Clinical characteristics.

GRIN2D-related developmental and epileptic encephalopathy (GRIN2D-related DEE) is characterized by mild-to-profound developmental delay or intellectual disability, epilepsy, abnormal muscle tone (hypotonia and spasticity), movement disorders (dystonia, dyskinesia, chorea), autism spectrum disorder, and cortical visual impairment. Additional findings can include sleep disorders and feeding difficulties. To date 22 individuals with GRIN2D-related DEE have been reported.

Diagnosis/testing.

The diagnosis of GRIN2D-related DEE is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) missense variant in GRIN2D identified by molecular genetic testing

Management.

Treatment of manifestations: There is no cure for GRIN2D-related DEE. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in pediatric neurology, pediatric ophthalmology, developmental pediatrics, feeding, orthopedics, physical medicine and rehabilitation, physical therapy, occupational therapy, and ethics.

Surveillance: In infancy: regular assessment of swallowing, feeding, and nutritional status to determine safety of oral vs gastrostomy feeding. For all age groups: routine monitoring of developmental progress, educational needs, and behavioral issues.

Genetic counseling.

GRIN2D-related DEE is an autosomal dominant disorder typically caused by a de novo pathogenic variant. If the proband represents a simplex case (i.e., the only affected family member) and the GRIN2D pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental mosaicism. Once the GRIN2D pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

GRIN2D-related DEE 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 presenting in infancy or childhood:
  • Epilepsy
  • Muscular tone abnormalities such as hypotonia and spasticity
  • Dystonic, dyskinetic, or choreiform movement disorder
  • Autism spectrum disorder
  • Cortical visual impairment

Imaging findings. Brain MRI can show generalized volume loss as a sign of cerebral atrophy.

Establishing the Diagnosis

The diagnosis of GRIN2D-related DEE is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) missense variant in GRIN2D identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous GRIN2D variant of uncertain significance does not establish or rule out the diagnosis of this disorder. (3) To date, a null variant in GRIN2D has not been reported in any individual with GRIN2D-related DEE.

Because the phenotype of GRIN2D-related DEE is indistinguishable from many other inherited disorders with developmental delay, intellectual disability, and epilepsy, recommended molecular genetic testing approaches include use of comprehensive genomic testing or a multigene panel.

Note: Single-gene testing (sequence analysis of GRIN2D, followed by gene-targeted deletion/duplication analysis) is not useful and NOT recommended.

• Comprehensive genomic testing does not require the clinician to determine which gene is likely involved and is therefore preferred by the authors over use of a multigene panel. 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.
• An intellectual disability or epilepsy multigene panel that includes GRIN2D and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and 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) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

GRIN2D-related developmental and epileptic encephalopathy (GRIN2D-related DEE) is characterized by mild-to-profound developmental delay or intellectual disability, epilepsy, abnormal muscle tone (hypotonia and spasticity), movement disorders (dystonia, dyskinesia, chorea), autism spectrum disorder, and cortical visual impairment. Additional findings can include sleep disorders and feeding difficulties.

To date, a pathogenic missense variant in GRIN2D has been identified in 22 individuals [Li et al 2016, Tsuchida et al 2018, Xiang-Wei et al 2019, Stenson et al 2020, Bertoli-Avella et al 2021, Jiao et al 2021] and an additional four unpublished individuals enrolled in the GRIN Portal/Registry. The following description of the phenotypic features associated with this condition is based on these reports.

Developmental delay / intellectual disability. All individuals have a variable degree of DD or ID, with 59% (13/22) showing severe/profound ID, 1/22 showing moderate ID, and 1/22 described with mild ID. In 31% (7/22), the level of ID was not specified.

In 36% (8/22), no speech was noted, while 2/22 were able to speak single words.

Of the 22 individuals reported, five (all of whom also had epilepsy) were noted to regress, consistent with an encephalopathic course. In 10% (2/22), the regression was further specified to primarily affect motor skills.

Epilepsy. Eighty-six per cent (19/22) of individuals had seizures. Average age at seizure onset was 11 months (range: 1 day – 41 months, median: 4 months).

When known, seizure type differed at onset and included the following:

• Febrile seizures (1/18)
• Focal seizures (4/18)
• Absence seizures (3/18)
• Generalized seizures (5/18)
• Epileptic spasms (5/18)

Eleven of the 19 individuals with seizures had multiple seizure types after the initial onset of seizures.

Use of anti-seizure medication varied considerably, with differing levels of success. No particularly successful treatment regimen was evident.

EEG findings include hypsarrhythmia, focal and multifocal as well as generalized epileptic discharges; different EEG patterns varied over time.

Other neurologic findings

• Muscular hypotonia: 54% (in 12/22)
• Movement disorder with athetoid movements, jerky movements, ballism, mild dyskinesia, and choreiform movements: 36% (8/22)
• Cortical visual impairment: 32% (7/22)
• Spasticity (primarily of the lower limbs): 18% (4/22)
• Ataxic gait: 3% (3/22)

Behavioral problems

• Autism spectrum disorder: 18% (4/22)
• Recurrent sleeping disorder 27% (6/22)

Feeding difficulties / gastrointestinal abnormalities

• Feeding difficulties in 27% (6/22), including one individual who required tube feeding [Li et al 2016]
• Recurrent vomiting and constipation

Growth. One individual had microcephaly. No other growth abnormalities were observed.

