Hyperekplexia and other startle syndromes

      Highlights

      • In humans the startle syndromes are classified into hyperekplexia, stimulus-induced, and neuropsychiatric startle syndromes
      • Hyperekplexia may be hereditary, idiopathic or symptomatic
      • Diagnosis of startle syndrome depends on clinical history, electrophysiology and genetic workup
      • The prognosis in genetic causes are good and other patients can be treated symptomatically

      Abstract

      Abnormal startle syndromes are classified into hyperekplexia, stimulus-induced, and neuropsychiatric startle syndromes. Hyperekplexia is attributed to a genetic, idiopathic, or symptomatic cause. Hereditary hyperekplexia is a treatable neurogenetic disorder. In patients with a hyperactive startle response, the first step is to characterize the extent and associations of ‘response.’ Secondary or symptomatic causes are particularly important in children, as they provide useful clinical clues to an underlying neurodevelopmental or neurodegenerative disorders. Particular attention should be given to any neonate or infant with generalized or episodic stiffness, drug-refractory seizures, recurrent apnea, stimulus-sensitive behavioral states, or sudden infant death syndrome. Eliciting a non-habituating head-retraction reflex to repeated nose tapping should be a part of routine examination of all new-borns. Vigevano maneuver should be taught to all families and health-care workers as an emergency rescue measure. The onset of excessive startle after infancy should direct investigations for an acquired cause such as brainstem injury, antibodies against glycine receptors, and neurodegeneration. Finally, one should not forget to evaluate unexplained cases of abnormal gait and frequent falls in adults for underlying undiagnosed startle syndromes. Oral clonazepam is an effective therapy besides behavioral and safety interventions for hereditary cases. The outcomes in genetic cases are good overall.

      Keywords

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      References

        • Matsumoto J.
        • Fuhr P.
        • Nigro M.
        • Hallett M.
        Physiological abnormalities in hereditary hyperekplexia.
        Ann. Neurol. 1992; 32: 41-50https://doi.org/10.1002/ana.410320108
        • Ea J.
        Response to a sudden unexpected stimulus.
        J. Exp. Psychol. 1926; 9: 19-25
        • Bakker M.J.
        • van Dijk J.G.
        • van den Maagdenberg A.M.
        • Tijssen M.A.
        Startle syndromes.
        Lancet Neurol. 2006; 5: 513-524https://doi.org/10.1016/S1474-4422(06)70470-7
        • Masri A.
        • Chung S.K.
        • Rees M.I.
        Hyperekplexia: report on phenotype and genotype of 16 Jordanian patients.
        Brain Dev. 2017; 39: 306-311https://doi.org/10.1016/j.braindev.2016.10.010
        • Mine J.
        • Taketani T.
        • Yoshida K.
        • Yokochi F.
        • Kobayashi J.
        • Maruyama K.
        • et al.
        Clinical and genetic investigation of 17 Japanese patients with hyperekplexia.
        Dev. Med. Child Neurol. 2015; 57: 372-377https://doi.org/10.1111/dmcn.12617
        • Strauss H.
        Das Zusammenschrecken.
        J. Psychol. Neurol. 1929; 39: 111
        • Gogan P.
        The startle and orienting reactions in man. A study of their characteristics and habituation.
        Brain Res. 1970; 18: 117-135https://doi.org/10.1016/0006-8993(70)90460-9
        • Dreissen Y.E.
        • Tijssen M.A.
        The startle syndromes: physiology and treatment.
        Epilepsia. 2012; 53: 3-11https://doi.org/10.1111/j.1528-1167.2012.03709.x
        • Dreissen Y.E.
        • Bakker M.J.
        • Koelman J.H.
        • Tijssen M.A.
        Exaggerated startle reactions.
        Clin. Neurophysiol. 2012; 123: 34-44https://doi.org/10.1016/j.clinph.2011.09.022
        • Brown P.
        • Rothwell J.C.
        • Thompson P.D.
        • Britton T.C.
        • Day B.L.
        • Marsden C.D.
        The hyperekplexias and their relationship to the normal startle reflex.
        Brain. 1991; 114: 1903-1928https://doi.org/10.1093/brain/114.4.1903
        • Brown P.
        • Rothwell J.C.
        • Thompson P.D.
        • Britton T.C.
        • Day B.L.
        • Marsden C.D.
        New observations on the normal auditory startle reflex in man.
