Hyperekplexia

Hyperekplexia
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Symptoms
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Differential diagnosis
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Hyperekplexia ("exaggerated surprise") is a neurologic disorder classically characterised by pronounced startle responses to tactile or acoustic stimuli and hypertonia. The hypertonia may be predominantly truncal, attenuated during sleep and less prominent after a 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'>,

 Startle Syndromes, 
 Lancet Neurology, 
 
 Vol. 5(Issue: 6),
 pp. 513–524,
 DOI: 10.1016/S1474-4422(06)70470-7,
 PMID: 16713923,</ref> but some disorders can mimic the exaggerated startle of hyperekplexia.<ref name='Non-Genetic HEP 1'>van de Warrenburg, B. P. C., 
 Persisting Hyperekplexia After Idiopathic, Self-Limiting Brainstem Encephalopathy, 
 Movement Disorders, 
 
 Vol. 22(Issue: 7),
 pp. 1017–20,
 DOI: 10.1002/mds.21411,
 PMID: 17415799,</ref>

Signs and symptoms

The three main signs of hyperekplexia are generalized stiffness, excessive startle beginning at birth and nocturnal myoclonus.<ref name="HEP in the Neonate">Koning-Tijssen, M.A.J.,

 Hyperekplexia in the Neonate, 
 Movement Disorders, 
 
 Vol. 15(Issue: 6),
 pp. 1293–6,
 DOI: <1293::aid-mds1047>3.0.co;2-k 10.1002/1531-8257(200011)15:6<1293::aid-mds1047>3.0.co;2-k,
 PMID: 11104232,</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'>Tijssen, M.A.J., 
 Molecular Genetic Reevaluation of the Dutch Hyperekplexia Family, 
 Archives of Neurology, 
 
 Vol. 52(Issue: 6),
 pp. 578–582,
 DOI: 10.1001/archneur.1995.00540300052012,
 PMID: 7763205,</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' />  There is only genetic evidence for the existence of the major form.<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 forms of heritance, vary based on which gene is affected.

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'>Lynch, J. W.,

 Native glycine receptor subtypes and their physiological roles, 
 Neuropharmacology, 
 
 Vol. 56(Issue: 1),
 pp. 303–9,
 DOI: 10.1016/j.neuropharm.2008.07.034,
 PMID: 18721822,
 
 
 Full text,</ref> Native glycine receptors are thus supposed to be 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'>,

 Recessive hyperekplexia mutations of the glycine receptor [alpha]-1 subunit affect cell surface integration and stability, 
 Journal of Neurochemistry, 
 2009,
 Vol. 111(Issue: 3),
 pp. 837–847,
 DOI: 10.1111/j.1471-4159.2009.06372.x,
 PMID: 19732286,</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 will result in a dominant form of the disease, while mutations that result in truncated or wildly 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'>Bormann, J.,

 Residues within transmembrane segment M2 determine chloride conductance of glycine receptor homo- and hetero-oligomers, 
 EMBO Journal, 
 1993,
 Vol. 12(Issue: 10),
 pp. 3729–37,
 DOI: 10.1002/j.1460-2075.1993.tb06050.x,
 PMID: 8404844,
 PMC: 413654,</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'>Meyer, G., 
 Identification of a Gephyrin Binding Motif on the Glycine Receptor Beta Subunit, 
 Neuron, 
 1995,
 Vol. 15(Issue: 3),
 pp. 563–572,
 DOI: 10.1016/0896-6273(95)90145-0,
 PMID: 7546736,</ref> As such, the defects within the GLRB gene show autosomal recessive inheritance.<ref name='GLRB3'>Rees, M. I., 
 Hyperekplexia associated with compound heterozygote mutations in the beta-subunit of the human inhibitory glycine receptor (GLRB), 
 Human Molecular Genetics, 
 
 Vol. 11(Issue: 7),
 pp. 853–860,
 DOI: 10.1093/hmg/11.7.853,
 PMID: 11929858,</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'>Rousseau, F.,

 The Glycine Transporter GlyT2 Controls the Dynamics of Synaptic Vesicle Refilling in Inhibitory Spinal Cord Neurons, 
 Journal of Neuroscience, 
 
 Vol. 28(Issue: 39),
 pp. 9755–68,
 DOI: 10.1523/JNEUROSCI.0509-08.2008,
 PMID: 18815261,</ref>  Mutations of the SLC6A5 gene have been associated with hyperekplexia in an autosomal recessive manner.<ref name='GlyT2-2'>, 
 Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease, 
 Nature Genetics, 
 2006,
 Vol. 38(Issue: 7),
 pp. 801–806,
 DOI: 10.1038/ng1814,
 PMID: 16751771,
 PMC: 3204411,</ref>  Defects within this gene are hypothesized either to effect the incorporation of the transporter into the cellular membrane or to 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.

