Medicine:Hyperekplexia

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Short description: Genetic disorder causing an exaggerated startle response
Hyperekplexia
Other namesExaggerated surprise, exaggerated startle response, startle disease[1]
PDB 1mot EBI.jpg
Mutations of the neuroreceptor glycine receptor subunit alpha-1 (GLRA1) can cause hyperekplexia.
Pronunciation
  • /ˌhaɪ.pɚ.ɛkˈplɛk.si.ə/
SpecialtyNeurology, genetics
SymptomsIncreased startle response to sudden auditory, visual, or tactile stimulation
ComplicationsIncreased alcohol and drug use
DurationChronic
CausesMutation of either the GLRA1 gene, GLRB gene, SLC6A5 gene, X-linked (ARHGEF9) gene, or GPHN gene[2]
Differential diagnosisJumping Frenchmen of Maine syndrome
MedicationClonazepam or phenobarbital, carbamazepine, 5-hydroxytryptophan, phenytoin, sodium valproate, diazepam, or piracetam[2]
Frequency1 in 40,000[2]

Hyperekplexia (/ˌhaɪ.pər.ɛkˈplɛk.si.ə/; "exaggerated surprise") is a very rare neurologic disorder, classically characterised by a pronounced startle responses 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;[3] some disorders can mimic the exaggerated startle of hyperekplexia.[4]

Signs and symptoms

The three main signs of hyperekplexia are generalized stiffness, excessive startle beginning at birth and nocturnal myoclonus.[5] 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.[6] 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.[6] Genetic evidence has only been found for the major form of the condition.[6]

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.[3]

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.[citation needed]

GLRA1

The first gene linked conclusively to hyperekplexia was GLRA1.[6] 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.[7] 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.[7]

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[6] inheritance was initially reported, there are at least as many cases described with autosomal recessive inheritance.[8] 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.[8]

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,[9] however, the beta subunit is essential for proper receptor localization, through its interactions with gephyrin, which results in receptor clustering at the synaptic cleft.[10] As such, the defects within the GLRB gene show autosomal recessive inheritance.[11]

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.[12] Mutations of the SLC6A5 gene have been associated with hyperekplexia in an autosomal recessive inheritance pattern.[13] 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.[13] 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]

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.[14] 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.[10] Gephyrin also assists in clustering GABA receptors at synapses and molybdenum cofactor synthesis.[15] Because of gephyrin's multi-functional nature, in mutated form it is not presumed to be a common genetic source of hyperekplexia.[14]

ARHGEF9

A defect within the gene coding for collybistin, ARHGEF9, has been shown to cause hyperekplexia occurring with epilepsy.[16] 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.[16]

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.[17] 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.[17] MRIs and CT scans will be normal unless other conditions are present.[17]

Treatment

The most commonly-used effective treatment is clonazepam, which leads to the increased efficacy of another inhibitory neurotransmitter, GABA.[3] There are anecdotal reports of the use of levetiracetam in genetic and acquired[clarification needed] hyperekplexia.[18] 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'.[19]

History

The disorder was first described in 1958 by Kirstein and Silfverskiold, who reported a family with 'drop seizures'.[20] In 1962 Drs. Kok and Bruyn reported an unidentified hereditary syndrome, which initially presented as hypertonia in infants.[21] Genetic analysis within this large Dutch pedigree revealed a mutation within the GLRA1 gene, the first gene to be implicated in hyperekplexia.[6]

