SYNGAP1-Related Disorders

Pathogenic variants (“mutations”) in the SYNGAP1 gene cause a spectrum of neurodevelopmental disorders that can include childhood-onset epilepsy, developmental delays, movement disorders and features of autism spectrum disorder. The symptoms a child experiences and the severity of the disorder can vary widely.

SYNGAP1 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 SYNGAP1 gene, it is called a SYNGAP1-related disorder.

In many children with SYNGAP1-related disorders, delays in achieving developmental milestones during infancy or early childhood may be the first indication of the condition. In other children, seizures are the first sign of the condition. In most individuals with SYNGAP1-related disorders, seizures begin in early childhood, usually around age 2. However, the age of onset varies widely between individuals, ranging from around 4 months to later in childhood. In rare cases, some people with SYNGAP1-related disorders may never develop epilepsy.

Nearly all children with SYNGAP1-related disorders have some degree of developmental delay and cognitive impairment, which typically ranges in severity from moderate to severe.

Epilepsy is a common feature of SYNGAP1-related disorders, and is present in more than 95% of children with this condition. Children with SYNGAP1-related disorders may develop different types of seizures, which are often difficult to control with anti-seizure medications. Common seizure types may include:

• Absence seizures
• Eyelid myoclonia
• Generalized tonic-clonic seizures, also called grand mal seizures (in which the body, arms and legs extend, then contract and shake)
• Atonic (drop) seizures

In some children with SYNGAP1-related disorders, seizures may be triggered by flickering lights or certain kinds of patterns, a condition known as photosensitivity. Other types of triggers, such as eating, may also elicit seizures.

Many children with SYNGAP1-related disorders also have:

• Decreased muscle tone (hypotonia)
• Movement disorders, particularly ataxia or tremor
• Behavior disorders, including aggression, hyperactivity or features of autism spectrum disorder
• High pain thresholds
• Eating difficulties
• Sleeping problems

Delays in reaching developmental milestones in infancy and early childhood combined with seizures is not specific but is consistent with a SYNGAP1-related disorder. However, there are no typical signs of a SYNGAP1-related disorder that enable a diagnosis based on clinical features alone.

Genetic testing is required to diagnose a SYNGAP1-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

Some children with SYNGAP1-related disorders 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 with eyelid myoclonias (also known as Jeavons syndrome)
• Epilepsy with myoclonic-atonic seizures (also known as Doose syndrome or myoclonic-atonic epilepsy)

In these cases, the epilepsy syndrome diagnosis is a description of the types of seizures the child is having, but the genetic diagnosis of SYNGAP1-related disorder is the primary diagnosis that explains why a child has developed epilepsy.

All children with a SYNGAP1-related disorder have a pathogenic variant in the gene SYNGAP1, which encodes the instructions to make a protein in the brain that is an important regulator of proteins in the synapse, the place where two neurons meet and communicate with one another. Disruptions to the SYNGAP1 protein lead to epilepsy and associated developmental differences.

In most children with SYNGAP1-related disorders, the pathogenic SYNGAP1 variant occurred spontaneously (de novo) and was not inherited from either parent. In rare cases, the pathogenic SYNGAP1 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 SYNGAP1 variant. However, a small proportion of cells do carry the pathogenic SYNGAP1 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 SYNGAP1-related disorder may be as high as 50%.

Treatment for SYNGAP1-related disorders will depend on the type and severity of the seizures and associated neurological features.

• A combination of seizure medications is typically used to control the different seizure types. Epilepsy Neurogenetics Initiative (ENGIN) providers at CHOP have experience in the management of epilepsy in children with SYNGAP1-related disorders 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 SYNGAP1-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. Children with SYNGAP1-related disorders who are cared for at CHOP 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 has 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, epilepsy surgery, cutting-edge research, clinical trials and ongoing follow-up care.

All individuals seen in the ENGIN Clinic are offered the opportunity to participate in research studies related to SYNGAP1.

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.

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SYNGAP Research
Fund Bridge the Gap: SYNGAP Education & Research Foundation 
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