• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details


Synonyms: Hyperekplexia, Hereditary; Startle Disease, Familial; Startle Syndrome. Includes: ARHGEF9-Related Hyperekplexia, GLRA1-Related Hyperekplexia, GLRB-Related Hyperekplexia, GPHN-Related Hyperekplexia, SLC6A5-Related Hyperekplexia

, MD and , PhD.

Author Information
, MD
Department of Neurology
University Medical Center Groningen
Groningen, Netherlands
, PhD
Director, Wales Epilepsy Research Network
School of Medicine
Swansea University
Swansea, Wales, United Kingdom

Initial Posting: ; Last Update: October 4, 2012.


Disease characteristics. Hereditary hyperekplexia (HPX) is characterized by generalized stiffness immediately after birth that normalizes during the first years of life; excessive startle reflex (eye blinking and a flexor spasm of the trunk) to unexpected (particularly auditory) stimuli; and a short period of generalized stiffness following the startle response during which voluntary movements are impossible. Exaggerated head-retraction reflex (HRR) consisting of extension of the head followed by violent flexor spasms of limbs and neck muscles elicited by tapping the tip of the nose is observed in most children. Other findings include periodic limb movements in sleep (PLMS) and hypnagogic (occurring when falling asleep) myoclonus. Sudden infant death (SIDS) has been reported. Intellect is usually normal; mild intellectual disability may occur.

Diagnosis/testing. The diagnosis of HPX is based on clinical findings. Mutations in five genes are known to cause HPX. GLRA1, encoding glycine receptor subunit α1, accounts for about 80% of HPX. The other genes in which mutations are causative are: SLC6A5, encoding the presynaptic sodium- and chloride-dependent glycine transporter 2 (GlyT2); GLRB, encoding glycine receptor subunit beta; GPHN, encoding the glycinergic clustering molecule, gephyrin; and ARHGEF9, encoding collybistin.

Management. Treatment of manifestations: The drug clonazepam is most effective in reducing symptoms, including stiffness in the neonatal period and stiffness related to the excessive startle reflex; other drugs with variable results include carbamazepine, phenytoin, diazepam, valproate, 5-hydroxytryptophan, piracetam, and phenobarbital. Physical and cognitive therapy may reduce the fear of falling and thereby improve walking.

Prevention of primary manifestations: Clonazepam.

Genetic counseling. HPX is inherited in an autosomal dominant, autosomal recessive, or, rarely, X-linked manner. Most individuals diagnosed with autosomal dominant HPX have an affected parent; de novo mutations are rare. Each child of an individual with autosomal dominant HPX has a 50% chance of inheriting the mutation. The parents of a child with autosomal recessive HPX are obligate heterozygotes and therefore carry one mutant allele. At conception, each sib of an individual with autosomal recessive HPX has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Prenatal testing for most families with hyperekplexia is possible if the mutation(s) have been identified.


Clinical Diagnosis

Diagnosis of hereditary hyperekplexia (HPX) requires the following three cardinal features:

  • Generalized stiffness immediately after birth, normalizing during the first years of life. The stiffness increases with handling and disappears during sleep [Koning-Tijssen & Brouwer 2000].
  • Excessive startle reflex to unexpected (particularly auditory) stimuli. This excessive startle reflex is present at birth. Consciousness is unaltered during startle responses.
  • Short period of generalized stiffness following the startle response during which voluntary movements are impossible. Note: On rare occasion this feature is absent.

Associated features that may be present but are not essential for the diagnosis of HPX include the following:

  • Exaggerated head-retraction reflex (HRR). In neonates HRR comprises extension of the head, followed by violent flexor spasms of limbs and neck muscles elicited by tapping the tip of the nose but no other part of the nose, forehead, or face [Kurczynski 1983, Dalla Bernardina et al 1989, Shahar et al 1991]. This response is present when the child is awake or asleep and shows no habituation. In adults only the excessive extension of the head is seen. Note: Some consider the HRR essential for diagnosis [Rees et al 2001].
  • Periodic limb movements in sleep (PLMS) and hypnagogic myoclonus (myoclonus occurring when falling asleep)
  • Inguinal, umbilical, or epigastric herniae
  • Congenital dislocation of the hip
  • Sudden infant death (SIDS)
  • Normal intelligence in most; mild intellectual disability in some


In general, all laboratory tests are normal in individuals with HPX, including CT and MRI of the brain.

