{{Short description|Genetic disorder causing an exaggerated startle response}} {{cs1 config|name-list-style=vanc}} {{Infobox medical condition | name = Hyperekplexia | synonyms = Exaggerated surprise, exaggerated startle response, startle disease<ref>{{cite book |last1=Beers |first1=Mark H. MD |title=The Merck Manual |date=2006 |publisher=Merck Research Laboratories |location=Whitehouse Station, NJ |isbn=0911910-18-2 |page=1764 |edition= 16th }}</ref> | image = PDB 1mot EBI.jpg | caption = Mutations of the neuroreceptor glycine receptor subunit alpha-1 (GLRA1) can cause hyperekplexia. | pronounce = /ˌhaɪ.pɚ.ɛkˈplɛk.si.ə/ | field = Neurology | meshName = | meshNumber = | symptoms = Increased startle response to sudden auditory, visual, or tactile stimulation | complications = Increased alcohol and drug use | onset = | duration = Chronic | types = | causes = Mutation of either the ''GLRA1'' gene, ''GLRB'' gene, ''SLC6A5'' gene, X-linked (''ARHGEF9'') gene, or ''GPHN'' gene<ref name="PainAssist">{{cite web |last1=Kerkar |first1=Pramod, M.D., FFARCSI, DA |title=Exaggerated Startle Response: Causes, Symptoms, Treatment, Recovery, Yoga |url=https://www.epainassist.com/genetic-disorders/exaggerated-startle-response |website=PainAssist |date=22 December 2015 |access-date=19 May 2020}}</ref> | risks = | diagnosis = | prevention = | treatment = | medication = Clonazepam, diazepam, or phenobarbital; carbamazepine; 5-hydroxytryptophan; phenytoin; valproate; piracetam<ref name="PainAssist">{{cite web |last1=Kerkar |first1=Pramod, M.D., FFARCSI, DA |title=Exaggerated Startle Response: Causes, Symptoms, Treatment, Recovery, Yoga |url=https://www.epainassist.com/genetic-disorders/exaggerated-startle-response |website=PainAssist |date=22 December 2015 |access-date=19 May 2020}}</ref> | prognosis = | frequency = 1 in 40,000<ref name="PainAssist"/> | deaths = }}
'''Hyperekplexia''' ({{IPAc-en|ˌ|h|aɪ|.|p|ər|.|ɛ|k|ˈ|p|l|ɛ|k|.|s|i|.|ə}}; "exaggerated surprise") is a neurological disorder characterized by a pronounced startle response to tactile or acoustic stimuli and an ensuing period of hypertonia. The hypertonia may be predominantly truncal, attenuated during sleep, or less prominent after one year of age.
Classic hyperekplexia is caused by genetic mutations in a number of different genes, all of which play an important role in glycine neurotransmission. Glycine is used by the central nervous system as an inhibitory neurotransmitter. Hyperekplexia is generally classified as a genetic disease;<ref name="Startle Review">{{cite journal|title=Startle Syndromes|journal=Lancet Neurology|date=2006-05-19|vauthors=Bakker MJ, van Dijk JG, van den Maagdenberg AM, Tijssen MA|pmid=16713923|volume=5|issue=6|pages=513–524|doi= 10.1016/S1474-4422(06)70470-7|s2cid=24056686}}</ref> some disorders can mimic the exaggerated startle of hyperekplexia.<ref name="Non-Genetic HEP 1">{{cite journal|title=Persisting Hyperekplexia After Idiopathic, Self-Limiting Brainstem Encephalopathy|journal=Movement Disorders|date=2007-04-05|first=B. P. C.|last=van de Warrenburg|author2=C. Cordivari |author3=P. Brown |author4=K. P. Bhatia |pmid=17415799|volume=22|issue=7|pages=1017–20|doi= 10.1002/mds.21411|s2cid=30137238 |doi-access=free}}</ref>