        Brain. 1991; 114: 1891-1902https://doi.org/10.1093/brain/114.4.1891
        • Brown P.
        Neurophysiology of the startle syndrome and hyperekplexia.
        Adv. Neurol. 2002; 89: 153-159
        • Wilkins D.E.
        • Hallett M.
        • Wess M.M.
        Audiogenic startle reflex of man and its relationship to startle syndromes. A review.
        Brain. 1986; 109: 561-573https://doi.org/10.1093/brain/109.3.561
        • Koch M.
        The neurobiology of startle.
        Prog. Neurobiol. 1999; 59: 107-128https://doi.org/10.1016/s0301-0082(98)00098-7
        • Timmann D.
        • Musso C.
        • Kolb F.P.
        • Rijntjes M.
        • Juptner M.
        • Muller S.P.
        • et al.
        Involvement of the human cerebellum during habituation of the acoustic startle response: a PET study.
        J. Neurol. Neurosurg. Psychiatry. 1998; 65: 771-773https://doi.org/10.1136/jnnp.65.5.771
        • Andermann F.
        • Keene D.L.
        • Andermann E.
        • Quesney L.F.
        Startle disease or hyperekplexia: further delineation of the syndrome.
        Brain. 1980; 103: 985-997https://doi.org/10.1093/brain/103.4.985
        • Kirstein L.
        • Silfverskiold B.P.
        A family with emotionally precipitated drop seizures.
        Acta Psychiatr. Neurol. Scand. 1958; 33: 471-476https://doi.org/10.1111/j.1600-0447.1958.tb03533.x
        • O S.
        • B G.W.
        • T J.A.
        Hyperekplexia, a hereditary startle syndrome.
        J. Neurol. Sci. 1966; : 577-605
        • Gastaut H.
        • Villeneuve A.
        The startle disease or hyperekplexia. Pathological surprise reaction.
        J. Neurol. Sci. 1967; 5: 523-542https://doi.org/10.1016/0022-510x(67)90090-1
        • Meinck H.M.
        Startle and its disorders.
        Neurophysiol. Clin. 2006; 36: 357-364https://doi.org/10.1016/j.neucli.2006.12.007
        • Harvey R.J.
        • Topf M.
        • Harvey K.
        • Rees M.I.
        The genetics of hyperekplexia: more than startle!.
        Trends Genet. 2008; 24: 439-447https://doi.org/10.1016/j.tig.2008.06.005
        • Lee C.G.
        • Kwon M.J.
        • Yu H.J.
        • Nam S.H.
        • Lee J.
        • Ki C.S.
        • et al.
        Clinical features and genetic analysis of children with hyperekplexia in Korea.
        J. Child Neurol. 2013; 28: 90-94https://doi.org/10.1177/0883073812441058
        • Thomas R.H.
        • Chung S.K.
        • Wood S.E.
        • Cushion T.D.
        • Drew C.J.
        • Hammond C.L.
        • et al.
        Genotype-phenotype correlations in hyperekplexia: apnoeas, learning difficulties and speech delay.
        Brain. 2013; 136: 3085-3095https://doi.org/10.1093/brain/awt207
        • Rees M.I.
        • Harvey K.
        • Ward H.
        • White J.H.
        • Evans L.
        • Duguid I.C.
        • et al.
        Isoform heterogeneity of the human gephyrin gene (GPHN), binding domains to the glycine receptor, and mutation analysis in hyperekplexia.
        J. Biol. Chem. 2003; 278: 24688-24696https://doi.org/10.1074/jbc.M301070200
        • Harvey K.
        • Duguid I.C.
        • Alldred M.J.
        • Beatty S.E.
        • Ward H.
        • Keep N.H.
        • et al.
        The GDP-GTP exchange factor collybistin: an essential determinant of neuronal gephyrin clustering.
        J. Neurosci. 2004; 24: 5816-5826https://doi.org/10.1523/JNEUROSCI.1184-04.2004
        • Davies J.S.
        • Chung S.K.
        • Thomas R.H.
        • Robinson A.
        • Hammond C.L.
        • Mullins J.G.
        • et al.
        The glycinergic system in human startle disease: a genetic screening approach.
        Front. Mol. Neurosci. 2010; 3: 8https://doi.org/10.3389/fnmol.2010.00008
        • Wolf N.I.
        • Zschocke J.
        • Jakobs C.
        • Rating D.
        • Hoffmann G.F.