Molecular Genetic Testing

Genes. Mutations in one of the following genes are known to cause HPX:

  • GLRA1, the gene encoding the α1 subunit of the glycine receptor, is the major genetic cause of HPX. Dominant and recessive mutations are identified in many individuals with the familial form of HPX and occasionally in simplex cases (i.e., a single occurrence of HPX in a family). For an overview see Bakker et al [2006].
  • SLC6A5, the gene encoding the presynaptic sodium- and chloride-dependent glycine transporter 2 (GlyT2), is probably also frequently involved [Rees et al 2006].
  • GLRB, the gene encoding glycine receptor subunit beta, has been associated with HPX in one individual, in whom compound heterozygous mutations were detected [Rees et al 2002].
  • GPHN, the gene encoding the glycinergic clustering molecule gephyrin, has been associated with HPX in one person [Rees et al 2003].
  • ARHGEF9, an X-linked gene encoding collybistin, has been associated with HPX in one person [Harvey et al 2004]. This child also had severe epilepsy and intellectual disability and died at age four years.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Hyperekplexia

Gene SymbolProportion of HPX Attributed to Mutations in This Gene 1 Test MethodMutations Detected
GLRA1Familial: ~80% 2
Simplex: see footnote 3
Sequence analysisSequence variants 4, 5
6 persons 3 Deletion / duplication analysis 6Deletion of exons 1-6 and novel deletions 7, 8
SLC6A58 persons 3 Sequence analysisSequence variants 4
Deletion / duplication analysis 6Exonic and whole-gene deletions / duplications 9
GLRB1 person 3 Sequence analysisSequence variants 4
Deletion / duplication analysis 6Exonic and whole-gene deletions / duplications 9
GPHN1 person 3 Sequence analysisSequence variants 4
ARHGEF91 person 3Sequence analysisSequence variants 4, 10, 11
Deletion / duplication analysis 6Exonic and whole-gene deletions / duplications 9

1. Based on more than 40 unrelated affected individuals

2. The mutation detection frequency for GLRA1 in familial hyperekplexia is high as befits a channelopathy disorder with highly penetrant mutations. The exact number is unknown, but in individuals with HPX and a first-degree family member with HPX, the mutation detection frequency is around 80% [author, personal experience/unpublished data].

3. The mutation detection frequency for all genes among individuals without a family history of HPX averages about 20% overall [Vergouwe et al 1997, Milani et al 1998, Rees et al 2001] and mainly involves compound heterozygotes or homozygotes from consanguineous relationships.

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

5. Missense and nonsense mutations have been identified in autosomal dominant and autosomal recessive HPX.

6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

7. Heterozygous carriers of the GLRA1 exon 1-6 deletion cannot be detected by PCR. Detection requires deletion/duplication analysis. Lack of PCR amplification of exons 1-6 implies presence of a homozygous deletion; confirmation may require deletion/duplication analysis.

8. An individual with autosomal recessive HPX and homozygous deletion of GLRA1 exons 1-6 was identified [Brune et al 1996]. Subsequently, this homozygous deletion was found in several Turkish individuals [Sirén et al 2006].

9. No deletions or duplications of GLRB, ARHGEF9, or SLC6A5 have been reported to cause hyperekplexia. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)

10. Identifies a mutation in exon 2 reported by Harvey et al [2004] as well as other as-yet unreported sequence variants

11. Lack of amplification by PCR prior to sequence analysis can suggest a putative exonic, multiexonic, or whole-gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

Testing Strategy

Confirmation of the diagnosis of HPX relies on molecular genetic testing. Additional imaging prior to molecular genetic testing is not necessary.

