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Hereditary Hyperekplexia

Table of Contents

Hereditary Hyperekplexia

Hyperekplexia; HPX; Startle Disease; Startle Syndrome; STHE; Stiff-Baby Syndrome; Congenital Stiff-Man Syndrome; Congenital Stiff-Person Syndrome

Hereditary hyperekplexia is a rare neurological disorder. Affected infants have increased muscle tone and an exaggerated startle reaction to unexpected stimuli, especially loud noises. Following the startle reaction, infants experience a brief period in which they are very rigid and unable to move. Learn more about causes and treatment.

infant Brain Development

Image by TheVisualMD

Summary

Stiff man human cerebellum

Image by Marta Rizzi et al

Stiff man human cerebellum

Healthy human cerebellum, Purkinje cell layer, t = 36 weeks after rituximab treatment stained with a reference anti-GAD65 monoclonal antibody. Thin arrows show presynaptic terminals staining only with the anti-GAD65 monoclonal antibody

Image by Marta Rizzi et al

What Is Hereditary Hyperekplexia?

Hereditary hyperekplexia is a condition in which affected infants have increased muscle tone (hypertonia) and an exaggerated startle reaction to unexpected stimuli, especially loud noises. Following the startle reaction, infants experience a brief period in which they are very rigid and unable to move. During these rigid periods, some infants stop breathing, which, if prolonged, can be fatal. Infants with hereditary hyperekplexia have hypertonia at all times, except when they are sleeping.

Other signs and symptoms of hereditary hyperekplexia can include muscle twitches when falling asleep (hypnagogic myoclonus) and movements of the arms or legs while asleep. Some infants, when tapped on the nose, extend their head forward and have spasms of the limb and neck muscles. Rarely, infants with hereditary hyperekplexia experience recurrent seizures (epilepsy).

The signs and symptoms of hereditary hyperekplexia typically fade by age 1. However, older individuals with hereditary hyperekplexia may still startle easily and have periods of rigidity, which can cause them to fall down. They may also continue to have hypnagogic myoclonus or movements during sleep. As they get older, individuals with this condition may have a low tolerance for crowded places and loud noises. People with hereditary hyperekplexia who have epilepsy have the seizure disorder throughout their lives.

Hereditary hyperekplexia may explain some cases of sudden infant death syndrome (SIDS), which is a major cause of unexplained death in babies younger than 1 year.

Source: MedlinePlus Genetics

Causes

Mutation

Image by National Human Genome Research Institute (NHGRI)

Mutation

A mutation is a change in the DNA sequence of an organism. Mutations can result from errors in DNA replication during cell division, exposure to mutagens or a viral infection. Germline mutations (that occur in eggs and sperm) can be passed on to offspring, while somatic mutations (that occur in body cells) are not passed on.

Image by National Human Genome Research Institute (NHGRI)

What Causes Hereditary Hyperekplexia?

Mutations in multiple genes have been found to cause hereditary hyperekplexia. Most of these genes provide instructions for producing proteins that are found in nerve cells (neurons). These proteins are involved in the response of neurons to a molecule called glycine. This molecule is an amino acid, which is a building block of proteins. Glycine also acts as a neurotransmitter, which is a chemical messenger that transmits signals in the nervous system. Gene mutations that cause hereditary hyperekplexia disrupt normal glycine signaling in neurons in the spinal cord and the part of the brain that is connected to the spinal cord (the brainstem). Abnormal signaling in neurons in the brain and neurons that send signals to muscles throughout the body result in abnormal muscle movements, exaggerated startle reaction, and other symptoms characteristic of this disorder.

Most cases of hereditary hyperekplexia are caused by mutations in the GLRA1 gene. The GLRA1 gene provides instructions for making one part, the alpha (α)1 subunit, of the glycine receptor protein. When this protein attaches (binds) to glycine, signaling between cells is stopped. GLRA1 gene mutations lead to the production of a receptor that cannot properly respond to glycine. As a result, glycine is less able to regulate signaling in the spinal cord and brainstem leading to increased cells signaling and the signs and symptoms of hereditary hyperekplexia. Mutations in other genes account for the remaining cases of hereditary hyperekplexia.

Source: MedlinePlus Genetics

GLRA1 Gene

Ideogram of human chromosome 5

Image by Office of Biological and Environmental Research of the U.S. Department of Energy Office of Science, the Biological and Environmental Research Information System, Oak Ridge National Laboratory.

