Autosomal dominant sleep-related hypermotor epilepsy

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Sleep-related hypermotor epilepsy (SHE) is a form of epilepsy that is characterized by seizures that typically begin while a person is sleeping. The seizures often appear during childhood or adolescence and involve varying degrees of muscle (motor) activity, which can include large, complex, and repetitive movements (hyperkinetic seizures). Autosomal dominant sleep-related hypermotor epilepsy (ADSHE) is a form of SHE that runs in families. The specific features of ADSHE can vary, even among members of the same family.

People with ADSHE typically have seizures that start in a specific region of the brain (focal seizures). The seizures often occur in clusters during a phase of sleep called nonrapid eye movement (non-REM) sleep. They typically begin and end abruptly, with each seizure lasting no more than 2 minutes. Some seizures are characterized by minor motor activity that may simply wake a person from sleep, while others are more complex and include repetitive motor activity, such as flinging or throwing motions of the arms and bicycling movements of the legs. Seizures may also include muscle stiffness or abnormal body positions. Some affected individuals may get out of bed and wander around during a seizure, which can be mistaken for sleepwalking. Rapid breathing (hyperventilation); a sense of breathlessness; and vocalizations, such as moaning or crying, can also occur.

In some types of epilepsy, a pattern of unusual feelings or sensations (aura) occurs before the seizure. Upon waking from sleep, people with ADSHE may experience an aura that warns them of an oncoming seizure. Auras in people with ADSHE can be associated with a feeling of numbness, shivering, a sense of fear, dizziness (vertigo), and a feeling of falling or being pushed.

People with ADSHE typically develop seizures before the age of 20 years. The episodes tend to become milder and less frequent over time. Although many people with ADSHE have seizures that can be effectively managed with medication, approximately 30 percent of affected individuals have seizures that become resistant to medication.

Psychiatric disorders, behavioral problems, and intellectual disabilities have been reported in some individuals with ADSHE. It is unclear whether these additional features are directly related to the seizures or to the underlying genetic cause.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Genetic changes that cause disease or that increase the risk of disease are sometimes called mutations or pathogenic variants. Pathogenic variants in one of several different genes can cause ADSHE.

Pathogenic variants in the CHRNA2, CHRNA4, and CHRNB2 genes cause some cases of ADSHE. These genes provide instructions for making different parts (subunits) of a larger protein complex called a nicotinic acetylcholine receptor (nAChR). The nAChR complex acts as a channel, allowing charged atoms (ions), including calcium, sodium, and potassium, to cross the cell membrane. The nAChR channels play an important role in chemical signaling between nerve cells (neurons) in the brain.

Researchers believe that some pathogenic variants in the nAChR genes can cause cells to produce subunits that make the channels more sensitive, which allows them to open more easily than usual. The increased flow of ions across the cell membrane changes how neurons communicate with each other. Specifically, the increased ion flow alters the release of chemical messengers that relay signals from one neuron to another. As a result, it is likely that certain neurons become more active than usual, which triggers the abnormal brain activity associated with seizures. Pathogenic variants in the CHRNA4 gene are more common in people with ADSHE than pathogenic variants in the CHRNA2 or CHRNB2 genes. Approximately 6 percent of people with ADSHE have a pathogenic variant in the CHRNA4 gene.

Pathogenic variants in the DEPDC5, NPRL2, and NPRL3 genes can also cause ADSHE. These genes provide instructions for the proteins that make up the GATOR1 complex. The GATOR1 complex is a group of proteins that is found in cells throughout the body. GATOR1 regulates an important signaling pathway, called the mTOR pathway, that is involved in cell metabolism, cell growth, and cell division. Specifically, GATOR1 turns off the mTOR pathway when it is not needed.

The pathogenic variants in the GATOR1 genes that are associated with ADSHE result in the production of proteins that disrupt the function of GATOR1, causing the mTOR pathway to be more active than usual. Research suggests that increased signaling in the brain changes the connections between nerve cells (synapses) and increases nerve cell activation (excitation), which can lead to seizures. Variants in the DEPDC5, NPRL2, and NPRL3 genes each account for approximately 5 to 7 percent of ADSHE cases.

