inheritance with variable penetrance.

A Case of Startle Disease with Atypical Clinical Features

A Case of Startle Disease with Atypical Clinical Features

Audiogenic startle reflex of man and its relationship to startle syndromes. A review.

The normal human audiogenic startle reflex is defined from a review of the literature, substantiated by a current investigation of normal subjects, and clarified pathophysiologically by a discussion of animal experimentation. The basic information is used to evaluate critically a variety of syndromes loosely termed 'startle' in the past. A new classification of startle syndromes is proposed.