  • Single gene testing. The most common strategy for molecular diagnosis of a proband who meets HPX clinical inclusion criteria is sequencing of GLRA1 and SLC6A5. Sequence analysis of ARHGEF9 may be considered in males without identified GLRA1 or SLC6A5 mutations, particularly if cognitive impairment and epilepsy are present. If clinical suspicion is strong and the above tests do not reveal a pathogenic change, molecular testing of GLRB, GPHN, and ARHGEF9 can be considered.
  • Multi-gene testing. Consider using a hyperekplexia multi-gene panel that includes genes associated with hyperekplexia. These panels vary by methods used and genes included; thus, the ability of a panel to detect a causative mutation or mutations in any given individual also varies.

Carrier testing for relatives at risk for autosomal recessive hyperekplexia requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Hereditary hyperekplexia (HPX) has three cardinal features: excessive startle reflexes, stiffness at birth, and stiffness related to the startle reflex.

Excessive startle response. The most striking feature of HPX is the excessive startle response to unexpected (particularly auditory) stimuli. The excessive startle response is present from birth.

The excessive startle leads to excessive stiffening in the neonate and young infant; however, not all infants with hyperekplexia can be startled during examination [Gherpelli et al 1995, Vergouwe et al 1997, Koning-Tijssen & Brouwer 2000].

The frequency of startle responses varies considerably among individuals and over time. Factors that increase the frequency of the startle responses include emotional tension, nervousness, fatigue, and even the expectation of being frightened. Holding objects or drinking alcohol reduces the intensity and frequency of startle responses.

The excessive startle reflex has major implications for daily life as unexpected stimuli from the outside world cannot be regulated.

Generalized stiffness immediately after birth. Generalized stiffness occurs immediately after birth, usually normalizing during the first years of life. The stiffness increases with handling and disappears during sleep. Held horizontally the baby is as "stiff as a stick." The baby is alert, but shows marked hypokinesia [Koning-Tijssen & Brouwer 2000]. Handling a baby, for example when changing diapers, is difficult because spreading of the legs is limited by stiffness. Affected children usually have delayed milestones but catch up later.

Generalized stiffness following the startle response. This is a short period during which voluntary movements are impossible [Bernasconi et al 1996]; the stiffness is so severe that it prevents the individual, who retains consciousness, from putting out his/her arms to break a fall. Adults with HPX often walk with a stiff-legged, mildly wide-based gait without signs of ataxia.

Other. A fourth feature considered to be a hallmark of HPX in stiff newborns and adults [Rees et al 2001] is an exaggerated head-retraction reflex (HRR), elicited by tapping on the nose. It has also been described in children with cerebral palsy resulting from severe neonatal asphyxia. Not all adults with HPX have an exaggerated HRR. In daily life persons with HPX note hypersensitivity in the mantle area (the area round the mouth).

Attacks of tonic neonatal cyanosis have been described in neonates with HPX [Vergouwe et al 1997, Miraglia Del Giudice et al 2003, Rees et al 2006, Rivera et al 2006]. These attacks can be associated with SIDS. Attacks of tonic neonatal cyanosis often resolve during infancy [Rees et al 2006].

Genotype-Phenotype Correlations

No specific genotype-phenotype correlations are known in HPX.

Bellini et al [2007] reported a male child with hyperekplexia and a dominant-negative GLRA1 mutation that suppressed normal GLRA1 channel function (heterozygous p.Ser296X).

Mutations in SLC6A5 may be regarded as a risk factor for attacks of tonic neonatal cyanosis and SIDS. Conversely, attacks of tonic neonatal cyanosis are rarely seen in infants with GLRA1 mutations [Matsumoto et al 1992].


Overall, the penetrance of hyperekplexia is 100%; however, in one family a mother who had the same mutation as her two children was asymptomatic [Kwok et al 2001].


Anticipation is not observed in HPX.


