What is KCNQ2 Developmental & Epileptic Encephalopathy
KCNQ2 Developmental & Epileptic Encephalopathy
- KCNQ2-Related Neonatal Epileptic Encephalopathy
- Early infantile epileptic encephalopathy 7 (EIEE7)
- KCNQ2 Epilepsy
- KCNQ2 Encephalopathy
- KCNQ2 Epileptic Encephalopathy
- Benign Familial Neonatal Convulsions/Seizures (BFNC/S)
The Discovery of the KCNQ2 Gene
The history of the identification of KCNQ2 developmental and epileptic encephalopathy as an identifiable disorder, begins with the identification and characterization of another related disorder, benign familial neonatal epilepsy (BFNE). This condition was initially described as a syndrome in 1964 by doctors 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 EEGs were 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 the 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 outcomes were 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 that group of 80 patients, with those children sharing many characteristics. Since that initial paper in 2011, many more individuals have been diagnosed and the syndrome has been defined further.
SIGNS and SYMPTOMS
KCNQ2 Developmental and Epileptic Encephalopathy (KCNQ2) typically present 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 KCNQ2 often resolve within months to years but children have some degree of developmental impairment involving one or more domains (motor, social, language, cognition). There is wide variability in the symptoms of patients with a KCNQ2 diagnosis. Some have very limited, or no noticeable seizure activity and the developmental impairment can range from mild to severe, depending on a number of different factors. Some children may also have autistic features or other comorbidities.
KCNQ2 and Seizures
Seizures are one of the hallmarks of KCNQ2. Nearly all of those affected by KCNQ2 experience seizures in the first several days of life. This is most often the symptom leading to testing resulting in a diagnosis of KCNQ2. Following this early, neonatal period, there is wide variability in the seizure activity each patient experiences. Many patients are able to gain good control of seizures with available medications, while some have refractory seizures which are difficult to control and continue into later life. Some see seizures dissipate early following initial seizure activity. Even for those whose seizures resolve during early life, many continue to be at risk for febrile or sporadic seizure activity even as they are older.
There are various seizure types experienced by those with KCNQ2. The classifications of seizures used by experts have recently been updated, and are described in the attached image.
KCNQ2 and Autism
Many children diagnosed with KCNQ2 also display symptoms of autism, as a result of the impact of KCNQ2. In addition to the general cognitive and developmental disabilities affecting nearly all of those with KCNQ2, many children also display repetitive movements, poor eye contact, self-harm, sensitivity to sound, or other symptoms associated with autism. As such, therapies known to be effective for the treatment of autism may be helpful. SimmonsVIP, one of the leaders in genetic research related to autism, is researching KCNQ2 as one of the genetic causes of autism.
Clinical Testing and Work-up Evaluations
EEG: One of the first steps in the evaluation of seizures 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. KCNQ2 is often associated with a burst-suppression pattern on EEG but may have other non-specific abnormalities and the EEG is typically not normal between seizures, in contrast to BFNE, in which the EEG can normalize.
When seizures present in infancy, there are a number of potential causes that physicians and insurers may need to 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.
MRI: 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 malformations of the potassium channel caused by the KCNQ2 mutation, are too small to be detected on an MRI.
Genetic Testing: The diagnosis of KCNQ2 is ultimately made by molecular genetic testing. his 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 epilepsy in infancy, or even whole genome or whole exome sequencing, which screen all, or nearly all genes.
Treatment decisions 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 KCNQ2. Anticonvulsant medications have many different mechanisms of action and it is not entirely clear which medications are best for KCNQ2. Some reports suggest that children respond best to medications which affect how 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 medications, most often in combinations, in children with KCNQ2. If seizures fail to respond to medication, other treatments including specialized diets, devices, and surgeries may be considered.
Genetics in KCNQ2
KCNQ2 is caused by a mutation on the KCNQ2 gene, located on chromosome 20.
Chromosomes: Chromosomes are located in the nucleus of human cells and carry the genetic information for each individual. Human body cells normally have 46 chromosomes in each cell. Pairs of human chromosomes numbered from 1 through 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 sub-divided into many bands that are numbered. 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 that are present on each chromosome.
Genes: Each chromosome contains thousands of genes, and each of those genes contains the code with the “instructions” for all of the components of the human body. Each gene is a segment of DNA with the instructions for a particular component. In the case of KCNQ2, there is an error in the code in the KCNQ2 gene. This error may be inherited from a parent, or occur spontaneously. In the cases in which the mutation is inherited, only one parent may have carry the mutation for it to be seen in the child. In some cases, the parent may not have ever displayed symptoms of the disease, if the mutation is only on 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 the genes are copied over and over as cells are dividing soon after conception. As the genes are copied, sometimes there is a random error in the genetic code, like a “typo”. This error can be a deletion of one of the “letters” in the code, or can be a substitution of an incorrect “letter” in the code.
Nucleotides: Genes are made up of nucleotides. The genes carry the code for making the human body using sequences of nucleotides. There are approximately 3 billion nucleotides comprising a human’s DNA. In most cases of KCNQ2, there is an error in just one of these 3 billion nucleotides, but it is in a location which codes for a critical protein.
