Autosomal dominant sleep-related hypermotor epilepsy

Description

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.

Frequency

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.

Causes

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

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.

Autosomal dominant inheritance with a new (de novo) mutation. Credit: U.S. National Library of Medicine.

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.

Other Names for This Condition

• ADNFLE
• ADSHE
• Autosomal dominant nocturnal frontal lobe epilepsy
• Autosomal dominant sleep-related hypermotor (hyperkinetic) epilepsy
• ENFL
• Nocturnal frontal lobe epilepsy
• Sleep-related hypermotor epilepsy

Where this page came from

This page was imported from MedlinePlus Genetics, National Library of Medicine. Courtesy of MedlinePlus from the National Library of Medicine; its genetics summaries and the illustrations credited to the library are in the public domain. Pictures credited to others are not copied.

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