STXBP1-Related Disorders

Pathogenic variants (“mutations”) in the STXBP1 gene cause a spectrum of neurodevelopmental disorders that can include early-onset epilepsy and developmental delay, sometimes accompanied by autism spectrum disorder, increased or decreased muscle tone, or movement disorders. The symptoms a child experiences and the severity of the disorder can vary widely.

STXBP1 is not the name of a medical condition but rather is the name of the gene that is affected. When a disorder is traced back to a pathogenic variant in the STXBP1 gene, it is called an STXBP1-related disorder.

In many children with STXBP1-related disorders, seizures are the first sign of the condition. In most individuals with STXBP1-related disorders, seizures occur in the first year of life. However, the age of onset varies widely between individuals, ranging from the first day of life to adolescence. In other children, delays in achieving developmental milestones during infancy may be the first indication of an STXBP1-related disorder. Some people with STXBP1-related disorders never develop epilepsy.

Children with STXBP1-related disorders may develop different types of seizures. Common seizure types may include:

• Neonatal seizures
• Infantile spasms
• Tonic (stiffening) seizures
• Clonic seizures (jerking movements on one part of the body)
• Focal impaired awareness seizures (seizures where children stop their usual behavior and become unaware)
• Generalized tonic-clonic seizures, also called grand mal seizures (in which the body, arms and legs extend, then contract and shake)

Many children with STXBP1-related disorders also have:

• Decreased muscle tone (hypotonia)
• Increased muscle tone (spasticity)
• Movement disorders, particularly ataxia or tremors (abnormal and uncoordinated movements of arms and legs)
• Behavior disorders, including repetitive behaviors (stereotypies) or autism spectrum disorder

Delays in reaching developmental milestones in infancy and early childhood combined with the early onset of seizures may suggest an STXBP1-related disorder. However, there are no typical signs of an STXBP1-related disorder and a diagnosis cannot be made based on clinical features alone.

Genetic testing is required to diagnose an STXBP1-related disorder.

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 changes in brain structure

Many children with STXBP1-related disorders are also 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:

• Ohtahara syndrome
• West syndrome
• Lennox-Gastaut syndrome

In these cases, the epilepsy syndrome diagnosis is a clinical description of the types of seizures, but the genetic diagnosis of an STXBP1-related disorder is the primary diagnosis that explains why a child has developed epilepsy. For example, a child may have West syndrome due to a disease-causing change in the STXBP1 gene.

All children with an STXBP1-related disorder have a pathogenic variant (“mutation”) in the gene STXBP1, which encodes the instructions to make a protein in the brain that is essential to how brain cells communicate with one another. Pathogenic variants in the STXBP1 gene lead to an underproduction of a protein that is important to the release of chemical messengers in the brain. These messengers are called neurotransmitters. Changes in this process lead to the developmental differences and epilepsy seen in children with STXBP1-related neurodevelopmental disorders.

In most children with STXBP1-related disorders, the pathogenic STXBP1 variant occurred spontaneously (de novo) and was not inherited from either parent. In rare cases, the pathogenic STXBP1 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 STXBP1 variant. However, a small proportion of cells do carry the pathogenic STXBP1 variant in very low levels that may be difficult or impossible to detect.

Treatment for STXBP1-related disorders will depend on the type and severity of the seizures and associated neurological features.

• A combination of antiseizure medications is typically used to control the different seizure types. The type of medication often depends on the specific epilepsy syndrome or type of seizures. No specific medication has been shown to be more effective than others in STXBP1-related disorders.
• 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 STXBP1 disorder treatment plan. Parents and caregivers must know how to watch for and respond to seizures.
Cognitive and developmental delays associated with STXBP1-related disorders are treated with physical, occupational, speech and socialization therapy, and with the support of early intervention services. Care may be provided by a developmental pediatrician.

Treatment of children with STXBP1-related disorders and research into this genetic condition are a focus of members of the Epilepsy Neurogenetics Initiative (ENGIN). We are currently one of the largest centers worldwide to provide care for children with STXBP1-related disorders. Families come to our ENGIN Clinic from all over the world. Children with STXBP1-related disorders who are cared for at CHOP will receive cutting-edge genetic testing to confirm the underlying cause of their condition, as well as parental testing to confirm the diagnosis and inform recurrence risk with a subsequent pregnancy.

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 epilepsy management, dietary treatment and epilepsy surgery. They will also have access to cutting-edge research and clinical trials, as well as ongoing follow-up care.

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

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.

• STXBP1 Foundation
• Simons SearchLight
• LGS Foundation
• Beyond the Ion Channel | Dr. Helbig’s Blog for The ILAE Genetics Commission