==Signs and symptoms== The three main signs of hyperekplexia are generalized stiffness, excessive startle response beginning at birth, and nocturnal myoclonus.<ref name="HEP in the Neonate">{{cite journal|last=Koning-Tijssen|first=M.A.J.|author2=O.F. Brouwer|date=2000-04-27|title=Hyperekplexia in the Neonate|journal=Movement Disorders|volume=15|issue=6|pages=1293–6|doi=10.1002/1531-8257(200011)15:6<1293::aid-mds1047>3.0.co;2-k|pmid=11104232|s2cid=29366280 }}<!--|access-date=2009-11-30 --></ref> Affected individuals are fully conscious during episodes of stiffness, which consist of forced closure of the eyes and an extension of the extremities followed by a period of generalised stiffness and uncontrolled falling at times.<ref name='Dutch Family Molecular Genetics'>{{cite journal|title=Molecular Genetic Reevaluation of the Dutch Hyperekplexia Family|journal=Archives of Neurology|date=1995-06-01|first=M.A.J.|last=Tijssen|author2=R. Shiang |author3=J. van Deutekom |author4=R. H. Boerman |author5=J. Wasmuth |author6=L. A. Sandkuijl |author7=R. R. Frants |author8=G. W. Padberg |pmid=7763205|volume=52|issue=6|pages=578–582|doi=10.1001/archneur.1995.00540300052012|hdl=2066/20657|s2cid=14067463 |url=https://repository.ubn.ru.nl/bitstream/2066/20657/1/20657___.PDF|hdl-access=free}}</ref> Initially, the disease was classified into a "major" and a "minor" form, with the minor form being characterized by an excessive startle reflex, but lacking stiffness.<ref name='Dutch Family Molecular Genetics' /> Genetic evidence has only been found for the major form of the condition.<ref name='Dutch Family Molecular Genetics' />
Other signs and symptoms of hyperekplexia may include episodic neonatal apnea, excessive movement during sleep and the head-retraction reflex. The link to some cases of sudden infant death remains controversial.<ref name='Startle Review' />
==Genetics== Hyperekplexia is known to be caused by a variety of genes, encoding both pre- and postsynaptic proteins. The symptoms displayed, as well as the types of inheritance, vary, based on the affected gene, as discussed in detail below.
===GLRA1=== The first gene linked conclusively to hyperekplexia was GLRA1.<ref name='Dutch Family Molecular Genetics' /> The GLRA1 gene encodes the glycine receptor, alpha 1 subunit, which, together with the glycine receptor beta subunit, forms synaptic glycine receptors. Inhibitory glycine receptors are ligand-gated chloride channels that facilitate fast responses in the brainstem and spinal-cord. Homomeric glycine receptors composed exclusively of alpha-1 subunits exhibit normal ion channel electrophysiology, but are not sequestered at the synaptic junction.<ref name='Glycine Receptor Review'>{{cite journal|title=Native glycine receptor subtypes and their physiological roles|journal=Neuropharmacology|date=2008-08-03|first=J. W.|last=Lynch|pmid=18721822|volume=56|issue=1|pages=303–9|doi= 10.1016/j.neuropharm.2008.07.034|s2cid=43613876|url=https://zenodo.org/record/895467}}</ref> Wild-type glycine receptors are thus presumed to be pentameric heteromers of the alpha-1 and beta subunits, in either a 3:2 or 2:3 ratio.<ref name='Glycine Receptor Review' />
Within these heteromers, it is believed that the alpha-1 subunits bind glycine and undergo a conformational change, inducing a conformational change in the pentamer, causing the ion-channel to open. Although autosomal dominant<ref name='Dutch Family Molecular Genetics' /> inheritance was initially reported, there are at least as many cases described with autosomal recessive inheritance.<ref name='Recessive GLRA1 Mutations'>{{cite journal|title=Recessive hyperekplexia mutations of the glycine receptor [alpha]-1 subunit affect cell surface integration and stability|journal=Journal of Neurochemistry|year=2009|vauthors=Villmann C, Oertel J, Melzer N, Becker CM|pmid=19732286|volume=111|issue=3|pages=837–847|doi= 10.1111/j.1471-4159.2009.06372.x|doi-access=|s2cid=35256060 }}</ref> Thus far, the general rule is that mutations causing structurally normal proteins that cannot bind glycine or cannot properly undergo a required conformational change in response to glycine will result in a dominant form of the disease, while mutations that result in truncated or greatly malformed subunits that cannot be integrated into a receptor protein will result in a recessive form.<ref name='Recessive GLRA1 Mutations' />
