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. The following genes are currently known to be associated with HPX:

• GLRA1, the gene encoding the α1 subunit of the glycine receptor, is the main gene associated with 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 an important associated gene [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, the 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

• Sequence analysis

  • GLRA1 mutations are analyzed by PCR and direct sequencing of the whole gene including all exons and flanking introns. Several missense and nonsense mutations have been identified in autosomal dominant and autosomal recessive HPX.

  • GLRB. Sequence analysis of GLRB is available clinically and is expected to identify missense, nonsense, splicing, and other small intragenic mutations.

• Deletion analysis. 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 [unpublished data]. Failure to get PCR amplimers across several contiguous exons is normally indicative of this mutation.

Table 1. Summary of Molecular Genetic Testing Used in Hyperekplexia

View in own window

Gene Symbol	Test Method	Mutations Detected	Proportion of HPX Attributed to Mutations in This Gene 1	Mutation Detection Frequency by Gene and Test Method 2	Test Availability
GLRA1	Sequence analysis of all exons and flanking introns	Sequence variants 3	Familial: ~80% 4 Simplex 5	Unknown	Clinical
		Deletion of exons 1-6 6	6 persons 5
SLC6A5	Sequence analysis	Sequence variants 3	8 persons 5		Research only
GLRB		Sequence variants 3	1 person 5		Clinical
GPHN		Sequence variants 3	1 person 5		Research only
ARHGEF9		Sequence variants 3	1 person 5

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. Based on more than 40 unrelated affected individuals

2. The ability of this test method to detect a mutation in an individual with an alteration in this gene

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

4. 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 rate is around 80% [based on author's personal experience, unpublished data].

5. The mutation detection rate 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. Failure to get PCR amplimers across several contiguous exons is normally indicative of deletion of GLRA1 exons 1-6.

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

Testing Strategy

Confirmation of the diagnosis of HPX relies on molecular genetic testing of GLRA1 and GLRB in individuals meeting HPX clinical inclusion criteria.

Note: Additional imaging prior to molecular genetic testing is not necessary.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are associated with mutations in GLRA1, SLC6A5, GLRB, or ARHGEF9.

Mutations in GPHN cause a severe metabolic defect, molybdenum deficiency syndrome (Moco deficiency), which is usually lethal in infancy [Feng et al 1998].

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 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 around 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 genotype-phenotype correlations are known in HPX.

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].

Penetrance

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

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 over 70 pedigrees from many different nationalities.

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

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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Hyperekplexia (HPX) is inherited in an autosomal dominant or autosomal recessive 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

• Most individuals diagnosed with autosomal dominant HPX have an affected parent.

• A proband with autosomal dominant HPX may have the disorder as the result of a new gene mutation; however, the proportion of cases caused by de novo mutations is very low: only two cases have been described [Miraglia Del Giudice et al 2003].

• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include molecular genetic testing if the disease-causing mutation(s) have been identified in the 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 available on a clinical basis 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 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 or at risk.

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. See for a list of laboratories offering DNA banking.

Prenatal Testing

No laboratories offering molecular genetic testing for prenatal diagnosis of HPX are listed in the GeneTests™ Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing mutation has been identified. For laboratories offering custom prenatal testing, see .

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation(s) have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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. Bernasconi A, Regli F, Schorderet DF, Pescia G. Rev Neurol (Paris). 1996;152:447–50. [PubMed: 8944241]
4. 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]
5. 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]
6. 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 Epilepsy. Geneva, Switzerland: Editions Medicine & Hygiene; 1989:409-14.
7. 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]
8. 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]
9. 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]
10. Koning-Tijssen MA, Brouwer OF. Hyperekplexia in the first year of life. Mov Disord. 2000;15:1293–6. [PubMed: 11104232]
11. Kurczynski TW. Hyperekplexia. Arch Neurol. 1983;40:246–8. [PubMed: 6830476]
12. 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]
13. 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]
14. Matsumoto J, Fuhr P, Nigro M, Hallett M. Physiological abnormalities in hereditary hyperekplexia. Ann Neurol. 1992;32:41–50. [PubMed: 1642471]
15. 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]
16. 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]
17. 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]
18. 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]
19. 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]
20. 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]
21. 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]
22. 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]
23. Suhren O, Bruyn GW, Tuynman A. Hyperexplexia, a hereditary startle syndrome. J Neurol Sci. 1966;3:577–605.
24. Tijssen MA, Padberg GW, van Dijk JG. The startle pattern in the minor form of hyperekplexia. Arch Neurol. 1996;53:608–13. [PubMed: 8929168]
25. 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]
26. 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]
27. 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]
28. 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]
29. 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]
30. 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, Ptáček L. Channelopathies: episodic disorders of the nervous system. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York: McGraw-Hill. Chap 204. Available at www.ommbid.com. Accessed 2-15-12.
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 Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York: McGraw-Hill. Chap 230. Available at www.ommbid.com. Accessed 2-15-12.
8. Tijssen MAJ, Brown P. Channelopathies of the nervous system. In: Rose M, Griggs RC, eds. Hyperekplexia. Oxford: Butterworth Heinemann; 2001:259-73.

Revision History

• 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