What are GRIN2B-related disorders?

Pathogenic variants (“mutations”) in the GRIN2B 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.

GRIN2B 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 GRIN2B gene, it is called a GRIN2B-related disorder.

Signs and symptoms of GRIN2B-related disorders

In many children, delays in achieving developmental milestones during infancy or early childhood may be the first indication of a GRIN2B-related disorder. In other children, seizures are the first sign of the condition. In most individuals with GRIN2B-related disorders, seizures begin in infancy or early childhood. However, the age of onset varies widely between individuals, ranging from shortly after birth to later in childhood. Many people with GRIN2B-related disorders may never develop epilepsy.

All children with GRIN2B-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 GRIN2B-related disorders, and is present in approximately half of children with this condition. Children with GRIN2B-related disorders may develop different types of seizures, which may be difficult to control with anti-seizure medications. Common seizure types may include:

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

Many children with GRIN2B-related disorders also have:

• Decreased muscle tone (hypotonia) centrally (in their “core”)
• Increased muscle tone (spasticity) peripherally (in the limbs)
• Movement disorders, including dystonia and chorea
• Behavior disorders, including aggression, hyperactivity or features of autism spectrum disorder
• Cortical visual impairment
• Small head size (microcephaly)
• Developmental brain differences, such as polymicrogyria

Diagnosis of GRIN2B-related disorders

Delays in reaching developmental milestones in infancy and early childhood combined with seizures is not specific but is consistent with a GRIN2B-related disorder. However, there are no typical signs of a GRIN2B-related disorder that enable a diagnosis based on clinical features alone.

Genetic testing is required to diagnose a GRIN2B-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. Although most children with GRIN2B-related disorders do not have developmental or structural differences in their brains, approximately 15% of individuals with GRIN2B-related disorders have extensive polymicrogyria.

Some children with GRIN2B-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:

• West syndrome
• 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 GRIN2B-related disorder is the primary diagnosis that explains why a child has developed epilepsy.

Genetics of GRIN2B-related disorders

All children with a GRIN2B-related disorder have a pathogenic variant in the gene GRIN2B, which encodes the instructions to make a protein in the brain that forms a subunit of the NMDA receptor. NMDA receptors are ion channels in the brain that are activated by the neurotransmitter glutamate and that are important for synaptic transmission, learning and memory. When glutamate binds to the NMDA receptor, this activates the ion channel allowing positively charged particles called ions to flow through the membrane of the neuron. The flow of ions through the NMDA receptor, of which GRIN2B is part, is critical to the proper function of neurons. Mutations in GRIN2B impair this process and lead to abnormal functioning of NMDA receptors, resulting in epilepsy and associated developmental differences.

In most children with GRIN2B-related disorders, the pathogenic GRIN2B variant occurred spontaneously (de novo) and was not inherited from either parent. In rare cases, the pathogenic GRIN2B 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 GRIN2B variant. However, a small proportion of cells do carry the pathogenic GRIN2B 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 GRIN2B-related disorder may be as high as 50%.

Treatment for GRIN2B-related disorders

Treatment for GRIN2B-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 GRIN2B-related disorders and can guide optimal medication selection.
• ENGIN providers have been involved in early efforts to develop targeted treatment approaches for GRIN2B-related disorders (Platzer K, et al. 2017 J Med Genet)
• 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 GRIN2B-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 GRIN2B-related seizure disorders?

Families come to our ENGIN Clinic from all over the world. Children with GRIN2B-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 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, 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 GRIN2B.

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 GRIN2B-related disorders

GRIN2B Foundation
CureGRIN Foundation
Simons SearchLight
Beyond the Ion Channel | Dr. Helbig’s Blog for The ILAE Genetics Commission

References

GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects. Platzer K, Yuan H, Schütz H, Winschel A, Chen W, Hu C, Kusumoto H, Heyne HO, Helbig KL, Tang S, Willing MC, Tinkle BT, Adams DJ, Depienne C, Keren B, Mignot C, Frengen E, Strømme P, Biskup S, Döcker D, Strom TM, Mefford HC, Myers CT, Muir AM, LaCroix A, Sadleir L, Scheffer IE, Brilstra E, van Haelst MM, van der Smagt JJ, Bok LA, Møller RS, Jensen UB, Millichap JJ, Berg AT, Goldberg EM, De Bie I, Fox S, Major P, Jones JR, Zackai EH, Abou Jamra R, Rolfs A, Leventer RJ, Lawson JA, Roscioli T, Jansen FE, Ranza E, Korff CM, Lehesjoki AE, Courage C, Linnankivi T, Smith DR, Stanley C, Mintz M, McKnight D, Decker A, Tan WH, Tarnopolsky MA, Brady LI, Wolff M, Dondit L, Pedro HF, Parisotto SE, Jones KL, Patel AD, Franz DN, Vanzo R, Marco E, Ranells JD, Di Donato N, Dobyns WB, Laube B, Traynelis SF, Lemke JR. J Med Genet. 2017;54(7):460-470.