Ideogram of human chromosome 5

Selected genes, traits, and disorders associated with the chromosome listed; (green and violet) regions reflecting the unique patterns of light and dark bands seen on human chromosomes stained to allow viewing through a light microscope; (red) the centromere, or constricted portion, of each chromosome; (yellow) chromosomal regions that vary in staining intensity and sometimes are called hererochromatin (meaning “different color”); (lines between yellow) variable regions, called stalks, that connect a very small chromosome arm (a “satellite”) to the chromosome.

Image by Office of Biological and Environmental Research of the U.S. Department of Energy Office of Science, the Biological and Environmental Research Information System, Oak Ridge National Laboratory.

GLRA1 Gene: Glycine Receptor Alpha 1

Normal Function

The GLRA1 gene provides instructions for making one part, the alpha (α)1 subunit, of the glycine receptor protein. The glycine receptor is embedded in the membrane of nerve cells (neurons) in the spinal cord and the part of the brain that is connected to the spinal cord (the brainstem). The glycine receptor is made up of five subunits: two α1 subunits and three beta (β) subunits. The β subunit is produced from a different gene.

Receptor proteins have specific sites into which certain other molecules, called ligands, fit like keys into locks. Together, ligands and their receptors trigger signals that affect cell development and function. The ligand for the glycine receptor is the protein building block (amino acid) glycine. This molecule also acts as a neurotransmitter, which is a chemical messenger that transmits signals in the nervous system.

When glycine attaches (binds) to the glycine receptor, the receptor opens to allow negatively charged chlorine atoms (chloride ions) to enter the neuron. This influx of chloride ions reduces the neurons's ability to transmit signals to other neurons. Because they stop (inhibit) signaling, glycine receptors are known as inhibitory receptors.

Health Conditions Related to Genetic Changes

Hereditary hyperekplexia

More than 60 mutations in the GLRA1 gene have been found to cause hereditary hyperekplexia. This condition is most often seen in infants who experience increased muscle tone (hypertonia) and an exaggerated startle reaction to unexpected stimuli, especially loud noises. The startle reaction can trigger a brief period of rigidity and immobility, and in some cases, infants stop breathing. Most GLRA1 gene mutations change single amino acids in the α1 subunit of the glycine receptor protein. The most common mutation replaces the amino acid arginine with the amino acid leucine at protein position 271 (written as Arg271Leu or R271L).

GLRA1 gene mutations that cause hereditary hyperekplexia impair the ability of the glycine receptor protein to respond to the ligand glycine. Some GLRA1 gene mutations alter the structure of the glycine receptor, which can prevent the receptor from opening or cause it to open without the presence of glycine. Other mutations prevent the receptor from reaching the cell membrane. When the glycine receptor is dysfunctional or missing, chloride ions enter the cell when they are not needed or cannot enter the cell at all. The resulting increase in cell signaling in the spinal cord and brainstem likely causes the abnormal muscle movements, exaggerated startle reaction, and other signs and symptoms of hereditary hyperekplexia.

Other Names for This Gene

GLRA1_HUMAN
glycine receptor, alpha 1
glycine receptor, alpha 1 isoform 1 precursor
glycine receptor, alpha 1 isoform 2 precursor
STHE

Genomic Location

The GLRA1 gene is found on chromosome 5.

Source: MedlinePlus Genetics

Diagnosis

Genetic testing

Image by genome.gov

Genetic testing

Genetic testing fact sheet

Image by genome.gov

How Is Hereditary Hyperekplexia Diagnosed?

Diagnosis of hereditary hyperekplexia requires the three main features: generalized stiffness immediately after birth, excessive startle reflex to unexpected stimuli, and a short period of generalized stiffness following the startle response. Of note, the results of routine blood tests, urinalysis, brain imaging studies, or EEG are usually normal. Hereditary hyperekplexia has different inheritance patterns and is associated with changes (mutations) in at least five genes. Genetic testing is available to detect the genetic changes.

Source: Genetic and Rare Diseases (GARD) Information Center

Genetic Testing

Genetic Testing

Also called: DNA Testing, Mutation Screening, Genetic Test

Genetic testing is a type of test that analyze your cells or tissue to look for any changes in your DNA. Genetic tests may be used to identify increased risks of health problems, to choose treatments, or to assess responses to treatments.

Genetic Testing

Also called: DNA Testing, Mutation Screening, Genetic Test

Genetic testing is a type of test that analyze your cells or tissue to look for any changes in your DNA. Genetic tests may be used to identify increased risks of health problems, to choose treatments, or to assess responses to treatments.

