Grin2b-Related Neurodevelopmental Disorder
Summary
Clinical characteristics.
GRIN2B-related neurodevelopmental disorder is characterized by mild to profound developmental delay / intellectual disability (DD/ID) in all affected individuals. Muscle tone abnormalities (spasticity and/or hypotonia, occasionally associated with feeding difficulties), as well as epilepsy and autism spectrum disorder (ASD) / behavioral issues, are common. Other infantile- or childhood-onset findings include microcephaly; dystonic, dyskinetic, or choreiform movement disorder; and/or cortical visual impairment. Brain MRI reveals a malformation of cortical development in a minority of affected individuals. To date, fewer than 100 individuals with GRIN2B-related neurodevelopmental disorder have been reported.
Diagnosis/testing.
The diagnosis of a GRIN2B-related neurodevelopmental disorder is established in a proband by identification of either a heterozygous pathogenic variant or exon or whole-gene deletion of GRIN2B on molecular genetic testing.
Management.
Treatment of manifestations: DD/ID, muscle tone abnormalities (spasticity, hypotonia, and feeding difficulties), epilepsy, ASD/behavioral issues, movement disorders, and/or cortical visual impairment are treated as per standard practice.
Surveillance: Of clinical manifestations as clinically indicated.
Genetic counseling.
GRIN2B-related neurodevelopmental disorder is inherited in an autosomal dominant manner. All probands reported to date with a GRIN2B-related neurodevelopmental disorder whose parents have undergone molecular genetic testing have the disorder as a result of a de novo GRIN2B pathogenic variant or deletion. Risk to future pregnancies is presumed to be low as the proband most likely has a de novo GRIN2B pathogenic variant or deletion; however, given the theoretic possibility of parental germline mosaicism, recurrence risk to sibs is estimated at 1%, and thus prenatal testing for pregnancies at risk and preimplantation genetic testing may be considered.
Diagnosis
Formal diagnostic criteria for GRIN2B-related neurodevelopmental disorder have not been established.
Suggestive Findings
GRIN2B-related neurodevelopmental disorder should be considered in individuals with the following clinical and/or brain MRI findings.
Clinical findings
- Mild-to-profound developmental delay (DD) or intellectual disability (ID)AND
- Any of the following features presenting in infancy or childhood:
- Epilepsy
- Autism spectrum disorder / behavioral issues
- Microcephaly
- Muscle tone abnormalities such as hypotonia (occasionally associated with feeding difficulties) and spasticity
- Dystonic, dyskinetic, or choreiform movement disorder
- Cortical visual impairment
Brain MRI findings. MRI reveals a malformation of cortical development (MCD) consisting of diffuse cortical dysplasia including polymicrogyria (see Polymicrogyria Overview), hypoplastic corpus callosum, enlarged/dysplastic basal ganglia, and hippocampal dysplasia. The MCD can also resemble the tubulinopathies spectrum (see Tubulinopathies Overview).
Establishing the Diagnosis
The diagnosis of a GRIN2B-related neurodevelopmental disorder is established in a proband by identification of either a heterozygous pathogenic variant or exon or whole-gene deletion of GRIN2B on molecular genetic testing (see Table 1). (Note that larger contiguous-gene deletions including but not limited to GRIN2B are not discussed in this GeneReview.)
Molecular genetic testing approaches can include use of a multigene panel, chromosomal microarray analysis, and/or more comprehensive genomic testing.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotypes of many disorders with intellectual disability overlap, most children with GRIN2B-related neurodevelopmental disorder are diagnosed by genomic testing. Note: Single-gene testing (sequence analysis of GRIN2B, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.
- An intellectual disability multigene panel that includes GRIN2B and other genes of interest (see Differential Diagnosis) typically provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost while limiting identification of pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For GRIN2B-related disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
- Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including GRIN2B) that cannot be detected by sequence analysis.
- Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in GRIN2B-Related Neurodevelopmental Disorder
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| GRIN2B | Sequence analysis 3 | 82/86 4 |
| Gene-targeted deletion/duplication analysis 5 or chromosomal microarray (CMA) 6 | 4/86 4 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
For references, see Molecular Genetics, Pathogenic variants. Note: Three additional individuals with contiguous gene deletions (not included in these calculations) have been reported: two with chromosome translocations and one with a chromosome inversion disrupting GRIN2B [Endele et al 2010, Talkowski et al 2012].
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including GRIN2B) that cannot be detected by sequence analysis. The ability to determine the size of the deletion/duplication depends on the type of microarray used and the density of probes in the 12p13.1 region (which includes GRIN2B). CMA designs in current clinical use target the 12p13.1 region.
Clinical Characteristics
Clinical Description
GRIN2B-related neurodevelopmental disorder is characterized in all affected individuals by mild to profound developmental delay / intellectual disability (DD/ID). Epilepsy (seen in 51%) and autism spectrum disorder (ASD) and autistic-like behaviors (26%) are common. Other infantile- or childhood-onset findings include microcephaly; muscle tone abnormalities (hypotonia, spasticity); dystonic, dyskinetic, or choreiform movement disorder; and/or cortical visual impairment. To date, fewer than 100 individuals with GRIN2B-related neurodevelopmental disorder have been reported in cohorts of individuals with DD/ID/ASD, early-onset epilepsy, and malformations of cortical development (MCD).