There are only four nucleotides used in all genetic code; they are cytosine (C), thymine (T), adenosine (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. It is in this way, that the nucleotides that make up the code for the genes, determine what proteins are formed. When there is an error or mutation in the sequence of nucleotides the resulting protein in malformed. In the case of KCNQ2, the mutation (the error in which nucleotide is present) is in the DNA sequence coding for KCNQ2, or the potassium channel. Because the potassium channel is important for the brain sending signals throughout the body, even a very minor change in the structure of the protein which results from just a single nucleotide change, can have a significant impact.
Gain or Loss of Function Mutations: Depending on where the error is, and what the error is (which nucleotide is replaced or missing), the mutation can result in the potassium channel having a “loss of function” (being closed more than it should be) or having a “gain of function” (being 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 data on the variants being collected, there is an increasing understanding of which mutations, or variants, cause a gain of function and which cause a loss of function. Understanding whether a patient is gain of function or loss of function can have implications for a recommended treatment course, particularly as more targeted therapies are being developed.
Reading Your Genetic Report
Most families receive the news of their child’s KCNQ2 diagnosis verbally from a medical professional, often followed by a written report from the lab performing the testing. This lab report will contain information about the specific variant of KCNQ2 mutation that may be useful in identifying potential treatments or possible outcomes.
To explain what the information means, we will use a specific example from a patient’s GeneDx genetic report. The report says:
The report is written in a “top down” approach. Starting with the first line describing the amino acid (or protein building block that is produced), the second line describing what the sequence of nucleotides is, that caused those particular amino acids to be produced, and the last line describing the coding DNA, which codes for the nucleotides. However, in actuality, the process happens in reverse order, as described in the section Genetics in KCNQ2. The mutation comes into play with an error in a nucleotide in the coding DNA, resulting in the error in the nucleotide sequence, resulting in an error in the amino acid produced.
The first line: p.Arg333Trp tells about the protein that is coded for (the “p” is an abbreviation for protein). In the case of this particular variant, the mutation results in the production of the amino acid tryptophan (abbreviated Trp) in place of arginine (abbreviated Arg) at the location 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 sequence of nucleotides TGG in place of CGG (which is the normal sequence). The sequence TGG codes for tryptophan, which explains why he has that amino acid instead of arginine (which is coded for by CGG). The “>” sign means it is a substitution. If there is a “_” sign it means it is a deletion. The table shows how these three-nucleotide sequences, or “DNA Codons”, code for the amino acids.
The last line c.997C>T explains about the mutation in the coding DNA (the coding DNA is what codes for the protein, described in the first line). This report says that the nucleotide cytosine (abbreviated as C) is replaced with thymine (abbreviated as T) at the nucleotide number (or position) 997. That’s why the letters are TGG instead of CGG in the sequence shown in line 2, above.
Participate in Variant Database and Access Information on Variants
Data on known KCNQ2 variants is being collected in the RIKEE Database, managed by Baylor College of Medicine. Click on this link for more information RIKEE.org
The KCNQ2 Gene
The gene that is altered in patients with KCNQ2 developmental and epileptic encephalopathy (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 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 into and out of cells. These ions play a key role in a cell’s ability to generate and transmit electrical signals.
The genes for the 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 2nd member of the Q subfamily which indicates that the channel is voltage-gated. Being voltage-gated means that the channel opens and closes according to the charge in environment in the cell. Mutations in the KCNQ2 gene cause a spectrum of disease that ranges from benign seizures in infancy, to developmental and epileptic encephalopathy. These differences are likely based on the degree of dysfunction in the potassium channel. Those mutations that cause encephalopathy are typically located in one of several particular areas. However, recent literature suggests that distinguishing presentations may be more complex than initially thought, other factors, other than the location of the KCNQ2 mutation, that affect outcomes, which can vary significantly even for individuals with the same variant of the mutation.
KCNQ2 is 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, or de novo mutation) in the affected individual. If one of the parents 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 cell. In such situations, the disorder is not inherited from the parents.
Most cases of KCNQ2 developmental and epileptic encephalopathy occur de novo (caused by a spontaneous mutation and not inherited from a parent). However, a small number of patients affected by KCNQ2 inherited the mutated gene from a parent. In many of these cases, the parent may have few if any symptoms of the disease, in comparison to the child, because only some cells in the parent’s body contain a copy of the affected gene, in a condition known as mosaicism. A parent who is mosaic for the KCNQ2 mutation may have enough properly functioning copies of the KCNQ2 gene (and thus enough correctly formed potassium channels) to exhibit no clinical symptoms, but the mutation may be passed to a child who then may carry the mutated gene in all of their cells.
KCNQ2 equally affects males and females, and equally affects individuals across ethnic backgrounds. Cases often are undiagnosed or misdiagnosed, making it difficult to determine the disorder’s true frequency in the general population. In addition, the relatively recent discovery of this disorder means that older patients exist in the community who have not been tested or have been given another, incorrect, 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 KCNQ2 (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. KCNQ2 is rare, representing around 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 annually worldwide), which is roughly half the number of births of Dravet Syndrome, the most common genetic cause of early infantile epileptic encephalopathy.
Symptoms of the following disorders can be similar to those of KCNQ2. 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 occur as a symptom of numerous 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 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. Ohtahara 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 receive an additional diagnosis of 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. KCNQ2 mutations are one of the causes of the symptoms of Ohtahara Syndrome.
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, including mutations in the KCNQ2 gene. (For more information on this disorder, choose “Lennox-Gastaut” as your search term in the Rare Disease Database.)