Hereditary hyperekplexia

Other Names: Startle disease, familial; Startle reaction, exaggerated; Exaggerated startle reaction; STHE; Stiff-baby syndrome; Stiff-man syndrome, congenital; Stiff-person syndrome, congenital; Kok disease; Hyperexplexia hereditary See Less

Hereditary hyperekplexia is a nervous system disorder (neurological disorder), that is usually noticed shortly after birth.

It 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.

Epidemiology

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

Cause

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.

Inheritance

Hereditary hyperekplexia has different inheritance patterns.

This condition can be inherited in an autosomal dominant pattern, which means a mutation in one copy of any of the associated genes in each cell is sufficient to cause the disorder. In some cases, an affected person inherits the mutation from one affected parent. Other cases may result from new mutations in the gene. These cases occur in people with no history of the disorder in their family.

Hereditary hyperekplexia can also be inherited in an autosomal recessive pattern, which means one of the associated genes has mutations in both copies of the gene in each cell. The parents of an individual with an autosomal recessive disorder typically each carry one copy of the altered gene, but do not show signs and symptoms of the disorder.

Signs and symptoms

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 hereditary hyperekplexia.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Ataxia
• Esophagitis(Inflammation of the esophagus)
• Fasciculations(Muscle twitch)
• Gastroesophageal reflux(Acid reflux)
• Hiatus hernia(Stomach hernia)
• [[Hyperreflexia](Increased reflexes)
• Joint stiffness(Stiff joint)
• Muscle stiffness
• Myoclonus
• Rigidity(Muscle rigidity)
• Spasticity(Involuntary muscle stiffness, contraction, or spasm)

30%-79% of people have these symptoms

• Gait disturbance(Abnormal gait)
• Sleep disturbance(Difficulty sleeping)
• Umbilical hernia

5%-29% of people have these symptoms

• Hip dislocation(Dislocated hips)
• Intellectual disability(Mental deficiency)
• Seizure

Diagnosis

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.

Treatment

Hereditary hyperekplexia is commonly treated with the anti-anxiety and anti-spastic drug clonazepam. Other medications which have been helpful for some people include carbamazepine, phenytoin, diazepam, valproate, 5-hydroxytryptophan, piracetam, phenobarbital, and fluoxetine. In some cases, a combination of treatments (i.e. clobazam and clonazepam) may be needed. 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.

NIH genetic and rare disease info

• NIH info on Hereditary hyperekplexia

Hereditary hyperekplexia is a rare disease.

Hereditary hyperekplexia Resources
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