Hyperekplexia

What Causes Hyperekplexia?

Hereditary hyperekplexia is caused by abnormal changes (mutations) in one of several different genes. Most cases of the disorder are caused by a mutation in the GLRA1, which is responsible for making a protein crucial in the function of the brain and central nervous system. Without this protein, nerve cells in the brain and spinal column can’t properly communicate, leading to hyperekplexia symptoms.

Is Hyperekplexia Hereditary?

Most cases of hyperekplexia result from gene mutations inherited by children from their parents. However, the disorder sometimes results from gene mutations that occur spontaneously in the sperm or egg cells or the developing embryo after fertilization. In these cases, the child with hyperekplexia has no family history of the disorder.

Most inherited cases of hyperekplexia are inherited in an autosomal dominant pattern. This means that children may develop the condition if they inherit even one copy of the mutated gene from either of their parents. If a parent carries the disorder-causing mutation, they will have a 50 percent chance of having an affected child with each pregnancy.

Sometimes hyperekplexia is inherited in an autosomal recessive pattern, meaning that a child must inherit two copies of the gene mutation, one from each parent, to develop the disorder. People who have only one copy of the mutated gene will not develop the condition but will be carriers who can pass the mutation on to their children. Two carrier parents have a 25 percent chance of having a child with the disease with each pregnancy. Half of their pregnancies will produce a carrier, and a quarter of the pregnancies will produce a child with no mutated genes.

One gene associated with hyperekplexia lies on the X chromosome. Women’s cells contain two X chromosomes, and men’s cells have one X and one Y chromosome. Everyone inherits one X chromosome from their mother and either an X or Y chromosome from their father, so the genetic mutation could be inherited from either parent. But because girls have two X chromosomes, they probably have inherited at least one healthy X chromosome, making it likely that they won’t experience any symptoms. However, boys who inherit the hyperekplexia mutation don’t have a healthy X chromosome to counteract the mutation and are much more likely to develop the disorder.

How Is Hyperekplexia Detected?

The symptoms of hyperekplexia typically begin early in infancy, and they may even be detected before birth. However, because the startle reflex and associated muscle rigidity resemble a seizure, the disorder is sometimes misdiagnosed as epilepsy.

In some cases, babies with hyperekplexia exhibit twitching muscles as they’re falling asleep, and they may also continue to move their arms and legs while they’re sleeping.

Some researchers believe that hyperekplexia, especially those cases in which a baby experiences breathing cessation (apnea), may be responsible for some cases of sudden infant death syndrome (SIDS). Because of this potentially life-threatening complication, early detection of hyperekplexia is essential.

How Is Hyperekplexia Diagnosed?

Doctors may take several different diagnostic steps when they suspect that a patient may have hyperekplexia. Indications of the disorder include the excessive startle response, muscle stiffness, and impaired movement after the startle. A doctor may also want to rule out hyperekplexia if a child is experiencing seizures.

Possible diagnostic steps include:

• Family medical history. The doctor will look for a family history of the disorder since most cases of hyperekplexia are inherited.
• Electroencephalography (EEG). This exam measures the electrical activity of the brain. It can give doctors an idea of what is going on in a patient’s brain during the startle response and may be used to rule out epilepsy.
• Electromyography. This exam measures electrical activity in the muscles.
• Genetic testing. These tests look for the gene mutations associated with hyperekplexia.  

How Is Hyperekplexia Treated?

Hyperekplexia has no cure, but its symptoms can be managed with anti-seizure medications in many cases. Commonly used drugs include clonazepam, carbamazepine, phenobarbital, phenytoin, diazepam, 5-hydroxytryptophan, piracetam, and sodium valproate.

How Does Hyperekplexia Progress?

Symptoms of hyperekplexia typically improve in infancy, but some relatively mild symptoms may continue through adulthood. Possible long-term effects of the disorder include:

• Tendency to startle easily
• Low tolerance for crowds or noisy situations
• Muscle stiffness
• Twitching or other movements while asleep
• Difficulty walking or susceptibility to falling down

How Is Hyperekplexia Prevented?

There is no known way to prevent hyperekplexia. People with a family history of the disorder are advised to speak with a genetic counselor to assess their risks if they plan to have children.

Hyperekplexia Caregiver Tips

Some people with hyperekplexia also suffer from other brain and mental health-related issues, a condition called co-morbidity. Here are a few of the disorders that may be associated with hyperekplexia:

• Hyperekplexia may be associated with an increased risk of depression.
• People with hyperekplexia may be at increased risk for anxiety.

Hyperekplexia Brain Science

Research has suggested that hyperekplexia is associated with problems related to a brain chemical called glycine. Glycine is a neurotransmitter, a chemical that allows nerve cells to communicate with each other and other types of cells.