===GLRB=== The GLRB gene encodes the beta subunit of the glycine receptor. Homomeric glycine receptors composed of beta subunits do not open in response to glycine stimulation,<ref name='GLRB'>{{cite journal|title=Residues within transmembrane segment M2 determine chloride conductance of glycine receptor homo- and hetero-oligomers|journal=EMBO Journal|year=1993|first=J.|last=Bormann|author2=N. Rundstrom |author3=H. Betz |author4=D. Langosch |volume=12|issue=10|pages=3729–37|pmc=413654 |pmid=8404844|doi=10.1002/j.1460-2075.1993.tb06050.x}}</ref> however, the beta subunit is essential for proper receptor localization, through its interactions with gephyrin, which results in receptor clustering at the synaptic cleft.<ref name='GLRB2'>{{cite journal|doi=10.1016/0896-6273(95)90145-0|title=Identification of a Gephyrin Binding Motif on the Glycine Receptor Beta Subunit|journal=Neuron|year=1995|first=G.|last=Meyer|author2=J. Kirsch |author3=H. Betz |author4=D. Langosch |volume=15|issue=3|pages=563–572|pmid=7546736 |s2cid=10164739|doi-access=free}}</ref> As such, the defects within the GLRB gene show autosomal recessive inheritance.<ref name='GLRB3'>{{cite journal|doi=10.1093/hmg/11.7.853|title=Hyperekplexia associated with compound heterozygote mutations in the beta-subunit of the human inhibitory glycine receptor (GLRB)|journal=Human Molecular Genetics|date=2002-04-01|first=M. I.|last=Rees|author2=T. M. Lewis |author3=J. B. Kwok |author4=G. R. Mortier |author5=P. Govaert |author6=R. G. Snell |author7=P. R. Schofield |author8=M. J. Owen |volume=11|issue=7|pages=853–860|pmid=11929858|doi-access=free}}</ref>
===SLC6A5=== The SLC6A5 gene encodes the GlyT2 transporter, a neuronal pre-synaptic glycine re-uptake transporter. In comparison to the GlyT1 transporter, found mostly in glial cells, GlyT2 helps maintain a high concentration of glycine within the axon terminal of glycinergic neurons.<ref name='GlyT2'>{{cite journal|title=The Glycine Transporter GlyT2 Controls the Dynamics of Synaptic Vesicle Refilling in Inhibitory Spinal Cord Neurons|journal=Journal of Neuroscience|date=2008-09-24|first=F.|last=Rousseau|author2=K. R. Aubrey |author3=S. Supplisson |pmid=18815261|volume=28|issue=39|pages=9755–68|doi= 10.1523/JNEUROSCI.0509-08.2008|pmc=6671229|doi-access=free}}</ref> Mutations of the SLC6A5 gene have been associated with hyperekplexia in an autosomal recessive inheritance pattern.<ref name='GlyT2-2'>{{cite journal|title=Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease|journal=Nature Genetics|year=2006|vauthors=Rees MI, Harvey K, Pearce BR, Chung SK, Duguid IC, Thomas P, Beatty S, Graham GE, Armstrong L, Shiang R, Abbott KJ, Zuberi SM, Stephenson JB, Owen MJ, Tijssen MA, van den Maagdenberg AM, Smart TG, Supplisson S, Harvey RJ|pmid=16751771|volume=38|issue=7|pages=801–806|doi= 10.1038/ng1814|pmc=3204411}}</ref> Defects within this gene are hypothesized either to affect the incorporation of the transporter into the cellular membrane or to affect its affinity for the molecules it transports: sodium ions, chloride ions and glycine.<ref name='GlyT2-2' /> Any of these actions would drastically reduce the pre-synaptic cell's ability to produce the high vesicular concentrations of glycine necessary for proper glycine neurotransmission. GPHN and ARHGEF9 are often included in lists of genetic causes of hyperekplexia - but, in fact, they produce a much more complex phenotype, very distinct from classical hyperekplexia. As such they are no longer considered to be causative genes.{{citation needed|date=September 2020}}