Terms used for hyperekplexia in the past that are no longer in use include the following:

  • Exaggerated startle reaction
  • Hyperexplexia
  • Stiff baby syndrome
  • Stiff person syndrome, congenital
  • Stiff man syndrome, congenital
  • Kok disease

Although the original Dutch family reported [Suhren et al 1966] was said to have a "major form" and a "minor form" consisting solely of a reportedly excessive response to startling stimuli [Andermann et al 1980], it now appears that no genetic entity conforms to the "minor form" [Tijssen et al 1995, Tijssen et al 1996, Crone et al 2001, Tijssen et al 2002, Bakker et al 2006] and thus the term is no longer in use. The etiology of the clinically detected "minor form" needs further investigation.


Hereditary HPX has been identified in more than 70 pedigrees and many different nationalities.

Differential Diagnosis

The following three types of disorders need to be considered in a person with excessive startle response (see Bakker et al [2006] for a detailed review).

Hyperekplexia (HPX) as described in this GeneReview (i.e., with excessive startle response, stiffness related to the startle reflex, and stiffness in the neonatal period) is rarely symptomatic of another disorder. Exceptions:

  • One individual with a similar neonatal phenotype who was determined to have molybdenum cofactor deficiency [Macaya et al 2005] (see Genetically Related Disorders). Molybdenum cofactor deficiency should be considered in those with apparent HPX who are refractory to treatment with clonazepam.
  • Those with late onset (i.e., without stiffness in the neonatal period), in whom damage to the brain stem should be considered

Neuropsychiatric startle syndromes. In addition to excessive startling, behavioral and/or psychiatric symptoms are observed. Included in this group:

  • Culture-specific syndromes, such as the “jumping Frenchman of Maine,” in which non-habituating hyperstartling occurs within a community, evoked by loud noises or a forceful poke in the side. Following a startle reflex other responses may be seen, including echolalia and echopraxia.
  • Hysterical jumps, which clinically resemble disorders like latah but are not culture specific
  • Anxiety disorders
  • Gilles de la Tourette syndrome, in which an exaggerated startle reflex has been described in some, but not all, affected individuals

Startle-induced disorders. In this diverse group of disorders the startle reflex itself is not excessive, but rather induces another clinical feature that is more prominent than the exaggerated startle response. Examples:

Another startle-induced disorder is stiff person syndrome (SPS), characterized by progressive axial stiffness and intermittent spasms that are usually evoked by unexpected stimuli. Onset is generally between ages 40 and 60 years. The combination of stiffness and startle-induced falls closely resembles HPX. The stiffness in SPS is, however, nearly continuous, contrasting sharply with stiffness in adult HPX, which only occurs after a startle and lasts one to two seconds. In SPS, electromyogram of the long back muscles shows continuous muscle activity.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).


Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with hyperekplexia (HPX), the following evaluations are recommended:

  • Neurologic examination
  • Evaluation for the head retraction reflex
  • Medical genetics consultation

Treatment of Manifestations

Clonazepam appears to be the most effective treatment for HPX [Tijssen et al 1997, Tsai et al 2004]. In adults the initial dose is 0.5 mg twice a day. The dose can be increased up to 2.0 mg three times a day. The stiffness in the neonatal period and stiffness related to startle diminish with the treatment.

Other drugs, mostly described in case reports, have shown variable results; they include carbamazepine, phenytoin, diazepam, valproate, 5-hydroxytryptophan, piracetam, and phenobarbital. For an overview see Bakker et al [2006].

Physical and cognitive therapy to reduce the fear of falling and thereby improve walking can be considered; no randomized trials have assessed the effectiveness of such treatment.

Attacks of tonic neonatal cyanosis can be stopped by the Vigevano maneuver, consisting of forced flexion of the head and legs towards the trunk [Vigevano et al 1989].

Prevention of Primary Manifestations

See Treatment of Manifestations, clonazepam.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Hyperekplexia (HPX) is inherited in an autosomal dominant, autosomal recessive, or (rarely) X-linked manner.

