The KCNT1 Gene
The KCNT1 gene plays a primary role in building a specific potassium ion channel in human brain cells. The KCNT1 channel is also referred to by scientists as the “Slack” channel. Generally, ion channels allow for the flow of differently charged ions from one side of a cell membrane to another, which permits cellular electrical activity. New research indicates that the KCNT1 gene also plays a role in cardiovascular cells and in other parts of the body, including a role in sensing pain. Unfortunately, this is only an emerging area of study, and these additional functions of the KCNT1 gene are not well understood.
Pathogenic mutations of the KCNT1 gene are very rare, and often appear de novo (that is, in most cases of KCNT1 Epilepsy the mutation just occurs in the child and is not inherited from either parent). There are numerous KCNT1 mutations that can cause epilepsy, but current data suggests that the particular mutation does not have a significant impact on symptom severity experienced by individual patients. All known mutations in KCNT1 that cause epilepsy result in a gain of function in the channel, allowing potassium to flow at an excessive rate through brain cell membranes. The exact mechanism by which increased current through the KCNT1 channel causes epilepsy is unknown.
KCNT1 epilepsy is a lifelong disorder that can present as: (1) Epilepsy of Infancy with Migrating Focal Seizures (EIMFS), also known as Malignant Migrating Partial Seizures of Infancy or Migrating Partial Seizures of Infancy (MMPSI/MPSI) with symptoms typically beginning in the first days or months of life, as (2) Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE) with symptoms typically presenting in later childhood or adolescence or 3) A nonspecific epileptic encephalopathy presenting in the first year of life, often associated with a seizure type called infantile spasms. It is likely that there are other types of epilepsy that may be caused by mutations in KCNT1 that have not yet been well described. While all these types of epilepsy can be caused by the same mutation, the symptoms of the presentations (phenotypes) are very different. At this point, we do not know why the same mutation presents so differently within the population.
KCNT1 MPSI EPILEPSY: The MPSI presentation of KCNT1 Epilepsy is the most severe. Patients typically experience seizures within the first days or weeks of being born, and epilepsy always starts before 6 months of age, although seizures may go unrecognized. Seizure frequency during infancy usually ranges from dozens to hundreds per day, and there is a significant danger of status epilepticus (a state of near constant seizure or where seizures last for dangerously long periods of time).
Patients typically have both clinical (visible) and subclinical (detectable only through EEG monitoring) seizures. Seizures may migrate (travel) from one part of the brain to another, sometimes resulting in a clinical seizure that starts on one side of the body and then switches to the other side. However, visualizing migrating seizures is not necessary for a diagnosis of MPSI, as migrating seizures may not always be present. Because seizures are not confined to one part of the brain, they vary in clinical presentation and range from very dramatic convulsions to very subtle. Patients may experience respiratory and/or cardiac problems during seizures. These complications are particularly common early in life and may require medical intervention. Seizure frequency tends to decrease as patients get older, but this too varies patient to patient.
Patients with MPSI almost always have global developmental delays, which are a symptom separate and apart from seizure activity (although seizure activity certainly can contribute to developmental delays). The cause of the developmental component of the disease is not well understood, but may be related to the fact that Slack channels in neurons directly bind proteins well-known to influence intellectual development and autism. When seizures are well controlled, some patients do have improvements in their development, but even patients with good seizure control typically remain very delayed.
Developmentally, many patients have very little or no self-directed control of their body, do not speak and have limited ability to process sensory information from their environment. While individual developmental milestones vary, most children are not able to walk, talk, or feed themselves. However, there are individuals that can walk, talk or make other significant developmental strides to varying degrees. Many patients lose the ability to eat orally early on and require placement of a feeding tube for nutrition. However, some patients retain the ability to feed orally.