        ATAD1 encephalopathy and stiff baby syndrome: a recognizable clinical presentation.
        Brain. 2018; 141e49https://doi.org/10.1093/brain/awy095
        • Piard J.
        • Umanah G.K.E.
        • Harms F.L.
        • Abalde-Atristain L.
        • Amram D.
        • Chang M.
        • et al.
        A homozygous ATAD1 mutation impairs postsynaptic AMPA receptor trafficking and causes a lethal encephalopathy.
        Brain. 2018; 141: 651-661https://doi.org/10.1093/brain/awx377
        • Ahrens-Nicklas R.C.
        • Umanah G.K.
        • Sondheimer N.
        • Deardorff M.A.
        • Wilkens A.B.
        • Conlin L.K.
        • et al.
        Precision therapy for a new disorder of AMPA receptor recycling due to mutations in ATAD1.
        Neurol. Genet. 2017; 3e130https://doi.org/10.1212/NXG.0000000000000130
        • Leventer R.J.
        • Hopkins I.J.
        • Shield L.K.
        Hyperekplexia as cause of abnormal intrauterine movements.
        Lancet. 1995; 345: 461https://doi.org/10.1016/s0140-6736(95)90448-4
        • Sahu J.K.
        • Choudhary A.
        • Ghosh I.
        • Gulati S.
        • Kabra M.
        • Taketani T.
        • et al.
        Hyperekplexia masquerading as epilepsy.
        Indian J. Pediatr. 2011; 78: 757https://doi.org/10.1007/s12098-010-0359-8
        • Saini A.G.
        • Taketani T.
        • Sahu J.K.
        • Singhi P.
        Startles, stiffness, and SLC6A5: do you know the condition?.
        Pediatr. Neurol. 2018; 81: 49-50https://doi.org/10.1016/j.pediatrneurol.2017.12.012
        • Lee Y.
        • Kim N.Y.
        • Hong S.
        • Chung S.J.
        • Jeong S.H.
        • Lee P.H.
        • et al.
        Familiar hyperekplexia, a potential cause of cautious gait: a new korean case and a systematic review of phenotypes.
        J. Mov. Disord. 2017; 10: 53-58https://doi.org/10.14802/jmd.16044
        • Zhang C.
        • Wang S.G.
        • Wang Y.
        • Liu X.L.
        • Cao L.
        Teaching video NeuroImages: cautious walking gait in siblings with hereditary hyperekplexia.
        Neurology. 2019; 92: e2068-e2069https://doi.org/10.1212/WNL.0000000000007375
        • Tijssen M.A.
        • Vergouwe M.N.
        • van Dijk J.G.
        • Rees M.
        • Frants R.R.
        • Brown P.
        Major and minor form of hereditary hyperekplexia.
        Mov. Disord. 2002; 17: 826-830https://doi.org/10.1002/mds.10168
        • Tijssen M.A.
        • Padberg G.W.
        • van Dijk J.G.
        The startle pattern in the minor form of hyperekplexia.
        Arch. Neurol. 1996; 53: 608-613https://doi.org/10.1001/archneur.1996.00550070046011
        • Rees M.I.
        • Lewis T.M.
        • Kwok J.B.
        • Mortier G.R.
        • Govaert P.
        • Snell R.G.
        • et al.
        Hyperekplexia associated with compound heterozygote mutations in the beta-subunit of the human inhibitory glycine receptor (GLRB).
        Hum. Mol. Genet. 2002; 11: 853-860https://doi.org/10.1093/hmg/11.7.853
        • Rivera S.
        • Villega F.
        • de Saint-Martin A.
        • Matis J.
        • Escande B.
        • Chaigne D.
        • et al.
        Congenital hyperekplexia: five sporadic cases.
        Eur. J. Pediatr. 2006; 165: 104-107https://doi.org/10.1007/s00431-005-0015-x
        • Scarcella A.
        • Coppola G.
        Neonatal sporadic hyperekplexia: a rare and often unrecognized entity.
        Brain Dev. 1997; 19: 226-228https://doi.org/10.1016/s0387-7604(97)00571-8
        • Hamelin S.
        • Rohr P.
        • Kahane P.
        • Minotti L.
        • Vercueil L.
        Late onset hyperekplexia.
        Epileptic Disord. 2004; 6: 169-172
        • Singanamalla B.
        • Saini A.G.
        • Sankhyan N.
        Exaggerated startle and cherry-red spots: important bedside clues.
