KCNQ2 Encephalopathy (KCNQ2E)
• KCNQ2-Related Neonatal Epileptic Encephalopathy
• Early infantile epileptic encephalopathy 7 (EIEE7)
• Benign Familial Neonatal Convulsions/Seizures (BFNC/S)
KCNQ2 typically presents with seizures in the first week of life. Seizures appear as stiffening of the body (tonic) often associated with jerking and changes in breathing or heart rate. The seizures are usually quite frequent (many per day) and often difficult to treat. Typically, the seizures are associated with abnormal brain wave patterns on EEG during this time. The seizures in KCNQ2E often resolve within months to years but children have some degree of developmental impairment involving one or more domains (motor, social, language, cognition). This can range from mild to severe depending on a number of different factors. Some children may also have autistic features.
The story of KCNQ2E begins with the identification and characterization of another related disorder, benign familial neonatal seizures (BFNS). This condition was initially described as a syndrome in 1964 by Rett and Teubel. They reported a family with eight affected individuals over 3 generations. The youngest infant had the onset of seizures at 3 days of age described as tonic-clonic events occurring multiple times per day. The EEG was normal in between seizures and children developed appropriately after the seizures stopped. This typically happened later in infancy. Over the next twenty years, additional families with similar stories were described. In a few instances, seizures persisted into later life but outcomes were otherwise favorable. The pattern of inheritance was determined to be autosomal dominant (see the Affected Populations section for further explanation) and genetic testing linked the disorder to the long arm of chromosome 20 (see the Cause section for further definition). In 1998, researchers identified a gene in the region that appeared similar in structure to a potassium channel within the heart. This new gene was named, according to convention, KCNQ2. Subsequently, several families were identified in which the outcome was not benign having either persistent seizures that did not respond to medication, developmental impairment, or both. This prompted a group of researchers to screen patients with severe neonatal epilepsy syndromes for mutations in KCNQ2. Eight cases were identified from the group of 80 patients and the children shared many characteristics. Since that initial paper in 2011, many more individuals have been diagnosed and the syndrome has been defined further.
SIGNS AND SYMPTOMS
The gene that is altered in patients with KCNQ2E is the gene for a potassium channel within the brain, located on the long arm of chromosome 20, at position 13.3 (20p13.3).
Chromosomes are located in the nucleus of human cells and carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes numbered from 1 through 22 are called autosomes and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11p13” refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
KCNQ2 belongs to a family of other ion channel genes and is sometimes abbreviated Kv7.2. Ion channels are pores in the cell membrane that allow charged atoms (ions) to flow into and out of cells and play a key role in a cell’s ability to generate and transmit electrical signals. These genes share important properties and are named to reflect them. “K” is the chemical symbol for potassium which is a positively charged atom. CN is an abbreviation for channel. This gene is the 2nd member of the Q subfamily which indicates that the channel is voltage gated. This means that the channel opens according to the charge in its cellular environment. Mutations in the KCNQ2 gene cause a spectrum of disease that ranges from benign seizures in infancy to epileptic encephalopathy likely based on the degree of dysfunction in this channel. Those that cause encephalopathy are typically located in several particular areas; however, recent literature suggests that distinguishing presentations may be more complex than initially thought.
Epilepsy is estimated to affect 1 in 26 people during their lifetime with an incidence of approximately 44/100,000 people. The incidence is highest in young children and older adults with children often having the most severe types of epilepsies. The incidence of epilepsy in children under 2 years of age is estimated to be 70.1 per 100,000 based on a recent population based study conducted in North London. In this research, severe epilepsies associated with abnormal development and EEG (epileptic encephalopathies) were identified in 22 (39%) of 57 infants.
KCNQ2E affects males and females in equal numbers. Cases can go undiagnosed or misdiagnosed, making it difficult to determine the disorder’s true frequency in the general population. In addition, the recent discovery of this disorder likely means that older patients exist in the community who have not been tested or have been given another diagnosis. Several researchers have attempted to determine the frequency of this disorder by testing groups of children with undiagnosed seizure disorders sharing some of the features of KCNQ2E (neonatal onset, epileptic encephalopathy). In a group of 84 patients with neonatal or early infantile seizures and associated developmental impairment, mutations in KCNQ2 were identified in 11 patients (13%). In another group of 239 patients with early infantile epileptic encephalopathy (EIEE), 12 patients (5%) harbored mutations in the KCNQ2 gene.
KCNQ2E is considered an autosomal dominant disorder. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. In some individuals, the disorder is due to a new (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents. Most cases of KCNQ2E occur de novo; however, a small number inherited them from an unaffected or mildly affected parent in a pattern called mosaicism. This means that only some cells in the parent’s body contain a copy of the affected gene.
