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What Causes Stiffness in a Baby Kok Disease

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Genetic disorder causing an exaggerated startle response

Medical condition

Hyperekplexia
Other names Exaggerated surprise, exaggerated startle response, startle disease[1]
PDB 1mot EBI.jpg
Mutations of the neuroreceptor glycine receptor subunit alpha-i (GLRA1) tin crusade hyperekplexia.
Pronunciation
  • /ˌhaɪ.pɚ.ɛkˈplɛk.si.ə/
Specialty Neurology, genetics
Symptoms Increased startle response to sudden auditory, visual, or tactile stimulation
Complications Increased alcohol and drug utilize
Duration Chronic
Causes Mutation of either the GLRA1 gene, GLRB gene, SLC6A5 gene, X-linked (ARHGEF9) factor, or GPHN factor[2]
Differential diagnosis Jumping Frenchmen of Maine syndrome
Medication Clonazepam or phenobarbital, carbamazepine, five-hydroxytryptophan, phenytoin, sodium valproate, diazepam, or piracetam[2]
Frequency 1 in twoscore,000[2]

Hyperekplexia (; "exaggerated surprise") is a very rare neurologic disorder classically characterised by pronounced startle responses to tactile or acoustic stimuli and hypertonia. The hypertonia may exist predominantly truncal, attenuated during slumber and less prominent later a year of age.

Classic hyperekplexia is caused past genetic mutations in a number of different genes, all of which play an of import role in glycine neurotransmission. Glycine is used past the primal nervous organization as an inhibitory neurotransmitter. Hyperekplexia is generally classified as a genetic disease,[3] but some disorders can mimic the exaggerated startle of hyperekplexia.[iv]

Signs and symptoms [edit]

The three main signs of hyperekplexia are generalized stiffness, excessive startle kickoff at birth and nocturnal myoclonus.[5] Afflicted individuals are fully conscious during episodes of stiffness, which consist of forced closure of the eyes and an extension of the extremities followed past a catamenia of generalised stiffness and uncontrolled falling at times.[6] Initially, the illness was classified into a "major" and a "modest" course, with the pocket-size form being characterized by an excessive startle reflex, merely lacking stiffness.[6] At that place is only genetic evidence for the existence of the major grade.[vi]

Other signs and symptoms of hyperekplexia may include episodic neonatal apnea, excessive motility during sleep and the head-retraction reflex. The link to some cases of Sudden Baby Decease remains controversial.[three]

Genetics [edit]

Hyperekplexia is known to be caused by a multifariousness of genes, encoding both pre- and postsynaptic proteins. The symptoms displayed, as well as the forms of heritance, vary based on which gene is affected.[ citation needed ]

GLRA1 [edit]

The first factor linked conclusively to hyperekplexia was GLRA1.[6] The GLRA1 gene encodes the glycine receptor alpha-i 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] Native glycine receptors are thus supposed to be heteromers of the alpha-1 and beta subunits, in either a three:two or 2:iii ratio.[seven]

Within these heteromers, it is believed that the alpha-1 subunits demark glycine and undergo a conformational alter, inducing a conformational change in the pentamer, causing the ion-channel to open. Although autosomal dominant[6] inheritance was initially reported, in that location are at least as many cases described with autosomal recessive inheritance.[viii] Thus far, the full general rule is that mutations causing structurally normal proteins that cannot bind glycine or cannot properly undergo a required conformational change volition result in a ascendant grade of the disease, while mutations that issue in truncated or wildly malformed subunits that cannot be integrated into a receptor protein will result in a recessive form.[8]

GLRB [edit]

The GLRB gene encodes the beta subunit of the glycine receptor. Homomeric glycine receptors equanimous of beta subunits practice not open in response to glycine stimulation,[ix] however, the beta subunit is essential for proper receptor localization through its interactions with gephyrin, which results in receptor clustering at the synaptic cleft.[ten] As such, the defects within the GLRB gene show autosomal recessive inheritance.[11]

SLC6A5 [edit]

The SLC6A5 factor 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 loftier 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 way.[13] Defects within this gene are hypothesized either to bear on the incorporation of the transporter into the cellular membrane or to its affinity for the molecules it transports: sodium ions, chloride ions and glycine.[thirteen] Any of these actions would drastically reduce the pre-synaptic jail cell'due south 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 - simply in fact they produce a much more than complex phenotype, very distinct from classical hyperekplexia. As such they are no longer considered to be causative genes.[ commendation needed ]