Note: In simplex cases (i.e., a single occurrence in a family), mode of inheritance is determined by testing the parents of a proband. When the parents are not available, sequence analysis is used to demonstrate biallelic inheritance in compound heterozygotes.

Risk to Family Members — Autosomal Dominant Inheritance

Parents of a proband

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • If a disease-causing mutation cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband. Each child of an individual with autosomal dominant HPX has a 50% chance of inheriting the mutation.

Other family members of a proband

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent is affected, his or her family members are at risk.

Risk to Family Members — Autosomal Recessive Inheritance

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) do not exhibit the hyperekplexia phenotype regardless of mutation type (i.e., missense or nonsense).

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with autosomal recessive HPX are obligate heterozygotes (carriers) for a disease-causing mutation.

Carrier Detection

Carrier testing for at-risk family members is possible once the mutation(s) have been identified in the proband.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Autosomal dominant or autosomal recessive HPX. If the disease-causing mutation(s) have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

X-linked HPX. If the disease-causing mutation has been identified in an affected family member, prenatal diagnosis for pregnancies at increased risk for ARHGEF9-related hyperekplexia is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation). Usually fetal sex is determined first and molecular genetic testing is performed if the karyotype is 46,XY.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation(s) have been identified.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Hyperekplexia: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Hyperekplexia (View All in OMIM)


See Figure 1.

Figure 1


Figure 1. Glycine receptor complex

Glycine transporters (GlyTs) are members of the Na+/Cl--dependent neurotransmitter transporter superfamily. GlyTs have dual functions at both inhibitory and excitatory synapses, resulting from the differential (more...)


Normal allelic variants. GLRA1 comprises nine exons (Reference sequence NM_001146040.1).

Pathologic allelic variants. Several missense and nonsense mutations have been identified in autosomal dominant, recessive, or compound heterozygote hyperekplexia (HPX). Abnormal allelic variants of GLRA1 in the public domain are summarized in Table 2 (pdf).

Sirén et al [2006] reported six affected individuals from two consanguineous Kurdish families from Turkey with HPX resulting from a homozygous deletion of the first seven GLRA1 exons, suggesting a founder mutation in this population.

Normal gene product. GLRA1 encodes alpha-1 subunit of the inhibitory glycine receptor. See Figure 1.

Abnormal gene product. In GLRA1 the abnormal gene products are categorized as missense or nonsense. Missense mutations cause biophysical alterations in the properties of the glycine channel which often lead to compromised channel dynamics.

In contrast to murine models of the disease, deletions in GLRA1 that are null mutations are not lethal in humans.

In GlyT2 the transporter functions are knocked out by a process of nonsense-mediated decay, disruption of the glycine uptake, or inhibition of Na+ ion coactivation.


Normal allelic variants. GLRB has ten exons (Reference sequence NM_000824.4).

Pathologic allelic variants. Abnormal allelic variants of GLRB in the public domain are summarized in Table 3 (pdf).

Normal gene product. GLRB encodes glycine receptor subunit beta, which is composed of 497 amino acids (NP_000815.1). See Figure 1.

Abnormal gene product. See Figure 1.


Normal allelic variants. SLC6A5 has 16 exons (Reference sequence NM_004211.3).

Pathologic allelic variants. Abnormal allelic variants of SLC6A5 in the public domain are summarized in Table 4 (pdf).

Normal gene product. SLC6A5 encodes sodium- and chloride-dependent glycine transporter 2, which has 797 amino acids (NP_004202.2).

Abnormal gene product. See Figure 1.


Normal allelic variants. GPHN has 23 exons (Reference sequence NM_020806.4).

Pathologic allelic variants. Abnormal allelic variants of GPHN in the public domain are summarized in Table 5 (pdf).

Normal gene product. Gephyrin, a pleiotropic protein with both a postsynaptic and metabolic biologic role, comprises 769 amino acids (NP_065857.1).

Abnormal gene product. See Figure 1.


Normal allelic variants. ARHGEF9 has ten exons (Reference sequence NM_015185.2).