See also

References

  1. ↑ Beers, Mark H. MD (2006). The Merck Manual (16th ed.). Whitehouse Station, NJ: Merck Research Laboratories. p. 1764. ISBN 0911910-18-2. 
  2. ↑ 2.0 2.1 2.2 Kerkar, Pramod, M.D., FFARCSI, DA (22 December 2015). "Exaggerated Startle Response: Causes, Symptoms, Treatment, Recovery, Yoga". https://www.epainassist.com/genetic-disorders/exaggerated-startle-response. 
  3. ↑ 3.0 3.1 3.2 "Startle Syndromes". Lancet Neurology 5 (6): 513–524. 2006-05-19. doi:10.1016/S1474-4422(06)70470-7. PMID 16713923. 
  4. ↑ van de Warrenburg, B. P. C.; C. Cordivari; P. Brown; K. P. Bhatia (2007-04-05). "Persisting Hyperekplexia After Idiopathic, Self-Limiting Brainstem Encephalopathy". Movement Disorders 22 (7): 1017–20. doi:10.1002/mds.21411. PMID 17415799. 
  5. ↑ Koning-Tijssen, M.A.J.; O.F. Brouwer (2000-04-27). "Hyperekplexia in the Neonate". Movement Disorders 15 (6): 1293–6. doi:10.1002/1531-8257(200011)15:6<1293::aid-mds1047>3.0.co;2-k. PMID 11104232. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 Tijssen, M.A.J.; R. Shiang; J. van Deutekom; R. H. Boerman; J. Wasmuth; L. A. Sandkuijl; R. R. Frants; G. W. Padberg (1995-06-01). "Molecular Genetic Reevaluation of the Dutch Hyperekplexia Family". Archives of Neurology 52 (6): 578–582. doi:10.1001/archneur.1995.00540300052012. PMID 7763205. https://repository.ubn.ru.nl/bitstream/2066/20657/1/20657___.PDF. 
  7. ↑ 7.0 7.1 Lynch, J. W. (2008-08-03). "Native glycine receptor subtypes and their physiological roles". Neuropharmacology 56 (1): 303–9. doi:10.1016/j.neuropharm.2008.07.034. PMID 18721822. https://zenodo.org/record/895467. 
  8. ↑ 8.0 8.1 "Recessive hyperekplexia mutations of the glycine receptor [alpha]-1 subunit affect cell surface integration and stability". Journal of Neurochemistry 111 (3): 837–847. 2009. doi:10.1111/j.1471-4159.2009.06372.x. PMID 19732286. 
  9. ↑ Bormann, J.; N. Rundstrom; H. Betz; D. Langosch (1993). "Residues within transmembrane segment M2 determine chloride conductance of glycine receptor homo- and hetero-oligomers". EMBO Journal 12 (10): 3729–37. doi:10.1002/j.1460-2075.1993.tb06050.x. PMID 8404844. 
  10. ↑ 10.0 10.1 Meyer, G.; J. Kirsch; H. Betz; D. Langosch (1995). "Identification of a Gephyrin Binding Motif on the Glycine Receptor Beta Subunit". Neuron 15 (3): 563–572. doi:10.1016/0896-6273(95)90145-0. PMID 7546736. 
  11. ↑ Rees, M. I.; T. M. Lewis; J. B. Kwok; G. R. Mortier; P. Govaert; R. G. Snell; P. R. Schofield; M. J. Owen (2002-04-01). "Hyperekplexia associated with compound heterozygote mutations in the beta-subunit of the human inhibitory glycine receptor (GLRB)". Human Molecular Genetics 11 (7): 853–860. doi:10.1093/hmg/11.7.853. PMID 11929858. 
  12. ↑ Rousseau, F.; K. R. Aubrey; S. Supplisson (2008-09-24). "The Glycine Transporter GlyT2 Controls the Dynamics of Synaptic Vesicle Refilling in Inhibitory Spinal Cord Neurons". Journal of Neuroscience 28 (39): 9755–68. doi:10.1523/JNEUROSCI.0509-08.2008. PMID 18815261. 
  13. ↑ 13.0 13.1 "Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease". Nature Genetics 38 (7): 801–806. 2006. doi:10.1038/ng1814. PMID 16751771. 
  14. ↑ 14.0 14.1 "Isoform Heterogeneity of the Human Gephyrin Gene (GPHN), Binding Domains to the Glycine Receptor, and Mutation Analysis in Hyperekplexia". Journal of Biological Chemistry 278 (27): 24688–96. 2003-04-08. doi:10.1074/jbc.M301070200. PMID 12684523. 
  15. ↑ Fritschy, J.-M.; R. J. Harvey; G. Schwarz (2008). "Gephyrin: where do we stand, where do we go?". Trends in Neurosciences 31 (5): 257–264. doi:10.1016/j.tins.2008.02.006. PMID 18403029. 
  16. ↑ 16.0 16.1 "The GDP-GTP Exchange Factor Collybistin: An Essential Determinant of Neuronal Gephyrin Clustering". Journal of Neuroscience 24 (25): 5816–26. 2004. doi:10.1523/JNEUROSCI.1184-04.2004. PMID 15215304. PMC 6729214. http://discovery.ucl.ac.uk/9558/1/9558.pdf. 
  17. ↑ 17.0 17.1 17.2 Tijssen, Marina A.J.; Rees, Mark I. (1993). "Hyperekplexia". in Adam, Margaret P.. GeneReviews®. Seattle (WA): University of Washington, Seattle. https://www.ncbi.nlm.nih.gov/books/NBK1260/. 
  18. ↑ Luef, G. J.; W. N. Loescher (June 2007). "The effect of levetiracetam in startle disease". Journal of Neurology 254 (6): 808–9. doi:10.1007/s00415-006-0437-z. PMID 17401745. 
  19. ↑ Vigevano, F.; M. Di Capua; B. Dalla Bernardina (1989). "Startle disease: an avoidable cause of sudden infant death". Lancet 1 (8631): 216. doi:10.1016/s0140-6736(89)91226-9. PMID 2563117. 
  20. ↑ Kirstein, L.; B. P. Silfverskiold (1958). "A Family with Emotionally Precipitated Drop Seizures". Acta Psychiatrica Scandinavica 33 (4): 471–6. doi:10.1111/j.1600-0447.1958.tb03533.x. PMID 13594585. 
  21. ↑ Kok, O.; G. W. Bruyn (1962). "An Unidentified Hereditary Disease". Lancet 279 (7243): 1359. doi:10.1016/S0140-6736(62)92475-3. 

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