{"label":"Genetic test reference range","description":"This is a type of test that analyzes cells or tissue to look for changes in a particular gene, chromosome, or protein of interest. Genetic tests may be used to identify increased risks of health problems, to choose treatments, or to assess responses to treatments. Results are reported as positive, negative or uncertain, and may include specific findings.","scale":"lin","step":0.25,"items":[{"flag":"negative","label":{"short":"Negative","long":"Negative","orientation":"horizontal"},"values":{"min":0,"max":1},"text":"A negative (normal) result means that the test did not find a change that is known to affect health or development in the gene, chromosome, or protein under consideration. This result can indicate that a person is not affected by a particular disorder, is not a carrier of a specific genetic variant, or does not have an increased risk of developing a certain disease. It is possible, however, that the test missed a disease-causing genetic alteration because many tests cannot detect all genetic changes that can cause a particular disorder.","conditions":[]},{"flag":"borderline","label":{"short":"Uncertain","long":"Uncertain","orientation":"horizontal"},"values":{"min":1,"max":2},"text":"An uncertain (variant of unknown or uncertain significance) result means there isn\u2019t enough information about that genetic change to determine whether it is benign (normal) or pathogenic (disease causing). This type of result may be also called uninformative, indeterminate, inconclusive, or ambiguous.","conditions":[]},{"flag":"positive","label":{"short":"Positive","long":"Positive","orientation":"horizontal"},"values":{"min":2,"max":3},"text":"A positive (abnormal) result means that the test found a change in a particular gene, chromosome, or protein of interest. Depending on the purpose of the test, this result may confirm a diagnosis, indicate that a person is a carrier of a particular genetic variant, identify an increased risk of developing a disease (such as cancer), or suggest a need for further testing.","conditions":[]}],"hideunits":true,"value":0.5}[{"negative":0},{"borderline":0},{"positive":0}]
Use the slider below to see how your results affect your health.
Your result is Negative.
A negative (normal) result means that the test did not find a change that is known to affect health or development in the gene, chromosome, or protein under consideration. This result can indicate that a person is not affected by a particular disorder, is not a carrier of a specific genetic variant, or does not have an increased risk of developing a certain disease. It is possible, however, that the test missed a disease-causing genetic alteration because many tests cannot detect all genetic changes that can cause a particular disorder.
Related conditions
Genetic testing may be done for many different reasons, including to:
- Find genetic diseases in unborn babies. This is one type of prenatal testing.
- Screen newborn babies for certain treatable conditions
- Lower the risk of genetic diseases in embryos that were created using assisted reproductive technology
- Find out if you carry a gene for a certain disease that could be passed on to your children. This is called carrier testing.
- See whether you are at increased risk of developing a specific disease. This may be done for a disease that runs in your family.
- Diagnose certain diseases
- Identify genetic changes that may be causing or contributing to a disease that you were already diagnosed with
- Figure out how severe a disease is
- Help guide your doctor in deciding the best medicine and dosage for you. This is called pharmacogenomic testing.
There are no known risks to having a saliva test. There is very little risk to having a blood test. You may have slight pain or bruising at the spot where the needle was put in, but most symptoms go away quickly.
The physical risks of the different types of genetic testing are small. But there can be emotional, social, or financial drawbacks:
- Depending on the results, you may feel angry, depressed, anxious, or guilty. This can be especially true if you are diagnosed with a disease that does not have effective treatments.
- You may be worried about genetic discrimination in employment or insurance
- Genetic testing may give you limited information about a genetic disease. For example, it cannot tell you whether you will have symptoms, how severe a disease might be, or whether a disease will get worse over time.
- Some genetic tests are expensive, and health insurance might only cover part of the cost. Or they may not cover it at all.
- Positive – the test found a genetic change known to cause disease.
- Negative – the test did not find a genetic change known to cause disease. Sometimes a negative result occurs when the wrong test was ordered or there isn’t a genetic cause for that person’s symptoms. A “true negative” is when there is a known genetic change in the family and the person tested did not inherit it. If your test results are negative and there is no known genetic change in your family, a negative test result may not give you a definite answer. This is because you might not have been tested for the genetic change that runs in your family.
- Uncertain – a variant of unknown or uncertain significance means there isn’t enough information about that genetic change to determine whether it is benign (normal) or pathogenic (disease causing).
1. Genetic Testing | CDC. Sep 23, 2022 [accessed on Feb 23, 2022]
2. Genetic Testing: MedlinePlus. National Library of Medicine. Jun 11, 2021 [accessed on Feb 23, 2022]
3. What is genetic testing?: MedlinePlus Genetics [accessed on Feb 23, 2022]
4. Genetic Testing FAQ. Genome.gov [accessed on Feb 23, 2022]
5. Genetic testing and your cancer risk: MedlinePlus Medical Encyclopedia [accessed on Feb 23, 2022]

Normal reference ranges can vary depending on the laboratory and the method used for testing. You must use the range supplied by the laboratory that performed your test to evaluate whether your results are "within normal limits."