Glycine is the primary inhibitory neurotransmitter in the spinal cord and some parts of the brain. One of its jobs is to counter the action of glutamate, an excitatory neurotransmitter. Glutamate allows the transmission of electrical signals from one nerve cell to another, and glycine helps inhibit signals when transmission of them is inappropriate. Glutamate and glycine work together to keep the central nervous system functioning correctly.

The gene mutations associated with hyperekplexia cause problems with receptors on nerve cells. Normally, these receptors bind with glycine released by other nerve cells and, in response, cause a chain reaction that inhibits the transmission of unwanted nerve signals. When the receptors don’t work properly, glycine is unable to do its job, and the unwanted signals are passed on.

When this inappropriate signaling happens in the spinal cord and brain stem, the parts of the central nervous system that regulate automatic reactions, the result can be uncontrolled and exaggerated responses to stimuli such as noises or movements.

Hyperekplexia Research

Title: Hyperekplexia in Patients With CTNNB1 Mutation (CTNNB1)

Stage: Not Yet Recruiting

Principal investigator: Laure Mazzola, MD

Centre Hospitalier Universitaire de Saint Etienne

Saint Etienne, France

A few years ago, a new genetic disorder (OMIM # 615075) was associated with loss-of-function variations in the CTNNB1 gene. The clinical features include delayed psychomotor development, usually leading to severe intellectual disability with or without autistic spectrum disorders, progressive spastic diplegia, and various visual defects. In addition, among over 30 cases described worldwide, two were reported with an exaggerated startle response to sudden stimulus corresponding to a very rare neurological phenomenon called hyperekplexia. The investigators also have a 3rd patient carrying a CTNNB1 syndrome associated with hyperekplexia.

Hyperekplexia can impair daily life because the affected person will fall unexpectedly and stiffly, causing repeated head- or body- wounds. It may be treated empirically by various drugs. Hyperekplexia has so far not been associated with CTNNB1 variations.

This study aims to describe the prevalence and clinical characteristics of hyperekplexia in CTNNB1 syndrome carriers to improve diagnosis and thus treatment.

The investigators will recruit CTNNB1 subjects through health care providers and by contacting the families through dedicated social media and databases. The families and health care providers will be invited to fill in a questionnaire related to hyperekplexia (clinical, pharmacological, and genetic data).

Title: Cause, Development, and Progression of Stiff-Person Syndrome

Stage: Completed

National Institute of Neurological Disorders and Stroke

Bethesda, MD

Stiff-person syndrome (SPS) is a progressive neurological disorder characterized by stiffness of the trunk or limb muscles and frequent muscle spasms induced by unexpected visual, auditory, or somatosensory stimuli. It is an incapacitating disorder that leads to recurrent falls and impaired ambulation. The cause of the disease is unknown, but autoimmune pathogenesis is implicated based on its association with other autoimmune diseases and auto-antibodies, specific HLA haplotypes, and high titer antibodies against GAD, the rate-limiting enzyme for the synthesis of GABA. Understanding the autoimmune mechanisms of SPS is fundamental to refining the diagnostic criteria and developing specific therapies. The goals of this study are: a) define the natural history of SPS in a homogeneous cohort of patients, b) explore a pathogenetic link between SPS and viral infections based on the known peptide homology between GAD and certain viruses, and c) establish GAD-specific T-cell clones and search for candidate antigenic epitopes using synthetic peptide libraries. Collected clinical data will be used to delineate the rate of disease progression and the frequency of association with other autoimmune illnesses, auto-antibodies, or malignancies. It is anticipated that the knowledge acquired from the study will help us understand the mechanism of the disease and design antigen-specific therapeutic strategies. This is an investigative study intended to define the natural history and pathogenesis of SPS. No new therapy will be provided except standard of care.

Title: Autologous Peripheral Blood Stem Cell Transplant for Neurologic Autoimmune Diseases

Stage: Recruiting

Principal investigator: Richard A. Nash

Colorado Blood Cancer Institute

Denver, CO

This phase II trial studies the side effects and how well carmustine, etoposide, cytarabine, and melphalan together with antithymocyte globulin before a peripheral blood stem cell transplant works in treating patients with autoimmune neurologic disease that did not respond to previous therapy. In autoimmune neurological diseases, the patient’s own immune system ‘attacks’ the nervous system, which might include the brain/spinal cord and/or the peripheral nerves. Giving high-dose chemotherapy, including carmustine, etoposide, cytarabine, melphalan, and antithymocyte globulin, before a peripheral blood stem cell transplant weakens the immune system and may help stop the immune system from ‘attacking’ a patient’s nervous system. When the patient’s own (autologous) stem cells are infused into the patient, they help the bone marrow make red blood cells, white blood cells, and platelets so the blood counts can improve.