GPHN [edit]

Gephyrin, an integral membrane poly peptide believed to coordinate glycine receptors, is coded by the gene GPHN. A heterozygous mutation in this gene has been identified in a sporadic case of hyperekplexia, though experimental data is inconclusive every bit to whether the mutation is 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 likewise assists in clustering GABA receptors at synapses and molybdenum cofactor synthesis.[15] Because of its multi-functional nature, information technology is not presumed to exist a mutual genetic source of hyperekplexia.[14]

ARHGEF9 [edit]

A defect within the gene coding for collybistin (ARHGEF9) has been shown to cause hyperekplexia in concert with epilepsy.[16] Since the ARHGEF9 factor 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 an artificial lack of glycine and GABA receptors at the synaptic fissure.[16]

Diagnosis [edit]

In that location are three conditions used to diagnose if an infant has hereditary hyperekplexia: if the child's body is stiff all over as shortly 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 assistance diagnose this condition in patients who have not displayed symptoms every bit children. The electroencephalogram volition not show abnormal activity other than a spike in wakefulness or alertness, while the electromyogram volition show rapid muscular responses and hyperreflexia. Otherwise, genetic testing is the just definitive diagnosis.[17] MRIs and CT scans will be normal unless other weather condition exist.[17]

Handling [edit]

The well-nigh commonly constructive handling is clonazepam, which leads to the increased efficacy of some other inhibitory neurotransmitter, GABA.[3] There are anecdotal reports of the utilise of levetiracetam in genetic and caused hyperekplexia.[18] During attacks of hypertonia and apnea, the limbs and head may be flexed towards the trunk in order to misemploy the symptoms. This is named the Vigevano maneuver after the doc who invented information technology.[19]

History [edit]

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

See also [edit]

  • Myotonia
  • Jumping Frenchmen of Maine
  • Latah
  • Stiff-person syndrome

References [edit]