===GPHN=== Gephyrin, an integral membrane protein believed to coordinate glycine receptors, is coded by the gene GPHN. A heterozygous mutation in this gene has been identified in one sporadic case of hyperekplexia, though experimental data is inconclusive as to whether the mutation itself is, in fact, pathogenic.<ref name='GPHN'>{{cite journal|title=Isoform Heterogeneity of the Human Gephyrin Gene (GPHN), Binding Domains to the Glycine Receptor, and Mutation Analysis in Hyperekplexia|journal=Journal of Biological Chemistry|date=2003-04-08|vauthors=Rees MI, Harvey K, Ward H, White JH, Evans L, Duguid IC, Hsu CC, Coleman SL, Miller J, Baer K, Waldvogel HJ, Gibbon F, Smart TG, Owen MJ, Harvey RJ, Snell RG|pmid=12684523|volume=278|issue=27|pages=24688–96|doi= 10.1074/jbc.M301070200|doi-access=free}}</ref> Gephyrin is essential for glycine receptor clustering at synaptic junctions, through its action of binding both the glycine receptor beta subunit and internal cellular microtubule structures.<ref name='GLRB2' /> Gephyrin also assists in clustering GABA receptors at synapses and molybdenum cofactor synthesis.<ref name='GPHN2'>{{cite journal|title=Gephyrin: where do we stand, where do we go?|journal=Trends in Neurosciences|year=2008|first=J.-M.|last=Fritschy|author2=R. J. Harvey |author3=G. Schwarz |pmid=18403029|volume=31|issue=5|pages=257–264|doi= 10.1016/j.tins.2008.02.006|s2cid=6885626}}</ref> Because of gephyrin's multi-functional nature, in mutated form it is not presumed to be a common genetic source of hyperekplexia.<ref name='GPHN' />
===ARHGEF9=== A defect within the gene coding for collybistin, ARHGEF9, has been shown to cause hyperekplexia occurring with epilepsy.<ref name='ARHGEF9'>{{cite journal |title=The GDP-GTP Exchange Factor Collybistin: An Essential Determinant of Neuronal Gephyrin Clustering|journal=Journal of Neuroscience|year=2004|vauthors=Harvey K, Duguid IC, Alldred MJ, Beatty SE, Ward H, Keep NH, Lingenfelter SE, Pearce BR, Lundgren J, Owen MJ, Smart TG, Lüscher B, Rees MI, Harvey RJ|pmid=15215304|volume=24|issue=25|pages=5816–26|doi= 10.1523/JNEUROSCI.1184-04.2004|pmc=6729214|url=http://discovery.ucl.ac.uk/9558/1/9558.pdf}}</ref> Since the ARHGEF9 gene is on the X chromosome, this gene displays X-linked recessive heritance. The collybistin protein is responsible for proper gephyrin targeting, which is crucial for the proper localization of glycine and GABA receptors. Deficiencies in collybistin function would result in a lack of glycine and GABA receptors at the synaptic cleft.<ref name='ARHGEF9' />
==Diagnosis== There are three signs used to diagnose if an infant has hereditary hyperekplexia: if the child's body is stiff all over as soon as they are born, if they overreact to noises and other stimuli, and if the reaction to stimuli is followed by an overall stiffness where the child is unable to make any voluntary movements.<ref name=":0">{{Cite book|chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK1260/|title=GeneReviews®|last1=Tijssen|first1=Marina A.J.|last2=Rees|first2=Mark I.|date=1993|publisher=University of Washington, Seattle|editor-last=Adam|editor-first=Margaret P.