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.

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.

Genetically Related (Allelic) Disorders

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

ARHGEF9

• Marco 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 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].

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 more than 70 pedigrees and 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
• 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.

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

• 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 small: 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 has 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 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.

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Suggested Reading

1. Breitinger HG, Becker CM. The inhibitory glycine receptor-simple views of a complicated channel. Chembiochem. 2002;3:1042–52. [PubMed: 12404628]
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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]
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8. Tijssen MAJ, Brown P. Channelopathies of the nervous system. In: Rose M, Griggs RC, eds. Hyperekplexia. Oxford, UK: Butterworth Heinemann; 2001:259-73.

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