PCDH19-Epilepsy

PCDH19-epilepsy is a genetic form of epilepsy characterized by treatment-resistant epilepsy that begins in the first year of life, often accompanied by differences in development and features of autism spectrum disorder. PCDH19-epilepsy mostly affects girls, although boys can have this condition as well. The condition is sometimes called PCDH19-girls clustering epilepsy

PCDH19 is not the name of a medical condition but is rather the name of the gene that is affected. When epilepsy is traced back to a disease-causing (pathogenic) variant in the PCDH19 gene, it is called PCDH19-epilepsy

Seizures, usually starting between the ages of 3 months and 3 years (average age 9 months), are typically the first sign of PCDH19-epilepsy. Seizures often occur with illness or fever (called febrile seizures) and may be tonic-clonic seizures (also called “grand mal” seizures), which involves convulsive movements (shaking) of the entire body. The seizures often do not stop on their own and may occur in clusters over a period of days or weeks. Many children experience long periods without seizures in between clusters.

Most children experience some level of developmental delay or cognitive impairment, ranging in severity from mild to severe. However, typical developmental outcomes are seen in approximately 30% of individuals with PCDH19-epilepsy.

Children with PCDH19-epilepsy may develop different types of seizures. Common seizure types may include:

• Focal impaired awareness seizures (seizures where children stop their usual behavior and lose consciousness)
• Generalized tonic-clonic seizures, also called grand mal seizures (in which the body, arms and legs extend, then contract and shake)
• Tonic (stiffening) seizures
• Atypical absence seizures
• Atonic (drop) seizures
• Myoclonic seizures

Many children with PCDH19-epilepsy also have:

• Decreased muscle tone (hypotonia)
• Behavior disorders, including ADHD or autism spectrum disorder
• Psychiatric illnesses, including obsessive-compulsive disorder, anxiety or schizophrenia, particularly later in life

The appearance of seizures in the first year of life in the setting of illness or fever, particularly in a female infant, may suggest PCDH19-epilepsy. Seizures that occur in clusters or that are prolonged may also suggest PCDH19-epilepsy.

Genetic testing is required to confirm a diagnosis.

Additional tests 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 PCDH19-epilepsy have a pathogenic variant (“mutation”) in the gene PCDH19, which encodes the instructions to make a protein in the brain called a protocadherin. The PCDH19 protein is important in how cells adhere to and communicate with one another. Pathogenic variants in PCDH19 affect how brain cells (neurons) communicate with one another through a process called cellular interference, leading to epilepsy and associated neurodevelopmental conditions.

The PCDH19 gene is located on the X chromosome, which determines biological sex. Because PCDH19 is located on a sex-determining chromosome, the effects of pathogenic variants (“mutations”) in PCDH19 affect males and females differently, since males typically have one X chromosome (and one copy of the PCDH19 gene) and females typically have two X chromosomes (and two copies of the PCDH19 gene). Males who carry only one copy of a PCDH19 mutation are typically unaffected, whereas females with a PCDH19 mutation will develop PCDH19-epilepsy. Approximately 95% of individuals with PCDH19-epilepsy are biologically female; 5% are biologically male.

In about half of all girls with PCDH19-epilepsy, the pathogenic PCDH19 variant occurred spontaneously (de novo) and was not inherited from either parent. However, in 30% of cases, the pathogenic PCDH19 variant was passed on from an asymptomatic carrier father. Males who carry a pathogenic PCDH19 variant, although not affected themselves, will pass on PCDH19-epilepsy to all of their daughters. In some cases, the pathogenic PCDH19 variant has been inherited from a mother who may or may not have a history of seizures.

Most boys with PCDH19-epilepsy are “mosaic” for the pathogenic PCDH19 variant, which means that it is present only in some of their cells. Just like a mosaic piece of art, in which each tile is different, a mosaic individual has distinct cell types. Some cells of a mosaic individual do not carry the pathogenic PCDH19 variant. However, a certain proportion of cells do carry the pathogenic PCDH19 variant, which leads to epilepsy and associated neurodevelopmental conditions. Mosaic PCDH19 mutations arise spontaneously (de novo) in the affected child and have not been passed on from either parent.

Treatment for PCDH19-epilepsy will depend on the type and severity of the seizures and associated neurological features.

• A combination of anti-seizure medications is typically used to control the different seizure types. ENGIN providers have experience in the management of PCDH19-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.
• Dietary therapy, such as the ketogenic diet, may be helpful.
• 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.

Cognitive and developmental delays or autism spectrum disorder associated with PCDH19-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.

Psychiatric and behavioral issues associated with PCDH19-epilepsy can be managed with the help of behavioral health professionals.

Families come to our ENGIN Clinic from all over the world. Children with PCDH19-epilepsy who are cared for at CHOP will receive cutting-edge genetic testing to attempt to confirm the underlying cause of epilepsy, as well as parental testing to confirm the diagnosis and inform recurrence risk with a subsequent pregnancy. Patients undergo genetic testing; epilepsy management; an assessment of physical, occupational and speech therapy needs; behavioral management and evaluation of psychiatric issues; evaluation of gastrointestinal issues; and sudden unexpected death in epilepsy (SUDEP) risk reduction.

Through ENGIN, your child will have access to any other medical specialists they may need, as well as a full range of epilepsy therapies provided through CHOP’s Pediatric Epilepsy Program, including medication, dietary treatment and epilepsy surgery. They will also have access to cutting-edge research and clinical trials, as well as ongoing follow-up care.

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.

• PCDH19 Alliance
• Epilepsy Foundation
• Beyond the Ion Channel | Dr. Helbig’s Blog for The ILAE Genetics Commission