Synonyms

• KCNQ2-related neonatal epileptic encephalopathy

• Early childhood epileptic encephalopathy 7 (EIEE7)

• Epilepsy KCNQ2

• KCNQ2 Encephalopathy

• KCNQ2 epileptic encephalopathy

Related ailments

• Benign familial neonatal seizures / convulsions (BFNC / S)

The discovery of the KCNQ2 gene

The history of identifying KCNQ2 epileptic and developmental encephalopathy as an identifiable disorder begins with the identification and characterization of another related disorder, benign familial neonatal epilepsy (BFNE). This condition was first described as a syndrome in 1964 by doctors Rett and Teubel. They reported a family with eight affected individuals over 3 generations. The youngest child had onset of seizures at 3 days of age described as tonic-clonic events occurring several times a day. EEGs were normal between seizures, and children developed appropriately after seizures subsided. This usually happened later in childhood. Over the next twenty years, other families with similar histories were described. In some cases, the seizures persisted into old age, but the results were otherwise favorable. The inheritance pattern was determined to be autosomal dominant (see the Affected Populations Section for further explanation) and genetic testing linked the disease to the long arm of chromosome 20 (see the Causes section for further definitions). In 1998, researchers identified a gene in the region that appeared similar in structure to a potassium channel within the heart. This new gene has been conventionally named KCNQ2. Subsequently, several families were identified in which outcomes were non-benign, having or persistent seizures that did not respond to drugs, 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 that group of 80 patients, with those children sharing many characteristics. Since initial document in 2011, many more people have been diagnosed and the syndrome has been further defined.

Signs and symptoms

Developmental and epileptic encephalopathy KCNQ2 (KCNQ2) typically presents with seizures in the first week of life. Seizures appear as stiffening of the body (tonic) often associated with spasms and changes in breathing or heart rate. Seizures are generally quite frequent (many a day) and often difficult to treat. Typically, seizures are associated with abnormal brain wave patterns on the EEG during this period. Crises in KCNQ2 often resolve within months or years, but children have some degree of developmental impairment involving one or more domains (motor, social, language, cognition). There is a wide variability in the symptoms of patients diagnosed with KCNQ2. Some have very little or no seizure activity, and developmental impairment can range from mild to severe, depending on a number of different factors. autistic characteristics or other comorbidities.

KCNQ2 and seizures

Seizures are one of the hallmarks of KCNQ2. Almost all people with KCNQ2 experience seizures in the first few days of life. This is most often the symptom that leads to the test leading to a diagnosis of KCNQ2. Following this early neonatal period, there is a wide variability in the seizure activity that each patient experiences. Many patients are able to achieve good seizure control with available medications, while some have refractory seizures that are difficult to control and continue into later life. Some see seizures dissipate soon after the initial seizure activity. Even for those whose seizures resolve during the first few years of life, many continue to be at risk for febrile or sporadic seizures even when they are older.

There are various types of seizures experienced by those with KCNQ2. The crisis classifications used by the experts have recently been updated and are described in the attached image.

KCNQ2 and autism

Many children diagnosed with KCNQ2 also show symptoms of autism, as a result of the impact of KCNQ2. In addition to the general cognitive and developmental disabilities that affect nearly everyone with KCNQ2, many children also exhibit repetitive motion, poor eye contact, self-harm, sound sensitivity, or other symptoms associated with autism. Therefore, therapies known to be effective for treating autism can be helpful. SimmonsVIP, one of the leaders in autism-related genetic research, is researching KCNQ2 as one of the genetic causes of autism.

Diagnosis of KCNQ2

Clinical tests and work-up evaluations

EEG: One of the first steps in seizure assessment is to characterize the brain activity patterns associated with seizures. This is done by doing an electroencephalogram or EEG. This is a painless, non-invasive means of recording the electrical activity patterns of the brain. Electrodes placed on the scalp collect and record electrical waves during periods of activity, sleep and seizures. KCNQ2 is often associated with a pattern of burst suppression on the EEG but may have other nonspecific abnormalities and the EEG is not typically normal between seizures, unlike BFNE, in which the EEG can normalize.

