KCNT1-Related Epilepsy

Pathogenic variants (“mutations”) in the gene KCNT1 cause epilepsy with a range of clinical features. In some cases, KCNT1 pathogenic variants can lead to a severe, early-onset epileptic encephalopathy. In other instances, KCNT1 pathogenic variants can lead to a form of frontal lobe epilepsy with additional psychiatric symptoms called autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE).

KCNT1 is not the name of a medical condition but rather is the name of the gene that is affected. When epilepsy is traced back to a pathogenic variant in the KCNT1 gene, it is called KCNT1-related epilepsy.

KCNT1-related epilepsies fall into two broad categories:

• KCNT1-related developmental and epileptic encephalopathy
• KCNT1-related frontal lobe epilepsy

Seizures beginning in infancy, not associated with a fever, may be the first indication of KCNT1-related epilepsy. Seizures from some KCNT1-related epilepsies may begin in the first year of life and even within days of birth. However, seizures in other children with KCNT1-related epilepsy may begin later in childhood.

Encephalopathy refers to a disease that affects the functioning of the brain. Children with KCNT1-related developmental and epileptic encephalopathy typically experience seizures that start early in infancy, sometimes even shortly after birth. Seizures typically consist of focal stiffening or shaking in one part of the body that may spread to involve both sides of the body. Epileptic spasms, a type of seizure that involves repeated muscle contractions or stiffening, are also common. These seizures may be difficult to control with anti-seizure medications. Children with KCNT1-related developmental and epileptic encephalopathy have delays in reaching developmental milestones and may not attain the ability to walk or talk.

Many children with KCNT1-related developmental and epileptic encephalopathy also have:

• Poor muscle tone (hypotonia)
• Movement disorders, such as dystonia, choreoathetosis or dyskinesia
• Small head size (microcephaly) KCNT1-related

Children with frontal lobe epilepsy (ADNFLE) caused by KCNT1 have onset of seizures before adolescence, but later than children with KCNT1-related developmental and epileptic encephalopathy. In these children, delays in achieving developmental milestones during infancy or early childhood may be the first sign of a KCNT1-related epilepsy. Seizures typically arise out of sleep and occur in clusters. During these seizures, children may experience thrashing or flailing movements, sometimes with stiffening or shaking movements. At times, these types of seizures can be confused with night terrors.

Many people with KCNT1-related frontal lobe epilepsy have some degree of developmental delay or cognitive impairment, but typically they are able to walk and talk. Many people with -related frontal lobe epilepsy may also have psychiatric or behavioral problems such as depression, anxiety or ADHD.

Rarely, patients with KCNT1-related epilepsy can have abnormalities in the white matter of the brain that is detectable on a brain MRI called leukodystrophy. Some patients have also been reported with abnormal blood vessels in the lungs. These blood vessels can lead to pulmonary hemorrhage, or bleeding into the lungs.

Delays in reaching developmental milestones in infancy and early childhood combined with seizures is not specific but is consistent with a KCNT1-related epilepsy. However, there are no typical signs of a KCNT1-related epilepsy that enable a diagnosis based on clinical features alone.

Genetic testing is required to diagnose a KCNT1-related epilepsy.

Additional tests may also be done, including:

• Electroencephalogram (EEG) to look for evidence of abnormal brain activity and seizures. Evidence of migrating focal seizures may be consistent with a diagnosis of KCNT1-related developmental and epileptic encephalopathy
• Magnetic resonance imaging (MRI) to look for changes in brain structure
• An ultrasound image of the heart (echocardiogram) may be recommended to evaluate for abnormal blood vessels in the lungs, particularly in young patients with KCNT1-related epilepsy.
• An electrocardiogram (ECG) of the heart may also be recommended to evaluate for heart rhythm abnormalities.

Many children with KCNT1-related epilepsies are diagnosed with specific epilepsy syndromes based on the types of seizures they have experienced and features of their EEG. Some of these epilepsy syndromes include:

• Epilepsy of infancy with migrating focal seizures
• West syndrome
• Ohtahara syndrome
• Lennox-Gastaut syndrome
• Nocturnal frontal lobe epilepsy

All children with a KCNT1-related epilepsy have a pathogenic variant in the gene KCNT1, which encodes the instructions to make a protein in the brain called a potassium channel. The KCNT1 potassium channel is activated by sodium ions. Pathogenic variants in KCNT1 affect the function of the KCNT1 potassium channel and typically increase the activity of the channel. This is presumed to lead to epilepsy by altering the electrical activity of neurons in the brain.