  1. ^ Beers, Marker H. MD (2006). The Merck Transmission (16th ed.). Whitehouse Station, NJ: Merck Research Laboratories. p. 1764. ISBN0911910-18-2.
  2. ^ a b c Kerkar, Pramod, M.D., FFARCSI, DA. "Exaggerated Startle Response: Causes, Symptoms, Handling, Recovery, Yoga". PainAssist. PainAssist. Retrieved nineteen May 2020.
  3. ^ a b c Bakker MJ, van Dijk JG, van den Maagdenberg AM, Tijssen MA (2006-05-19). "Startle Syndromes". Lancet Neurology. 5 (six): 513–524. doi:10.1016/S1474-4422(06)70470-7. PMID 16713923. S2CID 24056686.
  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". Motion Disorders. 22 (7): 1017–twenty. doi:10.1002/mds.21411. PMID 17415799.
  5. ^ Koning-Tijssen, M.A.J.; O.F. Brouwer (2000-04-27). "Hyperekplexia in the Neonate". Motion Disorders. xv (6): 1293–6. doi:10.1002/1531-8257(200011)fifteen:6<1293::aid-mds1047>3.0.co;2-chiliad. PMID 11104232.
  6. ^ a b c d e f Tijssen, K.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" (PDF). Archives of Neurology. 52 (vi): 578–582. doi:10.1001/archneur.1995.00540300052012. hdl:2066/20657. PMID 7763205.
  7. ^ a b Lynch, J. Westward. (2008-08-03). "Native glycine receptor subtypes and their physiological roles". Neuropharmacology. 56 (ane): 303–9. doi:10.1016/j.neuropharm.2008.07.034. PMID 18721822. S2CID 43613876.
  8. ^ a b Villmann C, Oertel J, Melzer Due north, Becker CM (2009). "Recessive hyperekplexia mutations of the glycine receptor [alpha]-1 subunit affect cell surface integration and stability". Journal of Neurochemistry. 111 (3): 837–847. doi:10.1111/j.1471-4159.2009.06372.x. PMID 19732286.
  9. ^ Bormann, J.; Northward. Rundstrom; H. Betz; D. Langosch (1993). "Residues within transmembrane segment M2 decide chloride conductance of glycine receptor human being- and hetero-oligomers". EMBO Journal. 12 (10): 3729–37. doi:10.1002/j.1460-2075.1993.tb06050.10. PMC413654. PMID 8404844.
  10. ^ a b Meyer, Grand.; J. Kirsch; H. Betz; D. Langosch (1995). "Identification of a Gephyrin Binding Motif on the Glycine Receptor Beta Subunit". Neuron. fifteen (3): 563–572. doi:ten.1016/0896-6273(95)90145-0. PMID 7546736. S2CID 10164739.
  11. ^ Rees, M. I.; T. M. Lewis; J. B. Kwok; Thousand. 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 man inhibitory glycine receptor (GLRB)". Man Molecular Genetics. 11 (7): 853–860. doi:x.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". Periodical of Neuroscience. 28 (39): 9755–68. doi:10.1523/JNEUROSCI.0509-08.2008. PMC6671229. PMID 18815261.
  13. ^ a b Rees MI, Harvey K, Pearce BR, Chung SK, Duguid IC, Thomas P, Beatty Due south, Graham GE, Armstrong 50, Shiang R, Abbott KJ, Zuberi SM, Stephenson JB, Owen MJ, Tijssen MA, van den Maagdenberg AM, Smart TG, Supplisson S, Harvey RJ (2006). "Mutations in the factor encoding GlyT2 (SLC6A5) define a presynaptic component of human startle affliction". Nature Genetics. 38 (vii): 801–806. doi:10.1038/ng1814. PMC3204411. PMID 16751771.
  14. ^ a b Rees MI, Harvey Thousand, 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 (2003-04-08). "Isoform Heterogeneity of the Human Gephyrin Gene (GPHN), Binding Domains to the Glycine Receptor, and Mutation Analysis in Hyperekplexia". Periodical of Biological Chemistry. 278 (27): 24688–96. doi:10.1074/jbc.M301070200. PMID 12684523.
  15. ^ Fritschy, J.-M.; R. J. Harvey; G. Schwarz (2008). "Gephyrin: where do we stand, where practise we go?". Trends in Neurosciences. 31 (5): 257–264. doi:x.1016/j.tins.2008.02.006. PMID 18403029. S2CID 6885626.
  16. ^ a b Harvey Yard, Duguid IC, Alldred MJ, Beatty SE, Ward H, Go on NH, Lingenfelter SE, Pearce BR, Lundgren J, Owen MJ, Smart TG, Lüscher B, Rees MI, Harvey RJ (2004). "The GDP-GTP Exchange Factor Collybistin: An Essential Determinant of Neuronal Gephyrin Clustering" (PDF). Periodical of Neuroscience. 24 (25): 5816–26. doi:10.1523/JNEUROSCI.1184-04.2004. PMC6729214. PMID 15215304.
  17. ^ a b c Tijssen, Marina A.J.; Rees, Marker I. (1993). "Hyperekplexia". In Adam, Margaret P.; Ardinger, Holly H.; Pagon, Roberta A.; Wallace, Stephanie E.; Bean, Lora J.H.; Stephens, Karen; Amemiya, Anne (eds.). GeneReviews®. Seattle (WA): University of Washington, Seattle. PMID 20301437.
  18. ^ Luef, Thou. J.; Due west. North. Loescher (June 2007). "The issue of levetiracetam in startle disease". Periodical of Neurology. 254 (vi): 808–ix. doi:10.1007/s00415-006-0437-z. PMID 17401745. S2CID 358799.
  19. ^ Vigevano, F.; Thousand. Di Capua; B. Dalla Bernardina (1989). "Startle illness: an avoidable cause of sudden baby death". Lancet. 1 (8631): 216. doi:10.1016/s0140-6736(89)91226-9. PMID 2563117. S2CID 32077413.
  20. ^ Kirstein, 50.; B. P. Silfverskiold (1958). "A Family with Emotionally Precipitated Drop Seizures". Acta Psychiatrica Scandinavica. 33 (iv): 471–6. doi:10.1111/j.1600-0447.1958.tb03533.ten. PMID 13594585. S2CID 143799581.
  21. ^ Kok, O.; One thousand. W. Bruyn (1962). "An Unidentified Hereditary Disease". Lancet. 279 (7243): 1359. doi:10.1016/S0140-6736(62)92475-iii.

External links [edit]

  • GeneReview/NIH/UW entry on Hyperekplexia

hooksafterely39.blogspot.com

Source: https://en.wikipedia.org/wiki/Hyperekplexia

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