GRIN2B-related neurodevelopmental disorder

GRIN2B-related neurodevelopmental disorder is a rare genetic condition that leads to intellectual disability, speech and motor delays, seizures, and a range of other neurological challenges.

Overview

GRIN2B-related neurodevelopmental disorder is a condition that affects the nervous system. Neurodevelopmental disorders result from impaired growth and development of the central nervous system, which includes the brain and spinal cord, and the nerves connecting them. These disorders often affect learning ability, memory, and behavior and can be associated with other neurological problems.

Individuals with GRIN2B-related neurodevelopmental disorder have mild to profound intellectual disability and delayed development of speech and motor skills, such as sitting and walking. Some affected individuals never develop speech or the ability to walk on their own. Many people with this condition have weak muscle tone (hypotonia), which can contribute to the problems developing motor skills and lead to difficulty eating. Some affected individuals have abnormal muscle stiffness (spasticity), which can also cause problems with movement.

Recurrent seizures (epilepsy) occur in about half of people with GRIN2B-related neurodevelopmental disorder. About one‑quarter of affected individuals have features of autism spectrum disorder, which is characterized by impaired communication and social interaction. Affected individuals may also be hyperactive, impulsive, or easily distractible, and some are described as being overly friendly. Sleeping difficulties can also occur in this condition.

Less common features include structural brain abnormalities, an unusually small head size, impaired vision, and involuntary muscle movements.

Frequency

The prevalence of GRIN2B-related neurodevelopmental disorder is unknown. Fewer than 100 cases have been reported in the medical literature.

Causes & Risk Factors

GRIN2B-related neurodevelopmental disorder is caused by mutations in a gene called GRIN2B. This gene provides instructions for making a protein called GluN2B, which is found in nerve cells in the brain primarily during development before birth. This protein is a part of specialized protein structures called NMDA receptors, which are involved in normal brain development, synaptic plasticity, learning, and memory.

Some GRIN2B gene mutations lead to production of a nonfunctional GluN2B protein or prevent the production of any GluN2B protein from one copy of the gene in each cell. A shortage of this protein may reduce the number of functional NMDA receptors, decreasing receptor activity in cells. Other mutations lead to production of abnormal GluN2B proteins that likely alter how the NMDA receptors function; some mutations reduce NMDA receptor signaling while others increase it. Researchers are unsure how abnormal activity of NMDA receptors prevents normal growth and development of the brain or why too much or too little activity leads to similar neurological problems.

Inheritance

This condition is inherited in an autosomal dominant manner, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

Most cases result from new (de novo) mutations in the gene that occur during the formation of reproductive cells (eggs or sperm) in an affected individual's parent or in early embryonic development. These cases occur in people with no history of the disorder in their family.

Clinical Features

• Intellectual disability (mild to profound)
• Delayed speech development; some never develop speech
• Delayed motor milestones (sitting, walking); some never walk independently
• Weak muscle tone (hypotonia)
• Abnormal muscle stiffness (spasticity)
• Recurrent seizures (epilepsy) in ~50% of individuals
• Autism spectrum disorder features in ~25% of individuals
• Hyperactivity, impulsivity, distractibility, overly friendly behavior
• Sleep difficulties
• Less common: structural brain abnormalities, microcephaly, impaired vision, involuntary movements

Other Names for This Condition

• EIEE27
• Epileptic encephalopathy, early infantile, 27
• GRIN2B encephalopathy
• GRIN2B related syndrome

Additional Information & Resources

Genetic Testing Information

• Genetic Testing Registry: Developmental and epileptic encephalopathy, 27
• Genetic Testing Registry: Intellectual disability, autosomal dominant 6

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Catalog of Genes and Diseases from OMIM

• DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 27; DEE27
• INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 6, WITH OR WITHOUT SEIZURES; MRD6

Scientific Articles on PubMed

• PubMed

References

• Bell S, Maussion G, Jefri M, Peng H, Theroux JF, Silveira H, Soubannier V, Wu H, Hu P, Galat E, Torres-Platas SG, Boudreau-Pinsonneault C, O'Leary LA, Galat V, Turecki G, Durcan TM, Fon EA, Mechawar N, Ernst C. Disruption of GRIN2B Impairs Differentiation in Human Neurons. Stem Cell Reports. 2018 Jul 10;11(1):183-196. doi: 10.1016/j.stemcr.2018.05.018.
• Fedele L, Newcombe J, Topf M, Gibb A, Harvey RJ, Smart TG. Disease-associated missense mutations in GluN2B subunit alter NMDA receptor ligand binding and ion channel properties. Nat Commun. 2018 Mar 6;9(1):957. doi: 10.1038/s41467-018-02927-4.
• Freunscht I, Popp B, Blank R, Endele S, Moog U, Petri H, Prott EC, Reis A, Rubo J, Zabel B, Zenker M, Hebebrand J, Wieczorek D. Behavioral phenotype in five individuals with de novo mutations within the GRIN2B gene. Behav Brain Funct. 2013 May 29;9:20. doi: 10.1186/1744-9081-9-20.
• Hu C, Chen W, Myers SJ, Yuan H, Traynelis SF. Human GRIN2B variants in neurodevelopmental disorders. J Pharmacol Sci. 2016 Oct;132(2):115-121. doi: 10.1016/j.jphs.2016.10.002.
• Platzer K, Lemke JR. GRIN2B-Related Neurodevelopmental Disorder. 2018 May 31 [updated 2021 Mar 25]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026.
• Platzer K, Yuan H, Schutz H, et al. GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects. J Med Genet. 2017 Jul;54(7):460-470. doi: 10.1136/jmedgenet-2016-104509.
• Swanger SA, Chen W, Wells G, et al. Mechanistic Insight into NMDA Receptor Dysregulation by Rare Variants in the GluN2A and GluN2B Agonist Binding Domains. Am J Hum Genet. 2016 Dec 1;99(6):1261-1280. doi: 10.1016/j.ajhg.2016.10.002.