Pathologic allelic variants. Pathologic alleles appear to disrupt interaction of collybistin with other important signaling proteins [Harvey et al 2004]. See Table A.

Normal gene product. Collybistin, also known as rho guanine nucleotide exchange factor 9, belongs to a family of regulators involved in cell signaling. The brain-specific collybistin interacts with gephyrin and subsequently regulates actin cytoskeleton dynamics.

Abnormal gene product. See Figure 1.


Literature Cited

  1. Andermann F, Keene DL, Andermann E, Quesney LF. Startle disease or hyperekplexia: further delineation of the syndrome. Brain. 1980;103:985–97. [PubMed: 6777025]
  2. Bakker MJ, van Dijk JG, van den Maagdenberg AM, Tijssen MA. Startle syndromes. Lancet Neurol. 2006;5:513–24. [PubMed: 16713923]
  3. Bellini G, Miceli F, Mangano S, Miraglia del Giudice E, Coppola G, Barbagallo A, Taglialatela M, Pascotto A. Hyperekplexia caused by dominant-negative suppression of GLYRA1 function. Neurology. 2007;68:1947–9. [PubMed: 17536053]
  4. Bernasconi A, Regli F, Schorderet DF, Pescia G. Familial hyperekplexia: startle disease. Clinical, electrophysiological and genetic study of a family. Rev Neurol (Paris). 1996;152:447–50. [PubMed: 8944241]
  5. Brune W, Weber RG, Saul B, von Knebel Doeberitz M, Grond-Ginsbach C, Kellerman K, Meinck HM, Becker CM. A GLRA1 null mutation in recessive hyperekplexia challenges the functional role of glycine receptors. Am J Hum Genet. 1996;58:989–97. [PMC free article: PMC1914607] [PubMed: 8651283]
  6. Crone C, Nielsen J, Petersen N, Tijssen MA, van Dijk JG. Patients with the major and minor form of hyperekplexia differ with regards to disynaptic reciprocal inhibition between ankle flexor and extensor muscles. Exp Brain Res. 2001;140:190–7. [PubMed: 11521151]
  7. Dalla Bernardina B, Fontana E, Colamaria V, La Selva L, Merlin D, Sgro V, Scarpa P. Neonatal hyperexplexia. In: Beaumanoir A, Gastaut H, Naquet R, eds. Reflex Seizures and Reflex Epilepsies. Geneva, Switzerland: Editions Médicine et Hygiène; 1989:409-14.
  8. Feng G, Tintrup H, Kirsch J, Nichol MC, Kuhse J, Betz H, Sanes JR. Dual requirement for gephyrin in glycine receptor clustering and molybdoenzyme activity. Science. 1998;282:1321–4. [PubMed: 9812897]
  9. Gherpelli JL, Nogueira AR, Troster EJ, Deutsch AD, Leone CR, Brotto MW, Diament A, Ramos JL. Hyperekplexia, a cause of neonatal apnea: a case report. Brain Dev. 1995;17:114–6. [PubMed: 7625544]
  10. Harvey K, Duguid IC, Alldred MJ, Beatty SE, Ward H, Keep NH, Lingenfelter SE, Pearce BR, Lundgren J, Owen MJ, Smart TG, Luscher B, Rees MI, Harvey RJ. The GDP-GTP exchange factor collybistin: an essential determinant of neuronal gephyrin clustering. J Neurosci. 2004;24:5816–26. [PubMed: 15215304]
  11. Kalscheuer VM, Musante L, Fang C, Hoffmann K, Fuchs C, Carta E, Deas E, Venkateswarlu K, Menzel C, Ullmann R, Tommerup N, Dalprà L, Tzschach A, Selicorni A, Lüscher B, Ropers HH, Harvey K, Harvey RJ. A balanced chromosomal translocation disrupting ARHGEF9 is associated with epilepsy, anxiety, aggression, and mental retardation. Hum Mutat. 2009;30:61–8. [PMC free article: PMC3621145] [PubMed: 18615734]
  12. Koning-Tijssen MA, Brouwer OF. Hyperekplexia in the first year of life. Mov Disord. 2000;15:1293–6. [PubMed: 11104232]
  13. Kurczynski TW. Hyperekplexia. Arch Neurol. 1983;40:246–8. [PubMed: 6830476]
  14. Kwok JB, Raskin S, Morgan G, Antoniuk SA, Bruk I, Schofield PR. Mutations in the glycine receptor alpha1 subunit (GLRA1) gene in hereditary hyperekplexia pedigrees: evidence for non-penetrance of mutation Y279C. J Med Genet. 2001;38:E17. [PMC free article: PMC1734885] [PubMed: 11389164]
  15. Macaya A, Brunso L, Fernandez-Castillo N, Arranz JA, Ginjaar HB, Cuenca-Leon E, Corominas R, Roig M, Cormand B. Molybdenum cofactor deficiency presenting as neonatal hyperekplexia: a clinical, biochemical and genetic study. Neuropediatrics. 2005;36:389–94. [PubMed: 16429380]