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 a sporadic case of hyperekplexia, though experimental data is inconclusive as to whether the mutation is pathogenic.<ref name='GPHN'>,

 Isoform Heterogeneity of the Human Gephyrin Gene (GPHN), Binding Domains to the Glycine Receptor, and Mutation Analysis in Hyperekplexia, 
 Journal of Biological Chemistry, 
 
 Vol. 278(Issue: 27),
 pp. 24688–96,
 DOI: 10.1074/jbc.M301070200,
 PMID: 12684523,</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 synpases and molybdenum cofactor synthesis.<ref name='GPHN2'>Fritschy, J.-M., 
 Gephyrin: where do we stand, where do we go?, 
 Trends in Neurosciences, 
 2008,
 Vol. 31(Issue: 5),
 pp. 257–264,
 DOI: 10.1016/j.tins.2008.02.006,
 PMID: 18403029,</ref> Because of its multi-functional nature, 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 in concert with epilepsy.<ref name='ARHGEF9'>,

 The GDP-GTP Exchange Factor Collybistin: An Essential Determinant of Neuronal Gephyrin Clustering, 
 Journal of Neuroscience, 
 2004,
 Vol. 24(Issue: 25),
 pp. 5816–26,
 DOI: 10.1523/JNEUROSCI.1184-04.2004,
 PMID: 15215304,
 
 
 Full text,</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 an artificial lack of glycine and GABA receptors at the synaptic cleft.<ref name='ARHGEF9' />

Diagnosis

There are three conditions 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">Marina AJ,

 GeneReviews®, 
  
 Seattle (WA):University of Washington, Seattle,</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 exist.<ref name=":0" />

Treatment

The most commonly 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'>Luef, G. J.,

 The effect of levetiracetam in startle disease, 
 Journal of Neurology, 
 
 Vol. 254(Issue: 6),
 pp. 808–9,
 DOI: 10.1007/s00415-006-0437-z,
 PMID: 17401745,</ref>  During attacks of hypertonia and apnea, the limbs and head may be flexed towards the trunk in order to dissipate the symptoms.  This is named the Vigevano maneuver after the doctor who invented it.<ref name='Vigevano'>Vigevano, F., 
 Startle disease: an avoidable cause of sudden infant death, 
 Lancet, 
 1989,
 Vol. 1(Issue: 8631),
 pp. 216,
 DOI: 10.1016/s0140-6736(89)91226-9,
 PMID: 2563117,</ref>

History

The disorder was first described in 1958 by Kirstein and Silfverskiold, who reported a family with 'drop seizures'.<ref name='Original Case'>Kirstein, L.,

 A Family with Emotionally Precipitated Drop Seizures, 
 Acta Psychiatrica et Neurologica, 
 1958,
 Vol. 33(Issue: 4),
 pp. 471–6,
 DOI: 10.1111/j.1600-0447.1958.tb03533.x,</ref> In 1962 Drs. Kok and Bruyn reported an unidentified hereditary syndrome, initially started as hypertonia in infants.<ref name='Kok and Bruyn'>Kok, O., 
 An Unidentified Hereditary Disease, 
 Lancet, 
 1962,
 Vol. 279(Issue: 7243),
 pp. 1359,
 DOI: 10.1016/S0140-6736(62)92475-3,</ref>  Genetic analysis within this large Dutch pedigree was later found to carry a mutation within the GLRA1 gene, which was the first gene implicated in hyperekplexia.<ref name='Dutch Family Molecular Genetics' />

See also

• Jumping Frenchmen of Maine
• Latah
• Stiff person syndrome

External links

• GeneReview/NIH/UW entry on Hyperekplexia