        Pediatr. Neurol. 2020; 105: 73-74https://doi.org/10.1016/j.pediatrneurol.2019.11.015
        • Nakamura S.
        • Saito Y.
        • Ishiyama A.
        • Sugai K.
        • Iso T.
        • Inagaki M.
        • et al.
        Correlation of augmented startle reflex with brainstem electrophysiological responses in Tay-Sachs disease.
        Brain Dev. 2015; 37: 101-106https://doi.org/10.1016/j.braindev.2014.01.011
        • Vigevano F.
        • Di Capua M.
        • Dalla Bernardina B.
        Startle disease: an avoidable cause of sudden infant death.
        Lancet. 1989; 1: 216https://doi.org/10.1016/s0140-6736(89)91226-9
        • Ryan S.G.
        • Sherman S.L.
        • Terry J.C.
        • Sparkes R.S.
        • Torres M.C.
        • Mackey R.W.
        Startle disease, or hyperekplexia: response to clonazepam and assignment of the gene (STHE) to chromosome 5q by linkage analysis.
        Ann. Neurol. 1992; 31: 663-668https://doi.org/10.1002/ana.410310615
        • Tijssen M.A.
        • Schoemaker H.C.
        • Edelbroek P.J.
        • Roos R.A.
        • Cohen A.F.
        • van Dijk J.G.
        The effects of clonazepam and vigabatrin in hyperekplexia.
        J. Neurol. Sci. 1997; 149: 63-67https://doi.org/10.1016/s0022-510x(97)05378-1
        • Zhou L.
        • Chillag K.L.
        • Nigro M.A.
        Hyperekplexia: a treatable neurogenetic disease.
        Brain Dev. 2002; 24: 669-674https://doi.org/10.1016/s0387-7604(02)00095-5
        • Sechi G.
        • Sotgiu S.
        • Valenti M.P.
        • Pitzolu M.G.
        • Peterlongo P.
        • Larizza L.
        • et al.
        Beneficial effect of fluoxetine in a case of sporadic hyperekplexia.
        Clin. Neuropharmacol. 2000; 23: 161-163https://doi.org/10.1097/00002826-200005000-00006
        • McAbee G.N.
        Clobazam-clonazepam combination effective for stimulus-induced falling in hyperekplexia.
        J. Child Neurol. 2015; 30: 91-92https://doi.org/10.1177/0883073813516677
        • Mineyko A.
        • Whiting S.
        • Graham G.E.
        Hyperekplexia: treatment of a severe phenotype and review of the literature.
        Can. J. Neurol. Sci. 2011; 38: 411-416https://doi.org/10.1017/s0317167100011793
        • Ng Y.T.
        • Conry J.
        • Paolicchi J.
        • Kernitsky L.
        • Mitchell W.
        • Drummond R.
        • et al.
        Long-term safety and efficacy of clobazam for Lennox-Gastaut syndrome: interim results of an open-label extension study.
        Epilepsy Behav. 2012; 25: 687-694https://doi.org/10.1016/j.yebeh.2012.09.039
        • Garg R.
        • Ramachandran R.
        • Sharma P.
        Anaesthetic implications of hyperekplexia--’startle disease’.
        Anaesth. Intensive Care. 2008; 36: 254-256https://doi.org/10.1177/0310057X0803600217
        • O’Shea S.M.
        • Becker L.
        • Weiher H.
        • Betz H.
        • Laube B.
        Propofol restores the function of “hyperekplexic” mutant glycine receptors in Xenopus oocytes and mice.
        J. Neurosci. 2004; 24: 2322-2327https://doi.org/10.1523/JNEUROSCI.4675-03.2004
        • Zou G.
        • Chen Q.
        • Chen K.
        • Zuo X.
        • Ge Y.
        • Hou Y.
        • et al.
        Human hyperekplexic mutations in glycine receptors disinhibit the brainstem by hijacking GABAA receptors.
        iScience. 2019; 19: 634-646https://doi.org/10.1016/j.isci.2019.08.018
        • Harvey R.J.
        Hijacking of GABAA receptors by mutant glycine receptors.
        Trends Mol. Med. 2019; 25: 823-825https://doi.org/10.1016/j.molmed.2019.08.010
        • Zou G.
        • Xia J.
        • Han Q.
        • Liu D.
        • Xiong W.
        The synthetic cannabinoid dehydroxylcannabidiol restores the function of a major GABAA receptor isoform in a cell model of hyperekplexia.