Additional Materials (21)

Genetic testing

Genetic testing fact sheet

Image by genome.gov

Genetic testing

Genetic testing existed before the Human Genome Project and the list of diseases that we can already screen for may be longer than you think.

Image by TheVisualMD

Genes and Genetic Defects

Genetic testing isn't new. In the 1960s, doctors were able to test newborn babies for certain rare single-gene disorders, such as phenylketonuria (PKU), a rare metabolic disease that causes mental retardation. (PKU can be prevented with a special diet if it's detected early, which was why it was critical to test newborns.)

Image by TheVisualMD

Mapping Your Future: Screening for Disease Risk

Image by TheVisualMD

Each person with Down syndrome has different talents and the ability to thrive.

Down syndrome is a lifelong condition. Services early in life will often help babies and children with Down syndrome to improve their physical and intellectual abilities. Most of these services focus on helping children with Down syndrome develop to their full potential. These services include speech, occupational, and physical therapy, and they are typically offered through early intervention programs in each state. Children with Down syndrome may also need extra help or attention in school, although many children are included in regular classes.

Image by CDC

genetic analysis

Biotechnology - DNA analysis and treatment

Image by OpenClipart-Vectors/Pixabay

Family history (medicine)

An extended family in Spain

Image by Ojedamd

Biotechnology

This diagram shows the basic method used for extraction of DNA.

Image by CNX Openstax

Genetic Counselor at Sanford Health Explains the Benefits to Genetic Testing

Video by Sanford Health/YouTube

What Is A Genetic Counselor & The Importance of Genetic Counselling | Ambry Genetics

Video by Ambry Genetics/YouTube

How Does The Genetic Testing Process Work? Genetic Testing FAQ | Ambry Genetics

Video by Ambry Genetics/YouTube

Should You Get Genetic Testing During Your Pregnancy?

Video by St. Louis Children's Hospital/YouTube

Debating Embryonic Genetic Testing -- The Doctors

Video by The Doctors/YouTube

Genetic Testing for Cancer — AMITA Health | NBC Chicago Ask the Doc

Video by AMITA Health/YouTube

MedGenome BRCA - Breast Cancer Genetic Testing

Video by MedGenome/YouTube

Genetic Testing for Hereditary Forms of Kidney Cancer - Brian Shuch, MD

Video by UCLA Health/YouTube

Do I need Genetic Testing for Ichthyosis?

Video by foundation for ichthyosis/YouTube

What Is Genetic Testing? Understanding the Process and Its Results

Video by uvahealth/YouTube

How to Understand Your Genetic Testing Results

Video by Breast Cancer Answers®/YouTube

Genetic Testing 101 for People with Rare Diseases

Video by National Organization for Rare Disorders (NORD)/YouTube

What's the difference between genetic and genomic testing?

Video by Cancer Treatment Centers of America - CTCA/YouTube

Genetic testing

genome.gov

Genetic testing

TheVisualMD

Genes and Genetic Defects

TheVisualMD

Mapping Your Future: Screening for Disease Risk

TheVisualMD

Each person with Down syndrome has different talents and the ability to thrive.

CDC

genetic analysis

OpenClipart-Vectors/Pixabay

Family history (medicine)

Ojedamd

Biotechnology

CNX Openstax

1:57

Genetic Counselor at Sanford Health Explains the Benefits to Genetic Testing

Sanford Health/YouTube

1:06

What Is A Genetic Counselor & The Importance of Genetic Counselling | Ambry Genetics

Ambry Genetics/YouTube

0:45

How Does The Genetic Testing Process Work? Genetic Testing FAQ | Ambry Genetics

Ambry Genetics/YouTube

3:04

Should You Get Genetic Testing During Your Pregnancy?

