NORD gratefully acknowledges Lee Haruno, NORD Editorial Intern from the University of Notre Dame, and Prof dr Marina AJ de Koning-Tijssen, Movement Disorders, Department of Neurology, University Medical Centre Groningen, the Netherlands, for assistance in the preparation of this report.
Hyperekplexia is a rare hereditary, neurological disorder that may affect infants as newborns (neonatal) or prior to birth (in utero). It may also affect children and adults. Individuals with this disorder have an excessive startle reaction (eye blinking or body spasms) to sudden unexpected noise, movement, or touch. Symptoms include extreme muscle tension (stiffness or hypertonia) that prevent voluntary movement and can cause the affected person to fall stiffly, like a log, without loss of consciousness. Exaggeration of reflexes (hyperreflexia), and an unstable way of walking (gait) may also occur. Hyperekplexia is usually inherited as an autosomal dominant trait, but autosomal recessive or rarely, X-linked inheritance, has also been reported.
Hyperekplexia is frequently misdiagnosed as a form of epilepsy so the process of getting an accurate diagnosis may be prolonged Treatment is relatively uncomplicated and involves the use of anti-anxiety and anti-spastic medicines Physical and cognitive therapy are supplemental treatment options.
There are major and minor forms of hyperekplexia. In the major form, hyperekplexia is characterized by an unusually extreme startle reaction to sudden unexpected noise, movement, or touch. Arching of the head (exaggerated head-retraction reflex or HRR), spastic jerking movements (myoclonic jerks) or falling stiffly to the ground (without losing consciousness) tend to occur when the individual is startled. The frequency and severity of the startle response can be increased by emotional tension, stress, or fatigue.
Jerking movements can also occur when the patient is trying to fall asleep (hypnagogic myoclonic jerks; for more information on myoclonic jerks, choose “myoclonus” as your search term in the Rare Disease Database). Extreme muscle tension or stiffness (hypertonia) is common in infants with hyperexplexia, especially at birth. Affected babies may not move around much, and when they do, they tend to move slowly (hypokinesia).
Other symptoms presented by infants as well as adults may include exaggeration of reflexes (hyperreflexia), interrupted breathing (intermittent apnea) and/or unstable walking (gait), usually with a mild wide-based stance. Some patients have a dislocation of the hip that is present at birth. Hernias are not uncommon in the lower abdomen (inguinal hernias).
In the minor form, individuals with hyperekplexia usually experience only an inconstant exaggerated startle reaction with few or none of the other symptoms. In infants with the minor form, the reaction may be brought on by fever. In children and adults, intensity of the startle response may be affected by stress or anxiety.
Onset of both major and minor forms of hyperekplexia is usually from birth, but in some patients it does not occur until adolescence or adulthood. Mild intellectual disability may also be observed.
In most cases, hyperekplexia is inherited as an autosomal dominant trait, but can also follow autosomal recessive or X-linked inheritance. Mutations in the following genes are associated with the condition: GLRA1, SLC6A5, GLRB, GPHN, and ARHGEF9 (X-linked). Most affected individuals have a mutation in either the GLRA1, SLC6A5 gene and have an affected parent.
The genes that cause hyperekplexia are involved in the production of the glycine protein Glycine diminishes the action of nerve cells in the brain and spinal cord. It is known as an “inhibitor transmitter”. If the glycine receptors are interfered with in some way or damaged, the nerve cells lack their inhibitions and thus react to stimuli too easily and excessively.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have a defective gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the defective gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a defective gene he will develop the disease.
Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.
If a male with an X-linked disorder is able to reproduce, he will pass the defective gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
Hyperekplexia is a rare genetic disorder that is most often present at birth and affects both males and females. In some individuals, onset of the disorder may be delayed until adolescence or adulthood. Hyperekplexia affects approximately one in 40,000 people in the United States.
Hyperekplexia is one thing that should be considered when an infant has seizures. A family history is an important part of the diagnosis, because of the usual genetic linkage. The major features of hyperekplexia are an excessive startle reflex/response, stiffness at birth, and brief impaired voluntary movement following the startle response
Testing for hyperekplexia can include electromyography (records of electrical impulses produced by the muscles) and electroencephalography (EEG, or records of electrical activity in the brain).
The first step in molecular genetic testing for an individual who meets the clinical criteria for the condition is to test for mutations in the GLRA1 and SLC6A5 genes. Sequence analysis of the ARHGEF9 gene may be considered in males without identified GLRA1 or SLC6A5 mutations, particularly if cognitive impairment and epilepsy are present. If mutations are not identified, molecular genetic testing for mutations in the GLRB and GPHN genes can be considered,
In both infants and adults, hyperekplexia is treated most effectively with the anti-anxiety and anti-spastic drug clonazepam. Other drugs that may be used include carbamazepine, phenobarbital, phenytoin, diazepam, 5-hydroxytryptophan, piracetam, and sodium valproate.
Genetic counseling may be of benefit for patients and their families. Other treatment, such as physical and/or cognitive therapy to reduce anxiety can be supportive.
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