Unless otherwise noted, the information in this section is based on extended data of Platzer et al [2017]. Detailed clinical assessment was available for 61 patients, with specification of ID in 54. Brain MRI was performed in 47 patients.
DD/ID
The degree of DD/ID can be severe or profound (61%, 33/54), moderate (24%, 13/54), or mild (15%, 8/54) using standard assessments of psychomotor development or IQ testing.
Signs of developmental regression have been noted in four children (7%, 4/61), one of whom had transient regression of language skills at age six years with improvement beginning at age eight years and another who had recurrent periods of global regression starting at age three years. No detailed information is available for the other two children.
Muscle Tone Abnormalities
Hypotonia has been reported in more than half the patients (56%, 34/61). Five (15% of those with muscular hypotonia) required tube feeding. All five of these individuals had severe ID.
Spasticity was seen in 14 (23%) of 61 patients, all with severe ID.
Epilepsy
Epilepsy is present in 31 (51%) of 61 of individuals and characterized by the following.
Features
- Onset is from birth to age nine years.
- Seizure frequency ranges from multiple episodes per day to a few seizures per year.
- Seizures are refractory to antiepileptic drugs in approximately half of individuals treated.
Seizure types
- Seizures may be generalized (58%, 18/31) and/or focal (48%, 15/31) and/or epileptic spasms (35%, 11/31) with some patients displaying multiple seizure types over time.
- EEG patterns comprise generalized, focal, and multifocal epileptiform activity and/or hypsarrhythmia.
Syndromes. Most children with epileptic spasms also show hypsarrhythmia or hypsarrhythmia-like EEG patterns and fulfill diagnostic criteria for West syndrome.
ASD
Autistic features were seen in 16 (26%) of 61 individuals. In addition, in one study of the behavioral phenotype of five individuals with GRIN2B-related neurodevelopmental disorder without ASD, the authors observed hyperactivity, impulsivity, distractibility, stereotypies, short attention span, sleeping problems, and social behavior that is friendly but lacking boundaries [Freunscht et al 2013].
Other
Microcephaly occurred in 11 (18%) of 61 individuals; all 11 had severe ID. Three of these also had an MCD.
Movement disorders (10%, 6/61) included involuntary dystonic, dyskinetic, and/or choreiform movements.
Cortical visual impairment (CVI) (8%, 5/61) has been reported in four patients: three also had an MCD, and the fourth, who had a normal brain MRI, was identified in a cohort of individuals with ID and CVI [Bosch et al 2016].
Note: A report of an individual with approximately 50% mosaicism for a GRIN2B pathogenic missense variant in blood (no other tissues were tested) did not provide sufficient clinical information to allow comparison of the phenotype with individuals with a heterozygous germline pathogenic variant [Stosser et al 2018].
Brain Imaging
A malformation of cortical development (MCD) has been seen in six (13%) of 47 patients; the diffuse cortical dysplasia was consistent with that of polymicrogyria (see Polymicrogyria Overview). Cortical findings included a mixture of large and small gyri separated by shallow sulci (Figure 1). The gray-white border appeared smooth.
Figure 1.
MRI of patients with malformation of cortical development A-D: patient 1; E-H: patient 2; I-L: patient 3; M-P: patient 4; Q-T: patient 5; U-X: patient 6; AA-DD: normal control
Other findings included the following:
- Hypoplastic corpus callosum of varying degrees
- Enlarged and mildly dysplastic basal ganglia
- Hippocampal dysplasia with thick leaves and open hilus
- Enlarged tecta
- Absent septum pellucidum
The malformation of cortical development is also consistent with that of tubulinopathies (see Tubulinopathies Overview). The identified individuals with MCD display a very similar degree of severity, and there are no reports of affected individuals with less pronounced malformations of cortical development.
Generalized cerebral volume loss indicating cerebral atrophy was seen in four other patients (9%, 4/47).
Genotype-Phenotype Correlations
Variant class and intellectual outcome show a significant correlation: heterozygotes for a GRIN2B pathogenic variant resulting in a null allele (e.g., nonsense or frameshift variants, deletion involving whole exons or the entire gene, translocation and inversion disrupting GRIN2B) tended to display mild or moderate ID, while heterozygotes for pathogenic missense variants displayed severe ID (Fisher's exact test, p=0.0079 ) [Platzer et al 2017].
Missense variants in GRIN2B that cause a malformation of cortical development are located in transmembrane domain M3, in the ligand-binding domain S2, and in the linker between S2 and the transmembrane domain M4, a finding consistent with GRIN1 variants causing an MCD [Fry et al 2018] (see GRIN1-Related Neurodevelopmental Disorder).
Penetrance
Penetrance of GRIN2B-related neurodevelopmental disorder is thought to be 100%.
Prevalence
The prevalence of GRIN2B-related neurodevelopmental disorder in the general population is unknown. To date, fewer than 100 individuals have been reported.
