What are the other Names for this Condition? (Also known as/Synonyms)

• Congenital Stiff-man syndrome
• Familial Startle disease
• Stiff-baby syndrome

What is Hereditary Hyperekplexia? (Definition/Background Information)

• Hereditary Hyperekplexia is a nervous system disorder (neurological disorder) that is usually noticed shortly after birth
• Symptoms in a newborn include generalized muscle stiffness while awake (hypertonia) and exaggerated startle reflex to unexpected loud noises, visual stimuli, or touch. Following the startle reaction, infants experience a brief period in which they are very rigid and are unable to move
• During these rigid periods, some infants may stop breathing (apnea), which can be fatal and has been associated with sudden infant death syndrome (SIDS). Muscle stiffness usually fades completely during the first few years of life. However, the exaggerated startle reflex and periods of rigidity may continue throughout a person's life
• Depending on the severity of the continued symptoms, a child or adult with Hereditary Hyperekplexia may have an increased risk of falling or otherwise injuring themselves. In some cases, children with Hereditary Hyperekplexia may have mild developmental delays. Abdominal hernias and congenital dislocation of the hip have also been associated with this condition
• Hereditary Hyperekplexia has different inheritance patterns and is associated with changes (mutations) in at least five genes
• Clonazepam is the most commonly used treatment and successfully reduces symptoms in most people

(Source: Hereditary Hyperekplexia; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Who gets Hereditary Hyperekplexia? (Age and Sex Distribution)

• Hereditary Hyperekplexia is a rare congenital disorder, with only about 150 cases reported worldwide
• The symptoms may become apparent soon after birth
• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Hereditary Hyperekplexia? (Predisposing Factors)

• A positive family history may be an important risk factor, since Hereditary Hyperekplexia can be inherited
• Currently, no other risk factors have been clearly identified for this disorder

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Hereditary Hyperekplexia? (Etiology)

• In about 30% of cases, Hereditary Hyperekplexia is caused by mutation(s) in GLRA1 gene, which codes for the alpha subunit of glycine receptor
• Causative mutation(s) in the GLRA1 gene are inherited in an autosomal dominant manner
• In addition, mutation(s) in GLRB, GPHN and SLC6A5 genes are also known to cause the disorder
• Autosomal recessive inheritance has also been reported for Hereditary Hyperekplexia

Autosomal dominant inheritance: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.

Autosomal recessive inheritance: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Hereditary Hyperekplexia?

The signs and symptoms of Hereditary Hyperekplexia may include:

• Apnea
• Aspiration
• Exaggerated startle response
• Frequent falls
• Hip dislocation
• Hypertonia
• Hypokinesia
• Inguinal hernia
• Myoclonus
• Umbilical hernia

(Source: Hereditary Hyperekplexia; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How is Hereditary Hyperekplexia Diagnosed?

Hereditary Hyperekplexia is diagnosed on the basis of the following information:

• Complete physical examination
• Thorough medical history evaluation
• Assessment of signs and symptoms, with the following essential features for the diagnosis of Hereditary Hyperekplexia:
• Generalized stiffness soon after birth
• Excessive startle reflex to unexpected stimuli (such as jerking violently to a sound or touch)
• A short duration with generalized stiffness after the startle response
• Laboratory tests
• Imaging studies
• Biopsy studies, if necessary
• Molecular genetic testing to check for or confirm causative gene mutation(s)

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Hereditary Hyperekplexia?

The complications of Hereditary Hyperekplexia may include:

• Risk of falls and injury due to startle response
• Developmental delay
• Severe pain, if hip dislocation occurs
• Abnormal gait
• Embarrassment
• Fear of falling
• Severe anxiety and phobia of being in or crossing open spaces
• Reduced quality of life

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Hereditary Hyperekplexia Treated?

There is no cure for Hereditary Hyperekplexia, since it is a genetic condition. The treatment is usually given to manage the signs and symptoms and any complication that develops. Treatment methods may include the following, either in isolation or combination:

• Anti-anxiety and anti-spastic drugs, such as clonazepam
• Anticonvulsant medications, such as carbamazepine, phenytoin, valproate
• Medications that treat anxiety and induce sleep, including diazepam, 5-hydroxytryptophan, phenobarbital
• Anti-depressants
• Memory enhancing medication/s (Example: Piracetam)
• Physical exercise
• Physiotherapy
• Cognitive behavioral therapy

How can Hereditary Hyperekplexia be Prevented?

Currently, Hereditary Hyperekplexia may not be preventable, since it is a genetic disorder.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy), if available, may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are recommended.

What is the Prognosis of Hereditary Hyperekplexia? (Outcomes/Resolutions)

• The prognosis of Hereditary Hyperekplexia is dependent upon the severity of the signs and symptoms and associated complications, if any
• In majority of cases, affected individuals are able to overcome their fear of falling by adolescent years, and as a result, their gait improves as well
• However, the startle responses persist into adulthood, and in some cases, phobic anxiety may develop, and affected individuals may be unable to overcome their fear. This may lead to hesitant gait disorder
• Typically, the prognosis may be assessed on a case-by-case basis

Additional and Relevant Useful Information for Hereditary Hyperekplexia:

Hereditary Hyperekplexia is also known by the following names:

• Startle reaction, exaggerated
• Exaggerated startle reaction
• STHE
• Stiff-person syndrome, congenital
• Kok disease
• Hyperexplexia hereditary

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/