When seizures are present in childhood, there are a number of potential causes that doctors and insurers may need to rule out before continuing with genetic testing. This often depends on the presentation and other clinical factors. Tests that may be done include assessments for infections, electrolyte disturbances, metabolic disturbances, and structural problems in the brain.

MRI: Magnetic resonance imaging (MRI) is a radiological technique that produces detailed images of cross-sections or sections of the brain using a magnetic field. The images can provide information regarding any malformations of brain structures or other types of lesions commonly seen in epilepsy. The potassium channel malformations caused by the KCNQ2 mutation are too small to be detected with an MRI.

Genetic tests: the diagnosis of KCNQ2 is finally made by means of molecular genetic tests. this can be done by examining only the potassium channel gene or by a genetic test that looks for mutations in a number of genes associated with childhood epilepsy, or even the entire genome or exome, which screen for all or almost all geniuses.

Standard therapies

Treatment decisions may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, developmental pediatricians and / or other healthcare professionals may need to systematically and comprehensively plan the treatment of an affected child.

In some cases, it is possible that treatment with anticonvulsant drugs can help reduce or control various types of seizure activity associated with KCNQ2. Anticonvulsant drugs have many different mechanisms of action and it is not entirely clear which drugs are best for KCNQ2. Some reports suggest that children respond better to drugs that affect the way sodium or potassium ions flow into nerve cells; however, the number of children evaluated in these studies may be too small to draw these conclusions. In practice, seizures are treated with a wide range of different drugs, most often in combination, in children with KCNQ2. If the seizures are unresponsive to medication, other treatments including diets, devices, and specialized surgeries may be considered.

Genetics in KCNQ2

KCNQ2 is caused by a mutation in the KCNQ2 gene, located on chromosome 20.

Chromosomes: Chromosomes are found in the nucleus of human cells and carry the genetic information for each individual. Cells in the human body normally have 46 chromosomes in each cell. Human chromosome pairs numbered 1 to 22 are called autosomes, in addition to the sex chromosomes, which 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". Each chromosome is further subdivided into many numbered bands. For example, "chromosome 11p13" refers to band 13 on the short arm (p) of chromosome 11. The numbered bands specify the location of the thousands of genes on each chromosome.

Genes: Each chromosome contains thousands of genes and each of these genes contains the code with the "instructions" for all the components of the human body. Each gene is a segment of DNA with instructions for a particular component. In the case of KCNQ2, there is an error in the code in the KCNQ2 gene. This error can be inherited from a parent or occur spontaneously. In cases where the mutation is inherited, only one parent may have carried the mutation for it to be seen in the child. In some cases, the parent may never have symptoms of the disease if the mutation is on only a small portion of the parent's cells, but the child may have the mutation in many more cells, leading to symptomatic disease. In many cases, the mutation in KCNQ2 is not inherited and is called "de novo". De novo mutations in the KCNQ2 gene occur when genes are copied over and over as cells divide soon after conception. When genes are copied, there is sometimes a random error in the genetic code, such as a "typo". This error can be the deletion of one of the "letters" in the code, or it can be a substitution of an incorrect "letter" in the code.

Nucleotides: Genes are made up of nucleotides. Genes carry the code to create the human body using nucleotide sequences. There are about 3 billion nucleotides that make up the DNA of a human. In most cases of KCNQ2, there is an error in only one of these 3 billion nucleotides, but it is in a position that codes for a critical protein.