  16. Marco EJ, Abidi FE, Bristow J, Dean WB, Cotter P, Jeremy RJ, Schwartz CE, Sherr EH. ARHGEF9 disruption in a female patient is associated with X linked mental retardation and sensory hyperarousal. J Med Genet. 2008;45:100–5. [PubMed: 17893116]
  17. Matsumoto J, Fuhr P, Nigro M, Hallett M. Physiological abnormalities in hereditary hyperekplexia. Ann Neurol. 1992;32:41–50. [PubMed: 1642471]
  18. Milani N, Mulhardt C, Weber RG, Lichter P, Kioschis P, Poustka A, Becker CM. The human glycine receptor beta subunit gene (GLRB): structure, refined chromosomal localization, and population polymorphism. Genomics. 1998;50:341–5. [PubMed: 9676428]
  19. Miraglia Del Giudice E, Coppola G, Bellini G, Ledaal P, Hertz JM, Pascotto A. A novel mutation (R218Q) at the boundary between the N-terminal and the first transmembrane domain of the glycine receptor in a case of sporadic hyperekplexia. J Med Genet. 2003;40:e71. [PMC free article: PMC1735464] [PubMed: 12746425]
  20. 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. Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease. Nat Genet. 2006;38:801–6. [PMC free article: PMC3204411] [PubMed: 16751771]
  21. 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. Isoform heterogeneity of the human gephyrin gene (GPHN), binding domains to the glycine receptor, and mutation analysis in hyperekplexia. J Biol Chem. 2003;278:24688–96. [PubMed: 12684523]
  22. Rees MI, Lewis TM, Kwok JB, Mortier GR, Govaert P, Snell RG, Schofield PR, Owen MJ. Hyperekplexia associated with compound heterozygote mutations in the beta-subunit of the human inhibitory glycine receptor (GLRB). Hum Mol Genet. 2002;11:853–60. [PubMed: 11929858]
  23. Rees MI, Lewis TM, Vafa B, Ferrie C, Corry P, Muntoni F, Jungbluth H, Stephenson JB, Kerr M, Snell RG, Schofield PR, Owen MJ. Compound heterozygosity and nonsense mutations in the alpha(1)-subunit of the inhibitory glycine receptor in hyperekplexia. Hum Genet. 2001;109:267–70. [PubMed: 11702206]
  24. Rivera S, Villega F, de Saint-Martin A, Matis J, Escande B, Chaigne D, Astruc D. Congenital hyperekplexia: five sporadic cases. Eur J Pediatr. 2006;165:104–7. [PubMed: 16211400]
  25. Shahar E, Brand N, Uziel Y, Barak Y. Nose tapping test inducing a generalized flexor spasm: a hallmark of hyperexplexia. Acta Paediatr Scand. 1991;80:1073–7. [PubMed: 1750341]
  26. Sirén A, Legros B, Chahine L, Mission JP, Pandolfo M. Hyperekplexia in Kurdish families: a possible GLRA1 founder mutation. Neurology. 2006;67:137–9. [PubMed: 16832093]
  27. Suhren O, Bruyn GW, Tuynman A. Hyperexplexia, a hereditary startle syndrome. J Neurol Sci. 1966;3:577–605.
  28. Tijssen MA, Padberg GW, van Dijk JG. The startle pattern in the minor form of hyperekplexia. Arch Neurol. 1996;53:608–13. [PubMed: 8929168]
  29. Tijssen MA, Schoemaker HC, Edelbroek PJ, Roos RA, Cohen AF, van Dijk JG. The effects of clonazepam and vigabatrin in hyperekplexia. J Neurol Sci. 1997;149:63–7. [PubMed: 9168167]
  30. Tijssen MA, Shiang R, van Deutekom J, Boerman RH, Wasmuth JJ, Sandkuijl LA, Frants RR, Padberg GW. Molecular genetic reevaluation of the Dutch hyperekplexia family. Arch Neurol. 1995;52:578–82. [PubMed: 7763205]
  31. Tijssen MA, Vergouwe MN, van Dijk JG, Rees M, Frants RR, Brown P. Major and minor form of hereditary hyperekplexia. Mov Disord. 2002;17:826–30. [PubMed: 12210885]
  32. Tsai CH, Chang FC, Su YC, Tsai FJ, Lu MK, Lee CC, Kuo CC, Yang YW, Lu CS. Two novel mutations of the glycine receptor gene in a Taiwanese hyperekplexia family. Neurology. 2004;63:893–6. [PubMed: 15365143]
  33. Vergouwe MN, Tijssen MA, Shiang R, van Dijk JG, al Shahwan S, Ophoff RA, Frants RR. Hyperekplexia-like syndromes without mutations in the GLRA1 gene. Clin Neurol Neurosurg. 1997;99:172–8. [PubMed: 9350397]
  34. Vigevano F, Di Capua M, Dalla Bernardina B. Startle disease: an avoidable cause of sudden infant death. Lancet. 1989;1:216. [PubMed: 2563117]

