DiagnosisClinical DiagnosisDiagnosis 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 TestingIn general, all laboratory tests are normal in individuals with HPX, including CT and MRI of the brain. Molecular Genetic TestingGenes. 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 HyperekplexiaView in own windowGene SymbolProportion of HPX Attributed to Mutations in This Gene ¹ Test MethodMutations DetectedTest AvailabilityGLRA1Familial: ~80% ²
Simplex: see footnote 3Sequence analysisSequence variants ^{4, 5Clinical6 persons 3 Deletion / duplication analysis 6Deletion of exons 1-6 and novel deletions 7, 8 SLC6A58 persons 3 Sequence analysisSequence variants 4Clinical Deletion / duplication analysis 6Exonic and whole-gene deletions / duplications 9GLRB1 person 3 Sequence analysisSequence variants 4ClinicalDeletion / duplication analysis 6Exonic and whole-gene deletions / duplications 9GPHN1 person 3 Sequence analysisSequence variants 4ClinicalARHGEF91 person 3Sequence analysisSequence variants 4, 10, 11ClinicalDeletion / duplication analysis 6Exonic and whole-gene deletions / duplications 91. Based on more than 40 unrelated affected individuals2. 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 variants11. 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 StrategyConfirmation 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.Genetically Related (Allelic) DisordersNo other phenotypes are associated with mutations in GLRA1, SLC6A5, or GLRB.ARHGEF9Marco et al [2008] reported a child with intellectual disability, hyperactivity, and sensory hyperarousal (pounding heartbeat, sweating, and active avoidance) especially to noise, who was found to have a paracentric inversion in which the break point disrupted ARHGEF9. Kalscheuer et al [2009] reported a female with a balanced chromosomal translocation disrupting ARHGEF9 associated with epilepsy, anxiety, aggression, and intellectual disability, but not associated with hyperekplexia. GPHN. Mutations in GPHN cause a severe metabolic defect, molybdenum deficiency syndrome (Moco deficiency), which is usually lethal in infancy [Feng et al 1998].}

Natural HistoryHereditary 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 CorrelationsNo 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].

Differential DiagnosisThe 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: Startle epilepsy Reticular and propriospinal myoclonus Paroxysmal kinesigenic choreoathetosis (see Familial Paroxysmal Kinesigenic Dyskinesia) Tic disorders Creutzfeldt-Jakob disease (see Prion Disease) Subacute sclerosing panencephalitis Paraneoplastic syndromes 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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).Infantile HPXHPX in adultsAutosomal recessive HPX

ManagementEvaluations Following Initial DiagnosisTo 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 consultationTreatment of ManifestationsClonazepam 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 ManifestationsSee Treatment of Manifestations, clonazepam.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch 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.

Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDGLRA15q33​.1Glycine receptor subunit alpha-1GLycine Receptor, Alpha 1 (GLRA1) @ LOVDGLRA1GLRB4q32​.1Glycine receptor subunit betaGLRB homepage - Mendelian genesGLRBSLC6A511p15​.1Sodium- and chloride-dependent glycine transporter 2SLC6A5 @ LOVDSLC6A5ARHGEF9Xq11​.1-q11.2Rho guanine nucleotide exchange factor 9ARHGEF9 homepage - Mendelian genesARHGEF9GPHN14q23​.3GephyrinGPHN homepage - Mendelian genesGPHNData 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) View in own window 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; SLC6A5See Figure 1.FigureFigure 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...)GLRA1 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.GLRB 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. SLC6A5 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. GPHN 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. ARHGEF9 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.