|location=Seattle (WA)|pmid=20301437|editor-last2=Ardinger|editor-first2=Holly H.|editor-last3=Pagon|editor-first3=Roberta A.|editor-last4=Wallace|editor-first4=Stephanie E.|editor-last5=Bean|editor-first5=Lora J.H.|editor-last6=Stephens|editor-first6=Karen|editor-last7=Amemiya|editor-first7=Anne|chapter=Hyperekplexia}}</ref> A combination of electroencephalogram and an electromyogram may help diagnose this condition in patients who have not displayed symptoms as children. The electroencephalogram will not show abnormal activity other than a spike in wakefulness or alertness, while the electromyogram will show rapid muscular responses and hyperreflexia. Otherwise, genetic testing is the only definitive diagnosis.<ref name=":0" /> MRIs and CT scans will be normal unless other conditions are present.<ref name=":0" />
==Treatment== The most commonly used effective treatment is clonazepam, which leads to the increased efficacy of another inhibitory neurotransmitter, GABA.<ref name='Startle Review' /> There are anecdotal reports of the use of levetiracetam in genetic and acquired hyperekplexia.<ref name='Levetiracetam'>{{cite journal|title=The effect of levetiracetam in startle disease|journal=Journal of Neurology|first=G. J.|last=Luef|author2=W. N. Loescher|pmid=17401745|volume=254|issue=6|pages=808–9|doi= 10.1007/s00415-006-0437-z|date=June 2007|s2cid=358799}}</ref> During attacks of hypertonia and apnea, the limbs and head may be forcibly manipulated towards the trunk in order to resolve the symptoms. This is referred to as the "Vigevano maneuver'.<ref name='Vigevano'>{{cite journal|title=Startle disease: an avoidable cause of sudden infant death|journal=Lancet|year=1989|first=F.|last=Vigevano|author2=M. Di Capua |author3=B. Dalla Bernardina |volume=1|issue=8631|pages=216|pmid=2563117|doi=10.1016/s0140-6736(89)91226-9|s2cid=32077413}}</ref>
==History== The disorder was first described in 1958 by Kirstein and Silfverskiold, who reported a family with 'drop seizures'.<ref name='Original Case'>{{cite journal|doi=10.1111/j.1600-0447.1958.tb03533.x|title=A Family with Emotionally Precipitated Drop Seizures|journal=Acta Psychiatrica Scandinavica|year=1958|first=L.|last=Kirstein|author2=B. P. Silfverskiold|volume=33|issue=4|pages=471–6|pmid=13594585|s2cid=143799581}}</ref> In 1962 Drs. Kok and Bruyn reported an unidentified hereditary syndrome, which initially presented as hypertonia in infants.<ref name='Kok and Bruyn'>{{cite journal|doi=10.1016/S0140-6736(62)92475-3|title=An Unidentified Hereditary Disease|journal=Lancet|year=1962|first=O.|last=Kok|author2=G. W. Bruyn|volume=279|issue=7243|pages=1359}}</ref> Genetic analysis within this large Dutch pedigree revealed a mutation within the GLRA1 gene, the first gene to be implicated in hyperekplexia.<ref name='Dutch Family Molecular Genetics' />
==See also== * Startle response * Myotonia * Jumping Frenchmen of Maine * Latah * Stiff-person syndrome * Hyperreflexia
==References== {{Reflist}}
== External links == * [https://www.ncbi.nlm.nih.gov/books/NBK1260/ GeneReview/NIH/UW entry on Hyperekplexia] {{Medical resources | DiseasesDB = 7208 | ICD10 = {{ICD10|G|25|8||g|25}} | ICD9 = {{ICD9|759.89}} | ICDO = | OMIM = 149400 | OMIM_mult = {{OMIM|138491||none}} {{OMIM|138492||none}} {{OMIM|300429||none}} {{OMIM|300607||none}} {{OMIM|603930||none}} {{OMIM|604159||none}} | MedlinePlus = | eMedicineSubj = | eMedicineTopic = | GeneReviewsNBK = NBK1260 | GeneReviewsName = Hyperekplexia | MeshID = D000071017 | Orphanet = 306773 }}
Category:Neurological disorders Category:Reflexes Category:Rare diseases