What are GABRG2-related disorders?
GABRG2-related neurodevelopmental disorders are caused by genetic variants in the GABRG2 gene. They are genetic epilepsy syndromes characterized by febrile and non-febrile seizures and developmental delay. The symptoms a child experiences and the severity of their condition can vary widely.
What causes GABRG2-related disorders?
The gene GABRG2 is responsible for instructing the brain to make a protein that is involved with regulating the excitability of neurons. Children with GABRG2-related neurodevelopmental disorders have a pathogenic variant (“mutation”) in the gene GABRG2. The genetic mutation may affect the ion channel in different ways for each child. In most cases, the GABRG2 mutation leads to decreased activity of the ion channel. In other cases, the mutation may lead to overactivity of the ion channel.
In many children with GABRG2-related neurodevelopmental disorders, the pathogenic GABRG2 variant occurred spontaneously (de novo) and was not inherited from either parent. However, there are cases where the pathogenic GABRG2 variant was inherited from either an affected or asymptomatic parent.
In rare cases, the pathogenic GABRG2 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 GABRG2 variant. However, a small proportion of cells do carry the pathogenic GABRG2 variant in very low levels that may be difficult or impossible to detect.
Signs and Symptoms of GABRG2-Related Disorders
Children with GABRG2-related disorders typically experience febrile or fever-sensitive seizures and delays in achieving developmental milestones within the first three years of life. However, the spectrum of GABRG2-related neurodevelopmental disorders can range from mild to severe.
- Mild disorders – Children have febrile seizures (seizures that are brought on by a fever) in infancy or early childhood. These seizures usually stop by age 6, although some individuals continue to have febrile or afebrile seizures later in life. Some individuals may have normal development and intellectual ability, while others will have mild to moderate developmental delay and intellectual disability. In mild cases, there may be a family history of febrile seizures in siblings or parents, suggesting the genetic mutation was inherited from a parent.
- Moderate disorders – Children may have both fever-induced and unprovoked seizures and normal development or mild/moderate developmental delays.
- Severe disorders – Children have developmental and epileptic encephalopathy (a disease of the brain that alters brain function or structure) characterized by difficult-to-treat seizures typically occurring within the first year of life. They may experience multiple seizure types, including febrile seizures, and may receive a clinical diagnosis of Dravet syndrome. Severely affected children typically have moderate to profound developmental delays in gross motor, fine motor and language function. Some individuals with GABRG2-related developmental and epileptic encephalopathy may also have moderate to profound intellectual disability, low muscle tone (hypotonia), variable movement disorders, and ocular abnormalities. In most children with a more severe presentation of GABRG2-related neurodevelopmental disorder, the genetic mutation is spontaneous (de novo) and was not inherited from either parent. However, there are reports of rare cases where significantly affected children inherited the pathogenic GABRG2 variant from either an asymptomatic parent or a parent with a personal history of seizures. A family history of epilepsy may suggest an inherited GABRG2 variant.
Testing and diagnosis
A molecular genetic test is required to diagnose a GABRG2-related neurodevelopmental disorder. A family history of febrile seizures may suggest a diagnosis of a milder familial GABRG2-related epilepsy.
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. While structural brain abnormalities are not seen in the majority of individuals with a GABRG2 diagnosis, few individuals have been reported with various neuroimaging findings.
Treatment for GABRG2-related disorders
Treatment for GABRG2-related neurodevelopmental disorders will depend on the type and severity of the seizures.
- A combination of seizure medications is typically used to control the different seizure types. No particular anti-seizure medication has been shown to be more effective than others.
- 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) 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 associated with GABRG2-related developmental and epileptic encephalopathy are treated with physical, occupational and speech therapy, and with the support of early intervention services. Care may be provided by a developmental pediatrician.
Why choose CHOP for treatment of GABRG2-related disorders?
Families come to CHOP’s Epilepsy Neurogenetics Initiative (ENGIN) clinic from all over the world. Children with GABRG2-related neurodevelopmental disorders who are cared for at CHOP will receive advanced 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 many additional medical specialists they may need. They will also have access to the full range of epilepsy therapies provided through our Pediatric Epilepsy Program — including epilepsy management, dietary treatment and epilepsy surgery — as well as cutting-edge research, clinical trials, if available, and 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 state-of-the-art 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.