In most children with KCNT1-related developmental and epileptic encephalopathy, the pathogenic KCNT1 variant occurred spontaneously (de novo) and was not inherited from either parent. In rare cases, the pathogenic KCNT1 variant has been passed on from an asymptomatic parent due to parental mosaicism. Just like a mosaic piece of art, in which each tile is different, a mosaic parent has distinct cell types. Most cells of a mosaic parent do not carry the pathogenic KCNT1 variant. However, a small proportion of cells do carry the pathogenic KCNT1 variant in very low levels that may be difficult or impossible to detect. In these families where a parent is mosaic, the chance that future siblings may also have a KCNT1-related epilepsy may be as high as 50%.

In some children with KCNT1-related frontal lobe epilepsy, the pathogenic variant was inherited from a parent who also has epilepsy. A family history of epilepsy may suggest an inherited KCNT1 variant in these families. However, in some cases, the pathogenic KCNT1 variant occurred spontaneously (de novo) and was not inherited from either parent.

There have been some cases reported in which people in a family with the same KCNT1 have different clinical presentations. In these families, some family members have more severe KCNT1-related developmental and epileptic encephalopathies and some family members have less severe KCNT1-related frontal lobe epilepsies. We do not yet understand why both types of epilepsy can sometimes be seen in the same family.

Treatment for KCNT1-related epilepsy will depend on the type and severity of seizures.

• A combination of seizure medications is typically used to control the different seizure types. Quinidine, a medication that blocks potassium channels, has been helpful for seizure control in some patients, but it may lead to significant side effects. Epilepsy Neurogenetics Initiative (ENGIN) providers have experience in the management of epilepsy in children with KCNT1-related epilepsy and can guide optimal medication selection.
• A different set of medications, known as “rescue therapies,” may be given to help stop or shorten clusters of seizures when they occur.
• Implantable devices such as vagus nerve stimulation (VNS) or responsive neurostimulation (RNS) may be considered when medications are not effective in controlling seizures.
• Dietary therapy, such as the ketogenic diet, may be helpful in some cases.

Family training and support is a key element in a successful epilepsy treatment plan. Parents and caregivers must know how to watch for and respond to seizures.

Cognitive and developmental delays or autism spectrum disorder associated with KCNT1-related epilepsy are treated with physical, occupational and speech therapy, and with the support of early intervention services. Care may be provided by a developmental pediatrician.

Families come to our ENGIN clinic from all over the world. Through ENGIN, children have access to any other medical specialists they may need. They also have access to a full range of epilepsy therapies provided through CHOP’s Pediatric Epilepsy Program, including medication, dietary treatment and ongoing follow-up care. ENGIN providers have significant experience caring for children with KCNT1-related epilepsy, and have been involved in research efforts to understand how to best treat the seizures associated with this condition.

All individuals seen in the ENGIN Clinic are offered the opportunity to participate in research studies related to KCNT1.

ENGIN integrates genetic testing into the diagnosis and treatment of children with difficult-to-treat or unexplained epilepsies, genetic epilepsy syndromes and other genetic neurodevelopmental disorders. We combine cutting-edge clinical care and advanced genetic testing with innovative research to identify the underlying cause of a child’s epilepsy and develop an individualized approach to treatment and management.

KCNT1 Epilepsy Foundation 
Beyond the Ion Channel | Dr. Helbig’s Blog for The ILAE Genetics Commission

Targeted treatment of migrating partial seizures of infancy with quinidine. Bearden D, Strong A, Ehnot J, DiGiovine M, Dlugos D, Goldberg EM. Ann Neurol. 2014;76(3):457-461.

Treatment responsiveness in KCNT1-related epilepsy. Fitzgerald MP, Fiannacca M, Smith DM, Gertler TS, Gunning B, Syrbe S, Verbeek N, Stamberger H, Weckhuysen S, Ceulemans B, Schoonjans AS, Rossi M, Demarquay G, Lesca G, Olofsson K, Koolen DA, Hornemann F, Baulac S, Rubboli G, Minks KQ, Lee B, Helbig I, Dlugos D, Møller RS, Bearden D. Neurotherapeutics. 2019;16(3):848-857.