What are SLC6A1-related disorders?

Pathogenic variants (“mutations”) in the SLC6A1 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. Because SLC6A1-related disorders have been discovered relatively recently, the full extent of symptoms has likely not yet been described.

SLC6A1 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 SLC6A1 gene, it is called an SLC6A1-related disorder.

Signs and symptoms of SLC6A1-related disorders

In many children with SLC6A1-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 SLC6A1-related disorders, seizures begin in early childhood, usually around age 2. However, the age of onset varies widely between individuals, ranging from around 6 months to later in childhood. Some people with SLC6A1-related disorders may never develop epilepsy.

Nearly all children with SLC6A1-related disorders have some degree of developmental delay and cognitive impairment, which ranges in severity from mild to severe.

Epilepsy is a common feature of SLC6A1-related disorders, and is present in more than 80% of children with this condition. Children with SLC6A1-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
• Atonic (drop) seizures
• Myoclonic seizures
• Generalized tonic-clonic seizures, also called grand mal seizures (in which the body, arms and legs extend, then contract and shake)

Many children with SLC6A1-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

Diagnosis of SLC6A1-related disorders

Delays in reaching developmental milestones in infancy and early childhood combined with seizures is not specific but is consistent with an SLC6A1-related disorder. However, there are no typical signs of an SLC6A1-related disorder that enable a diagnosis based on clinical features alone.

Genetic testing is required to diagnose an SLC6A1-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 SLC6A1-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 myoclonic-atonic seizures (also known as Doose syndrome or myoclonic-atonic epilepsy)
• Childhood absence epilepsy
• Epilepsy with eyelid myoclonias
• Lennox-Gastaut syndrome

In these cases, the epilepsy syndrome diagnosis is a description of the types of seizures the child is having, but the genetic diagnosis of SLC6A1-related disorder is the primary diagnosis that explains why a child has developed epilepsy.

Genetics of SLC6A1-related disorders

All children with an SLC6A1-related disorder have a pathogenic variant in the gene SLC6A1, which encodes the instructions to make a protein in the brain called a GABA transporter. GABA is one of the major neurotransmitters in the brain and functions as a “stop” signal, telling neurons to stop firing. The GABA transporter that is made by the gene SLC6A1 is essential in removing extra GABA from the spaces between two neurons — a place called the synapse. Disruptions in this process caused by mutations in SLC6A1 lead to epilepsy and associated developmental differences.

In most children with SLC6A1-related disorders, the pathogenic SLC6A1 variant occurred spontaneously (de novo) and was not inherited from either parent. In rare cases, the pathogenic SLC6A1 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 SLC6A1 variant. However, a small proportion of cells do carry the pathogenic SLC6A1 variant in very low levels that may be difficult or impossible to detect.

In some cases, the pathogenic SLC6A1 variant has been inherited from a parent who also has a history of seizures or epilepsy. A family history of epilepsy or developmental differences may suggest an inherited SLC6A1 variant in these families.

Treatment for SLC6A1-related disorders

Treatment for SLC6A1-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 have experience in the management of epilepsy in children with SLC6A1-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 SLC6A1-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.

Why choose CHOP for treatment of SLC6A1-related seizure disorders

Families come to our ENGIN Clinic from all over the world. Children with SLC6A1-related disorders who are cared for at Children's Hospital of Philadelphia (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 SLC6A1. 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.

Resources for SLC6A1-related disorders

SLC6A1 Connect 
Simons SearchLight 
Beyond the Ion Channel | Dr. Helbig’s Blog for The ILAE Genetics Commission

References

Defining the phenotypic spectrum of SLC6A1 mutations. Johannesen KM, Gardella E, Linnankivi T, Courage C, de Saint Martin A, Lehesjoki AE, Mignot C, Afenjar A, Lesca G, Abi-Warde MT, Chelly J, Piton A, Merritt JL 2nd, Rodan LH, Tan WH, Bird LM, Nespeca M, Gleeson JG, Yoo Y, Choi M, Chae JH, Czapansky-Beilman D, Reichert SC, Pendziwiat M, Verhoeven JS, Schelhaas HJ, Devinsky O, Christensen J, Specchio N, Trivisano M, Weber YG, Nava C, Keren B, Doummar D, Schaefer E, Hopkins S, Dubbs H, Shaw JE, Pisani L, Myers CT, Tang S, Tang S, Pal DK, Millichap JJ, Carvill GL, Helbig KL, Mecarelli O, Striano P, Helbig I, Rubboli G, Mefford HC, Møller RS. Epilepsia. 2018;59(2):389-402.

Mutations in the GABA transporter SLC6A1 cause epilepsy with myoclonic-atonic seizures. Carvill GL, McMahon JM, Schneider A, Zemel M, Myers CT, Saykally J, Nguyen J, Robbiano A, Zara F, Specchio N, Mecarelli O, Smith RL, Leventer RJ, Møller RS, Nikanorova M, Dimova P, Jordanova A, Petrou S; EuroEPINOMICS Rare Epilepsy Syndrome Myoclonic-Astatic Epilepsy & Dravet working group, Helbig I, Striano P, Weckhuysen S, Berkovic SF, Scheffer IE, Mefford HC. Am J Hum Genet. 2015;96(5):808-815.