        J. Biol. Chem. 2020; 295: 138-145https://doi.org/10.1074/jbc.RA119.011221
        • Xiong W.
        • Chen S.R.
        • He L.
        • Cheng K.
        • Zhao Y.L.
        • Chen H.
        • et al.
        Presynaptic glycine receptors as a potential therapeutic target for hyperekplexia disease.
        Nat. Neurosci. 2014; 17: 232-239https://doi.org/10.1038/nn.3615
        • Yang Z.
        • Ney A.
        • Cromer B.A.
        • Ng H.L.
        • Parker M.W.
        • Lynch J.W.
        Tropisetron modulation of the glycine receptor: femtomolar potentiation and a molecular determinant of inhibition.
        J. Neurochem. 2007; 100: 758-769https://doi.org/10.1111/j.1471-4159.2006.04242.x
        • Lopez-Corcuera B.
        • Arribas-Gonzalez E.
        • Aragon C.
        Hyperekplexia-associated mutations in the neuronal glycine transporter 2.
        Neurochem. Int. 2019; 123: 95-100https://doi.org/10.1016/j.neuint.2018.05.014
        • Shahar E.
        • Raviv R.
        Sporadic major hyperekplexia in neonates and infants: clinical manifestations and outcome.
        Pediatr. Neurol. 2004; 31: 30-34https://doi.org/10.1016/j.pediatrneurol.2003.12.007
        • Lynch J.W.
        • Zhang Y.
        • Talwar S.
        • Estrada-Mondragon A.
        Glycine receptor drug discovery.
        Adv. Pharmacol. 2017; 79: 225-253https://doi.org/10.1016/bs.apha.2017.01.003
        • Saenz-Lope E.
        • Herranz-Tanarro F.J.
        • Masdeu J.C.
        • Chacon Pena J.R.
        Hyperekplexia: a syndrome of pathological startle responses.
        Ann. Neurol. 1984; 15: 36-41https://doi.org/10.1002/ana.410150107
        • Vignal J.P.
        • Biraben A.
        • Chauvel P.Y.
        • Reutens D.C.
        Reflex partial seizures of sensorimotor cortex (including cortical reflex myoclonus and startle epilepsy).
        Adv. Neurol. 1998; 75: 207-226
        • Engel Jr., J.
        • E. International League Against
        A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE Task Force on Classification and Terminology.
        Epilepsia. 2001; 42: 796-803https://doi.org/10.1046/j.1528-1157.2001.10401.x
        • Yang Z.
        • Liu X.
        • Qin J.
        • Zhang Y.
        • Bao X.
        • Wang S.
        • et al.
        Clinical and electrophysiological characteristics of startle epilepsy in childhood.
        Clin. Neurophysiol. 2010; 121: 658-664https://doi.org/10.1016/j.clinph.2009.12.020
        • Nolan M.A.
        • Otsubo H.
        • Iida K.
        • Minassian B.A.
        Startle-induced seizures associated with infantile hemiplegia: implication of the supplementary motor area.
        Epileptic Disord. 2005; 7: 49-52
        • van der Veen S.
        • Zutt R.
        • Klein C.
        • Marras C.
        • Berkovic S.F.
        • Caviness J.N.
        • et al.
        Nomenclature of genetically determined myoclonus syndromes: recommendations of the International Parkinson and Movement Disorder Society task force.
        Mov. Disord. 2019; 34: 1602-1613https://doi.org/10.1002/mds.27828
        • Espay A.J.
        • Chen R.
        Myoclonus.
        Continuum (Minneap Minn). 2013; 19: 1264-1286https://doi.org/10.1212/01.CON.0000436156.54532.1a
        • Markand O.N.
        • Garg B.P.
        • Weaver D.D.
        Familial startle disease (hyperexplexia). Electrophysiologic studies.
        Arch. Neurol. 1984; 41: 71-74https://doi.org/10.1001/archneur.1984.04050130077028
        • Yen L.M.
        • Thwaites C.L.
        Tetanus.
        Lancet. 2019; 393: 1657-1668https://doi.org/10.1016/S0140-6736(18)33131-3
        • Lanska D.J.
        Jumping Frenchmen, Miryachit, and Latah: culture-specific hyperstartle-plus syndromes.
        Front. Neurol. Neurosci. 2018; 42: 122-131https://doi.org/10.1159/000475700