Cortical Visual Impairment (CVI) appears to be a very common symptom of the MPSI phenotype. CVI is a term that describes a dysfunction in the vision center of the brain that prevents the brain from properly interpreting visual information. In the case of KCNT1 Epilepsy, that dysfunction is caused by the excessive electrical activity in the neurons. While patients can technically see, their brains cannot process the images. The extent of the impairment, like most symptoms, varies, but many patients with MPSI have difficulty seeing complex images and tracking objects. A variety of other neurogenic symptoms, such as neuroirritability, gastroesphageal reflux, constipation, and neurogenic bladder, are also typical in people with MPSI.
Patients also suffer from poor muscle tone and a variety of resulting secondary complications. It is very common for patients with MPSI to have low tone as infants (that is, to seem floppy) and then gradually develop increased tone especially in the legs over the first few years of life. Scoliosis, hip dysplasia, aspiration, floppy airways and GI issues are very common.
In rare instances, patients with KCNT1 MPSI Epilepsy have developed abnormal blood vessels that go from the heart to the lungs, referred to as pulmonary collateral vessels. These blood vessels can sometimes burst, resulting in bleeding into the lungs, which can result in coughing up blood. This is a very serious symptom seen only in a small minority of patients with KCNT1 MPSI.
Diagnosing KCNT1 Epilepsy
Mutations in KCNT1 can be identified using genetic testing from a blood or saliva samples. In the U.S. and Europe, most patients with the onset of frequent seizures in infancy should receive genetic testing. Outside of the U.S. and Europe, genetic testing may be harder to access. KCNT1 mutations are now included in most gene panels sent for epilepsy in the U.S. and Europe and can also be picked up using technologies such as Whole Exome Sequencing or Whole Genome Sequencing. These tests can confirm KCNT1 Epilepsy and identify the patient’s specific variant (mutation). Once a diagnosis is received, genetic testing should be done on the child’s parents to confirm if they are carriers or if the mutation was de novo. If someone is a carrier, they have a 50% chance of passing along the mutation to their children.
Treating KCNT1 Epilepsy
There is currently no cure or disease modifying treatment for KCNT1 Epilepsy. Most patients with KCNT1 Epilepsy have seizures that are difficult to control despite multiple anti-seizure drugs. There is no single drug or combination of drugs that has been shown to be definitively better for the treatment of KCNT1 Epilepsy than other drugs. Patients with KCNT1 Epilepsy should work with an epilepsy specialist or child neurologist with experience treating children with treatment resistant epilepsy. The goal of therapy is generally to minimize dangerous seizures while optimizing quality of life; a good neurologist will work closely with families to try and find the right balance of seizure control and minimal medication side effects. Seizure freedom is often not possible, especially during infancy.
There are no known pharmacological interventions available to address the developmental delays associated with KCNT1 Epilepsy. Early intervention with physical therapy and occupational therapy is recommended.
Specific Medications: Several case reports or small case series have reported particular anti-seizure medications as effective in KCNT1 Epilepsy. Unfortunately, in most cases larger studies have not shown these medications to be particularly effective.
Off label use of Quinidine (a targeted potassium channel blocker) has been effective in reducing seizures in approximately 10% of children. Unfortunately, many children cannot tolerate Quinidine because of its cardiac side effects, and it is otherwise not effective in many others. Some patients can achieve a level of seizure control with available anticonvulsants, but individual responsiveness varies significantly. It is common to see an initial improvement with the introduction of a medication, but it often does not have lasting efficacy. The ketogenic diet, a special diet that is very high in protein and fat and low in carbohydrates, has been reported to be helpful in some patients.
Surgical Treatments: Most KCNT1 Epilepsy is not treatable with epilepsy surgery, though there may be exceptions in some patients. Because the KCNT1 channel is expressed throughout the brain, in most cases a resection of a particular part of the brain to treat the epilepsy is not possible. Some patients have had a good response to placement of a Vagal Nerve Stimulator, but there is minimal data on this and it does not appear to be effective in most patients.
 The information on this website is primarily geared to the more devastating MMPSI presentation. The Foundation is actively seeking parent/patient involvement from families struggling with ADNFLE so that we can better address the needs of that population. If you are interested in getting involved, please contact a member of our team.