The KCNT1 gene belongs to a family of genes that provide instructions for making potassium channels. These channels play a key role in the cell’s ability to generate and transmit electrical signals. The pathogenic variants in the KCNT1 gene that are associated with ADSHE typically increase the flow of ions across potassium channels, which contributes to the excitation of neurons and the seizures seen in people with ADSHE. Approximately 1 percent of people with ADSHE have a variant in the KCNT1 gene.

Pathogenic variants in other genes cause a small percentage of ADSHE cases. A genetic cause of ADSHE can be identified in approximately 19 percent of people with the condition. In most people with ADSHE, the cause of the condition is unknown. Researchers are investigating other possible genetic causes for this condition.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

ADSHE is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. However, only 60 to 80 percent of people who inherit a pathogenic variant that is associated with ADSHE develop the signs and symptoms of the disorder. This situation is called reduced penetrance. It is not clear why some people with an ADSHE gene variant develop signs and symptoms of the disorder while others do not.

In most cases, people with ADSHE have an affected parent. Other cases are described as sporadic, which means an affected person has no family history of the disorder. Sporadic cases may result from new (de novo) variants in the gene that occur during the formation of reproductive cells (eggs or sperm) in an affected individual's parent or during early embryonic development.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

SHE is an uncommon form of epilepsy, affecting about 1.8 out of every 100,000 individuals. More than 100 families with ADSHE have been reported in the medical literature.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Nocturnal seizures · Very frequent (99-80%)

Seizures that occur while the affected individual is sleeping.

Abnormal repetitive mannerisms · Frequent (79-30%)

Use of the same abnormal action in response to certain triggers or at random. They may be used as a way to regulate one's internal state but must otherwise have no apparent functional purpose.

Involuntary movements · Frequent (79-30%)

Involuntary contractions of muscle leading to involuntary movements of extremities, neck, trunk, or face.

Paroxysmal dystonia · Frequent (79-30%)

A form of dystonia characterized by episodes of dystonia (often hemidystonia or generalized) lasting from minutes to hours. There are no dystonic symptoms between episodes.

Anxiety · Occasional (29-5%)

Intense feelings of nervousness, tension, or panic often arise in response to interpersonal stresses. There is worry about the negative effects of past unpleasant experiences and future negative possibilities. Individuals may feel fearful, apprehensive, or threatened by uncertainty, and they may also have fears of falling apart or losing control.

Cognitive impairment · Occasional (29-5%)

Abnormal cognition is characterized by deficits in thinking, reasoning, or remembering.

Depression · Occasional (29-5%)

Frequently experiencing feelings of being down, miserable, and/or hopeless; struggling to recover from these moods; having a pessimistic outlook on the future; feeling a pervasive sense of shame; having a low self-worth; experiencing thoughts of suicide and engaging in suicidal behavior.

EEG with focal spikes · Occasional (29-5%)

EEG with focal sharp transient waves of a duration less than 80 msec.

Other findings in the same source

From: Orphanet

Additional reported features include Hyperkinetic seizures (Occasional (29-5%)); Hyperventilation (Occasional (29-5%)); Increased theta frequency activity in EEG (Occasional (29-5%)); Interictal epileptiform activity (Occasional (29-5%)); Somnambulism (Occasional (29-5%)); Suicidal ideation (Occasional (29-5%)); Urinary incontinence (Occasional (29-5%)); Confusional arousal (Occasional (29-5%)); Attention deficit hyperactivity disorder (Very rare (<4-1%)); Atypical behavior (Very rare (<4-1%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Autosomal dominant sleep-related hypermotor epilepsy is Neurology, with a neurologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Which nervous-system findings help explain the symptoms?
• Would an assessment of walking, communication or daily function be helpful?
• Are rehabilitation or other specialist services relevant?

Treatment discussions and follow-up

Where the source describes treatments, these are an overview of possible care, not a prescription for an individual. Ask which option applies to the confirmed diagnosis, what benefit is expected, what adverse effects to watch for and how progress will be assessed. Availability, approvals and local practice can differ from the country described in the source.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.