Suggested Reading

  1. Breitinger HG, Becker CM. The inhibitory glycine receptor-simple views of a complicated channel. Chembiochem. 2002;3:1042–52. [PubMed: 12404628]
  2. Brown P. Neurophysiology of the startle syndrome and hyperekplexia. Adv Neurol. 2002;89:153–9. [PubMed: 11968441]
  3. Eulenburg V, Armsen W, Betz H, Gomeza J. Glycine transporters: essential regulators of neurotransmission. Trends Biochem Sci. 2005;30:325–33. [PubMed: 15950877]
  4. Jen JC, Ptacek L. Channelopathies: episodic disorders of the nervous system. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 204. Available online. Accessed 9-28-12.
  5. Lerman-Sagie T, Watemberg N, Vinkler C, Fishhof J, Leshinsky-Silver E, Lev D. Familial hyperekplexia and refractory status epilepticus: a new autosomal recessive syndrome. J Child Neurol. 2004;19:522–5. [PubMed: 15526957]
  6. Lynch JW. Molecular structure and function of the glycine receptor chloride channel. Physiol Rev. 2004;84:1051–95. [PubMed: 15383648]
  7. Noebels JL. The inherited epilepsies. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 230. Available online. Accessed 9-28-12.
  8. Tijssen MAJ, Brown P. Channelopathies of the nervous system. In: Rose M, Griggs RC, eds. Hyperekplexia. Oxford, UK: Butterworth Heinemann; 2001:259-73.

Chapter Notes

Revision History

  • 4 October 2012 (me) Comprehensive update posted live
  • 19 May 2009 (cd) Revision: sequence analysis of GLRB available clinically
  • 31 July 2007 (me) Review posted to live Web site
  • 6 July 2006 (sgr) Original submission
Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1260PMID: 20301437
PubReader format: click here to try


Tests in GTR by Gene

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...