What are GRIN2D-related disorders?

Pathogenic variants (“mutations”) in the GRIN2D gene cause a spectrum of neurodevelopmental disorders that can include infantile-onset epilepsy, developmental delays and movement disorders. The symptoms a child experiences and the severity of the disorder can vary widely. Because GRIN2D-related disorders have been discovered relatively recently, the full extent of symptoms has likely not yet been described.

GRIN2D 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 GRIN2D gene, it is called a GRIN2D-related disorder.

Signs and symptoms of GRIN2D-related disorders

In many children with GRIN2D-related disorders, seizures are the first sign of the condition. In other children, delays in achieving developmental milestones during infancy or early childhood may be the first indication of a GRIN2D-related disorder. In most individuals with GRIN2D-related disorders, seizures begin in infancy, usually before 6 months of age. All children with GRIN2D-related disorders have some degree of developmental delay and cognitive impairment, which ranges in severity from moderate to severe.

Epilepsy is seen in all known individuals with GRIN2D-related disorders. Children with GRIN2D-related disorders may develop different types of seizures, which are often difficult to control with anti-seizure medications. Common seizure types may include:

• Infantile spasms
• Absence seizures
• 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 GRIN2D-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
• Cortical visual impairment
• Feeding difficulties
• Small head size (microcephaly)

Diagnosis of GRIN2D-related disorders

Delays in reaching developmental milestones in infancy and early childhood combined with seizures is not specific but is consistent with a GRIN2D-related disorder. However, there are no typical signs of a GRIN2D-related disorder that enable a diagnosis based on clinical features alone.

Genetic testing is required to diagnose a GRIN2D-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.

Genetics of GRIN2D-related disorders

All children with a GRIN2D-related disorder have a pathogenic variant in the gene GRIN2D, 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. 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 GRIN2D is part, is critical to the proper function of neurons. Mutations in GRIN2D impair this process and lead to abnormal functioning of NMDA receptors, resulting in epilepsy and associated developmental differences.

In most children with GRIN2D-related disorders, the pathogenic GRIN2D variant occurred spontaneously (de novo) and was not inherited from either parent. In rare cases, the pathogenic GRIN2D 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 GRIN2D variant. However, a small proportion of cells do carry the pathogenic GRIN2D 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 GRIN2D-related disorder may be as high as 50%.

Treatment for GRIN2D-related disorders

Treatment for GRIN2D-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 GRIN2D-related disorders and can guide optimal medication selection.
• ENGIN providers have been involved in early efforts to develop targeted treatment approaches for GRIN2D-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.
• 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 GRIN2D-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 GRIN2D-related seizure disorders?

Families come to our ENGIN Clinic from all over the world. Children with GRIN2D-related disorders who are cared for at Children's Hospital of Philadelphia (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. They will also have access to 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 GRIN2D.

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 GRIN2D-related disorders

CureGRIN Foundation
Simons SearchLight

References

GRIN2D recurrent de novo dominant mutation causes a severe epileptic encephalopathy treatable with NMDA receptor channel blockers. Li D, Yuan H, Ortiz-Gonzalez XR, Marsh ED, Tian L, McCormick EM, Kosobucki GJ, Chen W, Schulien AJ, Chiavacci R, Tankovic A, Naase C, Brueckner F, von Stülpnagel-Steinbeis C, Hu C, Kusumoto H, Hedrich UB, Elsen G, Hörtnagel K, Aizenman E, Lemke JR, Hakonarson H, Traynelis SF, Falk MJ. Am J Hum Genet. 2016;99(4):802-816.

Heterogeneous clinical and functional features of GRIN2D-related developmental and epileptic encephalopathy. XiangWei W, Kannan V, Xu Y, Kosobucki GJ, Schulien AJ, Kusumoto H, Moufawad El Achkar C, Bhattacharya S, Lesca G, Nguyen S, Helbig KL, Cuisset JM, Fenger CD, Marjanovic D, Schuler E, Wu Y, Bao X, Zhang Y, Dirkx N, Schoonjans AS, Syrbe S, Myers SJ, Poduri A, Aizenman E, Traynelis SF, Lemke JR, Yuan H, Jiang Y. Brain. 2019;142(10):3009-3027.