St. Louis Children's Hospital/YouTube

4:40

Debating Embryonic Genetic Testing -- The Doctors

The Doctors/YouTube

1:31

Genetic Testing for Cancer — AMITA Health | NBC Chicago Ask the Doc

AMITA Health/YouTube

2:10

MedGenome BRCA - Breast Cancer Genetic Testing

MedGenome/YouTube

1:37

Genetic Testing for Hereditary Forms of Kidney Cancer - Brian Shuch, MD

UCLA Health/YouTube

1:43

Do I need Genetic Testing for Ichthyosis?

foundation for ichthyosis/YouTube

2:01

What Is Genetic Testing? Understanding the Process and Its Results

uvahealth/YouTube

3:58

How to Understand Your Genetic Testing Results

Breast Cancer Answers®/YouTube

1:00:31

Genetic Testing 101 for People with Rare Diseases

National Organization for Rare Disorders (NORD)/YouTube

2:05

What's the difference between genetic and genomic testing?

Cancer Treatment Centers of America - CTCA/YouTube

Treatment

Clonazepam Pills

Image by ParentingPatch/Wikimedia

Clonazepam Pills

Clonazepam Pills

Image by ParentingPatch/Wikimedia

How Might Hereditary Hyperekplexia Be Treated?

If fear of falling has limited a person's willingness to go outside their home and/or caused the development of a cautious walking style, cognitive behavior therapy (CBT) and/or physical therapy, in combination with the medication to control the startle reflex and rigidity period, may help reduce anxiety, improve confidence in walking, and improve the person's quality of life.

Source: Genetic and Rare Diseases (GARD) Information Center

Additional Materials (6)

Clonazepam 2MG

Qualitest Generic 2mg

Image by Insomniac70/Wikimedia

White, Green, Red, and Orange Pills

White, Green, Red, and Orange Pills (Lutera, Sudafed, Clonazepam)

Image by ParentingPatch/Wikimedia

Clonazepam Pills and Pill Bottle

Clonazepam Pills and Pill Bottle

Image by ParentingPatch/Wikimedia

Clonazepam 3D animated

Clonazepam's 3D molecular structure

Image by User:Fuse809/Wikimedia

Rivotril 0,5 mg tbl

Rivotril, proprietary medicinal product, 1 tablet contains 0,5 mg of clonazepam. Manufacturer Roche.

Image by Tomino de WS/Wikimedia

Clonazepam(RIVOTRIL-0-5mg Tab) 2014-05-28 23-55

Clonazepam(RIVOTRIL-0.5mg Tab)

Image by User:ALT71/Wikimedia

Clonazepam 2MG

Insomniac70/Wikimedia

White, Green, Red, and Orange Pills

ParentingPatch/Wikimedia

Clonazepam Pills and Pill Bottle

ParentingPatch/Wikimedia

Clonazepam 3D animated

User:Fuse809/Wikimedia

Rivotril 0,5 mg tbl

Tomino de WS/Wikimedia

Clonazepam(RIVOTRIL-0-5mg Tab) 2014-05-28 23-55

User:ALT71/Wikimedia

Statistics

Statistically how often is a newborn affected

Image by OpenClipart-Vectors

Statistically how often is a newborn affected

How common

Image by OpenClipart-Vectors

How Common Is Hereditary Hyperekplexia?

The exact prevalence of hereditary hyperekplexia is unknown. This condition has been identified in more than 150 individuals worldwide.

Source: MedlinePlus Genetics

Related HealthJournals

Sudden Infant Death Syndrome

Sudden Infant Death Syndrome (SIDS) is the sudden, unexplained death of an infant and is the leading cause of death in children one month to one year old. Learn how to reduce the risk of SIDS.

Stiff-Person Syndrome

Stiff-person syndrome (SPS) is a rare neurological disorder with features of an autoimmune disease. SPS is characterized by fluctuating muscle rigidity in the trunk and limbs and a heightened sensitivity to stimuli such as noise and emotional distress, which can set off muscle spasms. Find out about the symptoms, causes, and prognosis of this condition.

Genetic Testing

Genetic testing is a type of medical test that identifies changes in chromosomes, genes, or proteins. Over 2000 tests are available. Genetic testing may be done for many reasons, from newborn baby screening to diagnosing certain diseases. Read about why you might consider testing.

Hypotonia

A diminution of the skeletal muscle tone marked by a diminished resistance to passive stretching.

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Hereditary Hyperekplexia

Hereditary hyperekplexia is a rare neurological disorder. Affected infants have increased muscle tone and an exaggerated startle reaction to unexpected stimuli, especially loud noises. Following the startle reaction, infants experience a brief period in which they are very rigid and unable to move. Learn more about causes and treatment.

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