There are only four nucleotides used in the entire genetic code; they are cytosine (C), thymine (T), adenine (A) and guanine (G). Various combinations of three nucleotides, depending on which nucleotides and in what order, code for various amino acids. These amino acids, in turn, are the building blocks of proteins. This is how the nucleotides that make up the code of genes determine which proteins are formed. When there is an error or mutation in the nucleotide sequence, the resulting protein is malformed. In the case of KCNQ2, the mutation (the error in which the nucleotide is present) is in the DNA sequence that codes for KCNQ2, or the potassium channel. Since the potassium channel is important for the brain which sends signals throughout the body,

Gain or loss of functional mutations: depending on where the error is and what the error is (which nucleotide is substituted or missing), the mutation can result in a "loss of function" of the potassium channel (being closed more than had to be) or have a "gain of function" (be open more than it should be). The vast majority of KCNQ2 cases are due to a loss of function in the potassium channel. With a growing community of patients being diagnosed and variant data collected, there is a growing understanding of which mutations, or variants, cause gain in function and which ones cause loss of function. Understanding whether a patient is gaining or losing function can have implications for a recommended course of treatment, particularly when more targeted therapies are being developed.

Read your genetic report

Most families get the news of the

KCNQ2 diagnosis of one's child verbally from

a doctor, often followed by a written report of the

laboratory performing the test. This report of

laboratory will contain information on the specific variant

of the KCNQ2 mutation which may be useful for

identify potential treatments or possible outcomes.

To explain what the information means,

we will use a specific example from the report

genetic GeneDx of a patient. The report says:

p.Arg333Trp

(CGG> TGG)

c.997C> T

The report is written in a "top down" approach. Starting with the first line describing the amino acid (or building block of the protein that is produced), the second line describing what the nucleotide sequence is, which caused the production of those particular amino acids, and the last line describing the coding DNA, which codes for nucleotides. However, in reality, the process occurs in reverse order, as described in the Genetics section in KCNQ2 . The mutation comes into play with an error in a nucleotide in the coding DNA, resulting in an error in the nucleotide sequence, resulting in an error in the amino acid produced.

The first line: p.Arg333Trp talks about the protein it is encoded for (the "p" is short for protein). In the case of this particular variant, the mutation results in the production of the amino acid tryptophan (abbreviated Trp) instead of arginine (abbreviated Arg) in position 333. The abbreviation is written (p = protein). (Correct amino acid, in this case Arg or arginine) (location of the mutation, in this case 333) (actual amino acid, in this case Trp or tryptophan).

The second line (CGG> TGG) means that this patient has the TGG nucleotide sequence in place of CGG (which is the normal sequence). The TGG sequence codes for tryptophan, which explains why it has that amino acid instead of arginine (which is encoded by CGG). The ">" sign means it is a replacement. If there is a "_" sign it means that it is a cancellation. The table shows how these three nucleotide sequences, or "DNA Codons", code for amino acids.

The last line c.997C> T explains the mutation in the coding DNA (the coding DNA is what codes for the protein, described in the first line). This report says that nucleotide cytosine (abbreviated to C) is replaced with thymine (abbreviated to T) at nucleotide number (or position) 997. This is why the letters are TGG instead of CGG in the sequence shown in line 2, above.

Join the variant database and access variant information

Data on known KCNQ2 variants is collected in the RIKEE database, which is maintained by Baylor College of Medicine. Click this link for more RIKEE.org information

CAUSE

The KCNQ2 gene

The gene that is altered in patients with epileptic and developmental encephalopathy KCNQ2 (KCNQ2) is the gene for a potassium channel within the brain, located on the long arm of chromosome 20, at position 13.3 (20p13.3).

The KCNQ2 gene belongs to a family of other ion channel genes and is sometimes abbreviated as Kv7.2. Ion channels are pores in the cell membrane, around the outside of the cells, with gates that allow charged atoms (ions) to flow in and out of the cells. These ions play a key role in a cell's ability to generate and transmit electrical signals.

Genes for ion channels share important properties and are named to reflect them. "K" is the chemical symbol for potassium, which is a positively charged ion. CN is an abbreviation for channel. The KCNQ2 gene is the second member of the Q subfamily indicating that the channel is voltage-dependent. Being energized means that the channel opens and closes based on the charge in the environment in the cell. Mutations in the KCNQ2 gene cause a spectrum of diseases ranging from benign seizures in childhood to developmental epileptic encephalopathy. These differences are likely based on the degree of potassium channel dysfunction. Those mutations that cause encephalopathy are typically found in one of several particular areas. However,

KCNQ2 is an autosomal dominant disease. Most genetic diseases are determined by the status of two copies of a gene, one received from the father and the other from the mother. Dominant genetic diseases occur when only a single copy of an abnormal gene is needed to cause a particular disease.

