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Hyperekplexia

Synonyms: Hyperekplexia, Hereditary; Startle Disease, Familial; Startle Syndrome

, MD and , PhD.

Author Information

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

Summary

Clinical 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. Pathogenic variants 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 pathogenic variants 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 pathogenic variants are rare. Each child of an individual with autosomal dominant HPX has a 50% chance of inheriting the pathogenic variant. The parents of a child with autosomal recessive HPX are obligate heterozygotes and therefore carry one mutated 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 pathogenic variant(s) have been identified.

Diagnosis

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

Testing

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

Molecular Genetic Testing

Genes. Pathogenic variants 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 pathogenic variants 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 pathogenic variants 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.

Table 1.

Summary of Molecular Genetic Testing Used in Hyperekplexia

Gene 1Proportion of HPX Attributed to Pathogenic Variants in This Gene 2Test MethodVariants Detected 3
GLRA1Familial: ~80% 4
Simplex: see footnote 5
Sequence analysis 6Sequence variants 7
6 persons 5Deletion/duplication analysis 8Deletion of exons 1-6 & novel deletions 9, 10
SLC6A58 persons 5Sequence analysis 6Sequence variants
Deletion/duplication analysis 6Exon & whole-gene deletions/duplications 11
GLRB1 person 5Sequence analysis 6Sequence variants
Deletion/duplication analysis 8Exon & whole-gene deletions/duplications 11
GPHN1 person 5Sequence analysis 6Sequence variants
ARHGEF91 person 5Sequence analysis 6Sequence variants 12, 13
Deletion/duplication analysis 8Exon & whole-gene deletions/duplications 11
1.
2.

Based on more than 40 unrelated affected individuals

3.

See Molecular Genetics for information on allelic variants.

4.

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and a first-degree family member with HPX, the variant detection frequency is around 80% [Author, personal experience/unpublished data].

5.

The variant 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.

6.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

7.

Pathogenic missense and nonsense variants have been identified in autosomal dominant and autosomal recessive HPX.

8.

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.

9.

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.

10.

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].

11.

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.)

12.

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

13.

Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon 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.

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 pathogenic variants, 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 pathogenic variant or variants in any given individual also varies.

Carrier testing for relatives at risk for autosomal recessive hyperekplexia requires prior identification of the pathogenic variants 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 pathogenic variant(s) in the family.

Clinical Characteristics

Clinical Description

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 pathogenic variant that suppressed normal GLRA1 channel function (heterozygous p.Ser296Ter).

Pathogenic variants 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 pathogenic variants [Matsumoto et al 1992].

Penetrance

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

Anticipation

Anticipation is not observed in HPX.

Nomenclature

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.

Prevalence

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.

Management

Evaluations Following Initial Diagnosis

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

  • Neurologic examination
  • Evaluation for the head retraction reflex
  • Clinical 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 pathogenic variant cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo pathogenic variant 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 pathogenic variant.

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 mutated allele.
  • Heterozygotes (carriers) do not exhibit the hyperekplexia phenotype regardless of variant 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 pathogenic variant.

Carrier Detection

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

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, it is likely that the proband has a de novo variant. 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 are 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the pathogenic variant(s) have been identified in an affected family member, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic diagnosis for hyperekplexia are possible.

Resources

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.

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 from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein 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)

138491GLYCINE RECEPTOR, ALPHA-1 SUBUNIT; GLRA1
138492GLYCINE RECEPTOR, BETA SUBUNIT; GLRB
149400HYPEREKPLEXIA, HEREDITARY 1; HKPX1
300429RHO GUANINE NUCLEOTIDE EXCHANGE FACTOR 9; ARHGEF9
300607EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 8; EIEE8
603930GEPHYRIN; GPHN
604159SOLUTE CARRIER FAMILY 6 (NEUROTRANSMITTER TRANSPORTER, GLYCINE), MEMBER 5; SLC6A5
614618HYPEREKPLEXIA 3; HKPX3
614619HYPEREKPLEXIA 2; HKPX2

See Figure 1.

Figure 1. . Glycine receptor complex Glycine transporters (GlyTs) are members of the Na+/Cl--dependent neurotransmitter transporter superfamily.

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 localization of (more...)

GLRA1

Gene structure. GLRA1 comprises nine exons (Reference sequence NM_001146040.1). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Several missense and nonsense variants have been identified in autosomal dominant, recessive, or compound heterozygote hyperekplexia (HPX). Pathogenic 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 variant 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 variants 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 variants 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.

GLRB

Gene structure. GLRB has ten exons (Reference sequence NM_000824.4). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Pathogenic 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.

SLC6A5

Gene structure. SLC6A5 has 16 exons (Reference sequence NM_004211.3). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Pathogenic 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.

GPHN

Gene structure. GPHN has 23 exons (Reference sequence NM_020806.4). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Pathogenic 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.

ARHGEF9

Gene structure. ARHGEF9 has ten exons (Reference sequence NM_015185.2). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Pathogenic 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.

References

Literature Cited

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Suggested Reading

  • Breitinger HG, Becker CM. The inhibitory glycine receptor-simple views of a complicated channel. Chembiochem. 2002;3:1042–52. [PubMed: 12404628]
  • Brown P. Neurophysiology of the startle syndrome and hyperekplexia. Adv Neurol. 2002;89:153–9. [PubMed: 11968441]
  • Eulenburg V, Armsen W, Betz H, Gomeza J. Glycine transporters: essential regulators of neurotransmission. Trends Biochem Sci. 2005;30:325–33. [PubMed: 15950877]
  • Jen JC, Ptáček L. Channelopathies: episodic disorders of the nervous system. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 204. Available online.
  • 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]
  • Lynch JW. Molecular structure and function of the glycine receptor chloride channel. Physiol Rev. 2004;84:1051–95. [PubMed: 15383648]
  • Noebels JL. The inherited epilepsies. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 230. Available online.
  • 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
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