Symptoms of the following disorders can be similar to those of KCNQ2E. Comparisons may be useful for a differential diagnosis:
Epilepsy is a group of neurological disorders characterized by abnormal electrical discharges in the brain. It is characterized by loss of consciousness, convulsions, spasms, sensory confusion, and disturbances in the autonomic nervous system. There are many different types of epilepsy and seizures and the exact cause is frequently unknown. (For more information on this disorder, choose “epilepsy” as your search term in the Rare Disease Database.) Epilepsy can also occur as part of larger genetic syndromes. Types of epilepsy or disorders associated with epilepsy include Rett syndrome, Angleman syndrome, Dravet syndrome, and West syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
Ohtahara syndrome (OS), sometimes referred to as early infantile epileptic encephalopathy (EIEE) is a rare type of epilepsy that typically becomes apparent during the first 1-3 months of life. It is characterized by frequent tonic seizures that are difficult to treat. Tonic seizures appear as stiffening of a limb or the body. The disorder is also characterized by a severely abnormal electroencephalogram (EEG) called “burst-suppression” in which short periods of abnormal brain activity are separated by several seconds of quiet. Otahara syndrome is considered an epileptic encephalopathy because this abnormal brain activity is thought to contribute to the cognitive and behavioral impairments associated with the disorder. Most children will go on to develop additional seizure types such as infantile spasms or Lennox-Gastaut syndrome as they grow older. There are many causes of this epilepsy syndrome including metabolic disorders, genetic, and structural brain malformations or injuries.
Lennox-Gastaut syndrome (LGS) is a rare type of epilepsy that typically becomes apparent during infancy or early childhood. The disorder is characterized by frequent episodes of uncontrolled electrical disturbances in the brain (seizures) and, in many cases, delays in the acquisition of skills that require the coordination of mental and muscular activity (psychomotor retardation). Individuals with the disorder may experience several different types of seizures including drop attacks, tonic seizures, absence, and convulsions. Lennox-Gastaut syndrome may be due to, or occur in association with, a number of different underlying disorders or conditions. (For more information on this disorder, choose “Lennox-Gastaut” as your search term in the Rare Disease Database.)
Clinical Testing and Work-up Evaluations
One of the first steps in the evaluation of new onset seizures in an infant is to characterize the patterns of brain activity associated with the seizures. This is done by performing an electroencephalogram or EEG. This is a painless and non-invasive means of recording the patterns of electrical activity of the brain. Electrodes placed on the scalp pick up and record the electrical waves during periods of activity, sleep, and during seizures. KCNQ2E is often associated with a burst-suppression pattern on EEG but may have other non-specific abnormalities and is typically not normal between seizures, in contrast to BFNC.
When seizures present in infancy, there are a number of potential causes that may need to be excluded before genetic testing is pursued. This often depends on the presentation and other clinical factors. Tests that may be performed include evaluations for infection, electrolyte disturbance, metabolic disorders, and structural problems in the brain.
Magnetic Resonance Imaging (MRI) is a radiological technique that produces detailed images of cross-sections or slices of the brain by using a magnetic field. The images can provide information concerning any malformation of the brain structures or other types of lesions commonly seen in epilepsy.
The diagnosis of KCNQ2E is ultimately made by molecular genetic testing. This can be done by examining only the potassium channel gene or by sending testing that looks for sequence changes in a number of genes associated with epilepsy in infancy.
Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, developmental pediatricians, and/or other health care professionals may need to systematically and comprehensively plan an affected child’s treatment.
In some cases, it is possible that treatment with anticonvulsant drugs may help reduce or control various types of seizure activity associated with KCNQ2E. Anticonvulsant medications have many different mechanisms of action and it is not entirely clear which medications are best for KCNQ2E. Some reports suggest that children respond best to medications which affect how sodium or potassium flow into nerve cells; however, the number of children reported may be too small to draw these conclusions. If seizures fail to respond to medication, other treatments including specialized diets, devices, and surgeries may be considered.
List of reported Symptoms of EIEE7
- Seizures, tonic
- Seizures, clonic
- Generalized stiffening
- Automatisms (repetitive actions performed unconsciously)
- Delayed development
- Intellectual disability
- Hypotonia (low muscle tone)
- Dystonia (abnormal muscle tone)
- Spastic quadriparesis
- EEG shows burst suppression pattern
- EEG shows multifocal epileptic activity
- Hyperintensities in the basal ganglia and/or thalamus on MRI
- Thin corpus callosum (in some patients)
- Reduced posterior white matter volume (in some patients)
- Onset of seizures in infancy
- Multiple seizures daily at onset
- Seizure frequency decreases during early childhood
- Most patients become seizure-free by age 3 or 4 years
- Variable severity of seizures seen in family members and can be inherited
- Mutations may also occur de novo (not see in either parent)
- Seizures are often unresponsive to treatment