The abnormal gene can be inherited from one of the parents or it can be the result of a new mutation (genetic change or de novo mutation) in the affected individual. If one parent carries the gene, 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. In such situations, the disorder is not inherited from the parents.

Most cases of KCNQ2 epileptic and developmental encephalopathy occur de novo (caused by a spontaneous mutation and not inherited from a parent). However, a small number of KCNQ2 patients inherited the mutated gene from a parent. In many of these cases, the parent may have few or no symptoms of the disease, compared to the child, because only a few cells in the parent's body contain a copy of the affected gene, in a condition known as mosaicism. A parent who is a mosaic for the KCNQ2 mutation may have enough properly functioning copies of the KCNQ2 gene (and therefore enough properly formed potassium channels) to show no clinical symptoms, but the mutation can be passed on to a child who can then carry the gene. mutated in all their cells.

Populations affected

KCNQ2 affects males and females equally and affects individuals of ethnic origin equally. Cases are often not diagnosed or misdiagnosed, making it difficult to determine the true frequency of the disorder in the general population. Furthermore, the relatively recent discovery of this disorder means that there are older patients in the community who have not been tested or who have received another misdiagnosis.

Several researchers have attempted to determine the frequency of this disorder by testing groups of children with undiagnosed seizure disorders who share some of the characteristics of KCNQ2 (neonatal onset, epileptic encephalopathy). In a group of 84 patients with early neonatal or infantile seizures and associated developmental impairment, mutations in KCNQ2 were identified in 11 patients (13%). In another group of 239 patients with early childhood epileptic encephalopathy (EIEE), 12 patients (5%) had mutations in the KCNQ2 gene. KCNQ2 is rare and accounts for approximately 10% of patients with epileptic encephalopathy with onset in the first three months of life; however, the incidence of KCNQ2 is approximately 2.8 / 100,000 live births (or over 3,000 new cases per year worldwide), which is about half the number of Dravet syndrome births.

Related ailments

Symptoms of the following disorders may be similar to those of KCNQ2. Comparisons can 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, seizures, spasms, sensory confusion, and disorders of the autonomic nervous system. There are many different types of epilepsy and seizures, and the exact cause is often unknown. (For more information on this disorder, choose "epilepsy" as the search term in the rare disease database.) Epilepsy can occur as a symptom of many genetic diseases. Genetic diseases commonly associated with epilepsy include Rett syndrome, Angelman syndrome, Dravet syndrome, Lennox-Gastaut syndrome, and West syndrome.

Ohtahara syndrome (OS), sometimes referred to as early childhood epileptic encephalopathy (EIEE) is a rare type of epilepsy that typically occurs during the first 1-3 months of life. It is characterized by frequent tonic crises that are difficult to treat. Tonic seizures appear as stiffening of a limb or 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 stillness. Ohtahara syndrome is considered an epileptic encephalopathy because this abnormal brain activity is thought to contribute to the cognitive and behavioral disturbances associated with the disorder. Most children will develop additional types of seizures such as infantile spasms or receive an additional diagnosis of Lennox-Gastaut syndrome as they grow up. There are many causes of this epileptic syndrome including metabolic disorders, genetic and structural brain malformations or lesions. KCNQ2 mutations are one of the causes of Ohtahara syndrome symptoms.

Lennox-Gastaut syndrome (LGS) is a rare type of epilepsy that typically occurs in 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 coordination of mental and muscular activity (psychomotor retardation). Individuals with the disorder can experience different types of seizures including falling attacks, tonic seizures, absence, and seizures. Lennox-Gastaut syndrome can be due to or occur in association with a number of different underlying disorders or conditions, including mutations in the KCNQ2 gene. (For more information on this disorder, choose "Lennox-Gastaut" as the search term in the rare disease database.)