Hereditary Hyperekplexia

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The symptoms of Hereditary Hyperekplexia (HPX) are mainly present in infancy and childhood, although for some people symptoms persist lifelong.

The severity of HPX varies widely. Classically the condition causes an excessive startle reaction with someone startling easily at a sudden sound, unexpected touch or bump, or unexpected sight of people or objects. When this happens, the individual will become stiff due to extreme muscle tension and may fall and be injured, as they are unable to put out their arms to save themselves. Arching of the head (exaggerated head-retraction reflex), jerking movements (myoclonic jerks) or falling stiffly to the ground without losing consciousness tends to occur when the individual is startled. The frequency and severity of the startle response can be increased by stress, emotional tension or fatigue.

Other symptoms may include jerking movements when trying to fall asleep (hypnagogic myoclonic jerks), persistent limb movements during sleep, exaggeration of reflexes (hyperreflexia), interrupted breathing (intermittent apnea) and unstable walking.

Babies with HPX commonly have extreme muscle tension or stiffness (hypertonia) and tend to move slowly (hypokinesia). When a baby startles, there may be a tendency for severe non-epileptic convulsions with increased stiffness and fast quivering. These convulsions are potentially dangerous because they can induce loss of consciousness (syncope) due to a lack of oxygen reaching the brain. These episodes can be recurrent and are also known as 'breathing attacks' or 'apnoea attacks'.

Some children with HPX may have a delay in reaching developmental milestones, such as a delay in speaking or walking. The majority of individuals with the condition have normal intelligence, but those most severely affected may have a learning disability.

The exact prevalence of HPX has been estimated to be less than 1 in 100,000. At least 150 cases have been reported in the medical literature.

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Diagnosis

The diagnosis of HPX is based on clinical signs, electrophysiology studies and genetic test results. The condition is frequently misdiagnosed as a form of epilepsy, such as Startle Epilepsy.

Treatment

There is currently no known cure for HPX but certain medications can help reduce the excessive startle and muscle stiffness. The condition responds well to treatment with a class of drugs known as benzodiazepines. Physical and cognitive therapy are supplemental treatment options.

For babies with severe breathing problems, parents can be trained in resuscitation techniques and provided with breathing and heart rate monitors.

Genetics and Inheritance

There are at least five genes in which genetic changes (mutations) have been reported to cause HPX. Changes in a gene called GLRA1 on chromosome 5 account for about 80% of cases. The other four genes are SLC6A5 on chromosome 11, GLRB on chromosome 4, GPHN on chromosome 14 and ARHGEF9 on the X chromosome.

HPX is most often inherited in an autosomal dominant pattern. In this situation, each child of someone with the condition has a 1 in 2 (50%) chance of inheriting the disorder. This chance is the same for males and females. 

HPX can also sometimes be inherited in an autosomal recessive pattern. When inherited in this manner, an individual with the condition will have two changed copies of an HPX gene. They will have inherited one changed copy from their mother and the other from their father. Someone with one changed and one working copy of the gene is known as a carrier. Each full sibling of someone with recessive HPX has a 1 in 4 (25%) chance of inheriting the condition. This chance is the same for males and females. 

Rarely, when caused by a change in the ARHGEF9 gene, HPX is passed on in an X-linked pattern of inheritance. In this situation, the condition can affect males as they have only one copy of the ARHGEF9 gene on their single X chromosome. Females have two X chromosomes and therefore two copies of the ARHGEF9 gene. If they have a change in one copy of the gene, they are an unaffected carrier of the condition. Women who are carriers of X-linked HPX have a 1 in 2 (50%) chance of passing the condition on to each son they have.

Genetic Services and Testing

Genetic testing methods change over time. A consultant geneticist from an NHS genetic clinic can assess the family history and arrange genetic testing as appropriate. Testing of at least the GLRA1, SLC6A5 and GLRB genes is currently possible and can identify the genetic cause of the condition in 45-50% of cases.

Families are welcome to seek advice from genetic clinics at various times of life. For example, when an individual with HPX or their siblings want more details as they get older, they could ask about the condition for themselves.

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