The prevalence of GRIN2B-related neurodevelopmental disorder among individuals with neurodevelopmental disorders and/or childhood-onset epilepsy is around 0.2% [Platzer et al 2017].
Differential Diagnosis
Phenotypic features associated with heterozygous GRIN2B pathogenic variants are not sufficient to diagnose GRIN2B-related neurodevelopmental disorder.
All genes known to be associated with ID, early-onset epileptic encephalopathy, and malformations of cortical development (especially diffuse polymicrogyria and tubulinopathies) should be included in the differential diagnosis of GRIN2B-related neurodevelopmental disorder (see Table 2) as individuals with GRIN2B-related neurodevelopment disorder can present with a combination of clinically unspecific phenotypes such as DD/ID/ASD and/or epilepsy. The underlying genetic causes of these phenotypes comprise a very heterogeneous group of disorders, as is the case with tubulinopathies, polymicrogyria, and their differential diagnoses.
Table 2.
Genes to Consider in the Differential Diagnosis of GRIN2B-Related Neurodevelopmental Disorder
| Phenotype | Genes 1 | GeneReview/OMIM |
|---|---|---|
| Intellectual disability | >180 | Autosomal dominant: OMIM PS156200 Autosomal recessive: OMIM PS249500 Nonsyndromic, X-linked: OMIM PS309530 Syndromic, X-linked: OMIM PS309510 |
| Early-onset epileptic encephalopathy | >50 | OMIM PS308350 |
| Polymicrogyria | ~50 | Polymicrogyria Overview |
| Tubulinopathies | TUBA1A TUBA8 TUBB TUBG1 TUBB2A TUBB2B TUBB3 | Tubulinopathies Overview |
- 1.
See linked GeneReview or OMIM phenotypic series entry for further information.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with GRIN2B-related neurodevelopmental disorder, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with GRIN2B-Related Neurodevelopmental Disorder
| System/Concern | Evaluation | Comment |
|---|---|---|
| Ocular | Ophthalmologic | Assess for cortical visual impairment. |
| Gastrointestinal/ Feeding | Feeding, nutrition status, weight gain | Determine if tube feeding is required. |
| Musculoskeletal | Clinical evaluation for tone abnormalities | Assess for muscular hypotonia &/or spasticity. |
| Neurologic | Neurologic | Incl clinical evaluation for movement disorders, EEG, brain MRI |
| Psychiatric/ Behavioral | Neuropsychiatric | For individuals age >12 mos: screening for behavior concerns incl sleep disturbances, ADHD, anxiety, &/or traits suggestive of ASD |
| Miscellaneous/ Other | Developmental assessment | Incl motor, speech/language, general cognitive, vocational skills |
| Consultation w/clinical geneticist &/or genetic counselor |
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder
Treatment of Manifestations
Table 4.
Treatment of Manifestations in Individuals with GRIN2B-Related Neurodevelopmental Disorder
| Manifestation/Concern | Treatment | Considerations/Other |
|---|---|---|
| Abnormal vision &/or strabismus | Standard treatment(s) as recommended by experienced ophthalmologist | |
| Seizures | Standard treatment w/AEDs by experienced neurologist 1 | Many different AEDs may be effective; no one AED has been demonstrated effective specifically for this disorder. |
| Hypotonia, spasticity, & movement disorder | Standard treatment(s) as recommended by experienced neurologist |
AED = antiepileptic drug
- 1.
Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.
Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy. In the United States, early intervention is a federally funded program available in all states.
Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed.
Ages 5-21 years
- In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
- Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
- Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
- Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Motor Dysfunction
Gross motor dysfunction
- Physical therapy is recommended to maximize mobility.
- Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.
Oral motor dysfunction. Assuming that the individual is safe to eat by mouth, feeding therapy, typically from an occupational or speech therapist is recommended for affected individuals who have difficulty feeding due to poor oral motor control.
Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties.
Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications (e.g., medication used to treat ADHD) when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
Surveillance
Table 5.
Recommended Surveillance for Individuals with GRIN2B-Related Neurodevelopmental Disorder
| System/Concern | Evaluation | Frequency |
|---|---|---|
| Ocular | Ophthalmologic | As clinically indicated |
| Gastrointestinal | Feeding, nutrition status, weight gain | |
| Musculoskeletal | Monitor gross & fine motor development in those w/tone abnormalities. | |
| Neurologic | Monitor treatment effectiveness in those w/seizures, movement disorders, &/or spasticity. | |
| Psychiatric | Behavioral assessment for anxiety, attention, & aggressive or self-injurious behavior | |
| Miscellaneous/ Other | Monitor developmental progress & educational needs. |
Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
In vitro studies on oocytes of Xenopus laevis suggest a beneficial treatment response of pathogenic missense GRIN2B gain-of-function variants to blockers of the N-methyl D-aspartate receptor (e.g., memantine, radiprodil) [Lemke et al 2014, Mullier et al 2017, Platzer et al 2017]. However, a significant clinical benefit from treatment with such compounds has not yet been demonstrated [Platzer et al 2017].
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.