KCNC1-Related Disorders

Pathogenic variants (“mutations”) in the KCNC1 gene cause a spectrum of neurological conditions, including a form of progressive myoclonus epilepsy called myoclonic epilepsy and ataxia due to potassium (K+) channel mutation (MEAK), as well as other severe myoclonic epilepsies beginning in infancy or early childhood. Some children with KCNC1-related disorders never develop epilepsy. The symptoms a child experiences and the severity of the disorder can vary widely and may depend on the specific KCNC1 mutation the child has.

KCNC1 is not the name of a medical condition but is rather the name of the gene that is affected. When a disorder is traced back to a disease-causing (pathogenic) variant in the KCNC1 gene, it is called a KCNC1-related disorder.

KCNC1-related disorders fall into defined clinical categories including the following:

• Myoclonic epilepsy and ataxia due to potassium (K+) channel mutation (MEAK)
• Developmental and epileptic encephalopathy (DEE)

Myoclonic Epilepsy and Ataxia Due to Potassium (K+) Channel Mutation (MEAK)

MEAK is a form of progressive myoclonus epilepsy that typically begins between the ages of 3 and 15 years (the average of onset is 10 years). The first symptoms may include ataxia and myoclonus (unsteadiness and difficulty coordinating movements), along with generalized tonic-clonic (“grand mal”) seizures. Individuals with MEAK typically do not experience developmental delays. The symptoms are progressive, and individuals with MEAK often need to use a wheelchair by their late teenage years because of movement difficulties and myoclonus. Many individuals with MEAK report temporary improvement of symptoms when they have a high fever. Seizures may become less frequent in adulthood, but other neurological complications, including myoclonus, ataxia and tremor, may worsen.

KCNC1-related Developmental and Epileptic Encephalopathy (DEE)

Children with KCNC1-related DEE typically present in infancy or early childhood with seizures, ataxia and myoclonus. The ataxia and myoclonus are typically stable and do not become worse over time, although seizures may be difficult to control. Children with KCNC1-related DEE often have associated developmental and cognitive delays. Some children exhibit features of autism spectrum disorder. In rare cases, children with KCNC1-related DEE never develop epilepsy.

The appearance of myoclonus and/or ataxia and epilepsy in childhood or adolescence may suggest a KCNC1-related disorder. Worsening of myoclonus and ataxia may indicate a diagnosis of MEAK. However, a diagnosis of a KCNC1-related disorder cannot be made based on clinical features alone.

Genetic testing is required to confirm a diagnosis. The presence of a specific pathogenic variant in KCNC1 (c.959G>A; p.Arg320His) is diagnostic of MEAK. The presence of other pathogenic KCNC1 variants may indicate a KCNC1-related DEE.

Additional testing may also be done, including:

• Electroencephalogram (EEG) to look for evidence of abnormal brain activity and seizures
• Magnetic resonance imaging (MRI) to look for structural brain abnormalities

All children with KCNC1-related disorders have a pathogenic variant (“mutation”) in the gene KCNC1, which encodes the instructions to make a protein in the brain called a potassium (abbreviated “K+”) channel. The KCNC1 potassium channel allows potassium ions to flow out of cells, which is critical for electrical communication between brain cells (neurons). A KCNC1 mutation leads to changes in the flow of potassium ions into neurons in the brain, causing epilepsy and associated neurological conditions.

Myoclonic epilepsy and ataxia due to potassium (K+) channel mutation (MEAK) is caused by a specific pathogenic variant (“mutation”) in KCNC1 (c.959G>A; p.Arg320His). KCNC1-related developmental and epileptic encephalopathy is associated with other pathogenic variants in KCNC1. In most individuals with KCNC1-related disorders, the pathogenic KCNC1 variant occurred spontaneously (de novo) and was not inherited from either parent. In rare cases, the pathogenic KCNC1 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 KCNC1 variant. However, a small proportion of cells do carry the pathogenic KCNC1 variant in very low levels that may be difficult or impossible to detect.

Treatment for KCNC1-related disorders will depend on the type and severity of seizures and associated neurological symptoms. Anti-seizure drugs are used for the treatment of seizures. No specific anti-seizure medications have been shown to be more effective than another.

A combination of anti-seizure medications is typically used to control the different seizure types. These medications may also be used for treatment of myoclonus.

A different set of medications, known as “rescue medications,” 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.

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.

Individuals with MEAK exhibit progressive myoclonus, tremor and ataxia, decreased ability for independent ambulation, and impairment of functional limb use (both upper and lower), typically requiring assistive devices.

Cognitive and developmental delays or autism spectrum disorder associated with KCNC1-related disorders 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, you and/or your child will have access to any medical specialist that might be needed. You will also have access to the full range of epilepsy therapies provided through CHOP’s Pediatric Epilepsy Program, including medication, dietary treatment and epilepsy surgery, as needed, as well as ongoing follow-up care.

ENGIN team members are involved in ongoing preclinical and clinical studies of KCNC1-related epilepsies and are leading ongoing efforts to develop new treatments for KCNC1-related epilepsies. Opportunities exist for enrollment in research studies.

• KCNC1 Foundation
• Lauren Arena Foundation for MEAK Research
• Beyond the Ion Channel | Dr. Helbig’s Blog for The ILAE Genetics Commission