Neuroimaging. MRI, performed in 17 of 22 individuals, was normal in nine individuals and showed signs of brain atrophy in seven individuals, including two with a thin corpus callosum.

Prognosis. As no older individuals with a GRIN2D-related DEE have been described to date, reliable prognostic statements are currently not possible.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Penetrance

Penetrance of GRIN2D-related DEE is thought to be 100%.

Prevalence

The prevalence of GRIN2D-related DEE in the general population is unknown. To date, reports on fewer than 30 individuals have been published.

Use of an empiric incidence estimation algorithm [Lemke 2020, López-Rivera et al 2022] predicted the number of newborns with a de novo GRIN2D variant in the US in 2018 to be 175.

A genetic contribution to neurodevelopmental disorders can be estimated at 0.006% based on the presence of two de novo GRIN2D variants in the largest study on de novo variants to date [Kaplanis et al 2020].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with GRIN2D-related DEE, the evaluations summarized in Table 2 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for GRIN2D-related DEE.

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in pediatric neurology, pediatric ophthalmology, developmental pediatrics, feeding, orthopedics, physical medicine and rehabilitation, physical therapy, occupational therapy, and ethics.

Surveillance

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Given the understanding of the drug memantine on GRIN2D function [Kotermanski & Johnson 2009], anti-convulsant effects in animal models [Ghasemi & Schachter 2011], and safety profile in children [Chez et al 2007, Erickson et al 2007], memantine was tried in three affected individuals. While one showed a beneficial response, two did not [Li et al 2016, Xiang-Wei et al 2019]. Due to the varying success of treatment with memantine, a targeted treatment recommendation cannot be given at this point.

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.

Mode of Inheritance

GRIN2D-related developmental and epileptic encephalopathy (GRIN2D-related DEE) is an autosomal dominant disorder typically caused by a de novo pathogenic missense variant.

Risk to Family Members

Parents of a proband

• All probands reported to date with GRIN2D-related DEE whose parents have undergone molecular genetic testing have the disorder as the result of a de novo GRIN2D pathogenic missense variant.
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If the proband represents a simplex case (i.e., the only affected family member) and the GRIN2D pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental mosaicism [Rahbari et al 2016].
• In a study assessing mosaicism in the apparently asymptomatic parents of children with developmental and epileptic encephalopathy, the frequency of parental somatic and (inferred) germline mosaicism was found to be 10% [Myers et al 2018].

Offspring of a proband. Individuals with a GRIN2D-related DEE are not known to reproduce; however, many are not yet of reproductive age.

Other family members. Given that all probands with GRIN2D-related DEE reported to date have the disorder as the result of a confirmed or apparent de novo GRIN2D pathogenic variant, the risk to other family members is presumed to be low.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Risk to future pregnancies is presumed to be low, as the proband most likely has a de novo GRIN2D pathogenic variant. However, based on the theoretic possibility of parental mosaicism (reported to be 10% in one study on apparently asymptomatic parents of children with developmental and epileptic encephalopathy [Myers et al 2018]), the recurrence risk to sibs is estimated to be 1% [Rahbari et al 2016]. Given this risk, prenatal testing and preimplantation genetic testing may be considered.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

N-methyl D-aspartate receptors (NMDARs) are ligand-gated subunit receptors that mediate excitatory synaptic transmission in the central nervous system. NMDARs, tetrameric assemblies of two GluN1 and two GluN2 subunits, play important roles in brain development, synaptic plasticity, learning, and memory.

The NMDARs encoded by the GRIN gene family include GRIN1, GRIN2A, GRIN2B, GRIN2C, GRIN2D, GRIN3A, and GRIN3B.

All GluN subunits have a similar structure: an amino terminal domain (ATD), an agonist-binding domain (ABD; S1 and S2), a transmembrane domain (M1, M2, M3, and M4), and a C-terminal domain (CTD) [Traynelis et al 2010]. Previous studies suggested that three control elements – the pre-M1 helix, the M3 transmembrane helix (especially the SYTANLAAF motif), and the M4 transmembrane helix/pre-M4 region – play important roles in NMDAR channel gating. Moreover, pathogenic missense variants specifically affecting these regions in other NMDAR subunits such as GRIN1, GRIN2A, and GRIN2B have been shown to cause neurodevelopmental disorders with epilepsy.

Mechanism of disease causation. De novo missense variants in GRIN2D disrupt the GluN-2D-subunit of the NMDAR and result in either loss- or gain-of-function effects on the receptor.

GRIN2D-specific laboratory technical considerations. To date, all reported GRIND2D-related DEE-causing pathogenic variants have been missense variants.

Author Notes

Konrad Platzer, MD
Institute of Human Genetics
University of Leipzig Medical Center
Philipp-Rosenthal-Str. 55
04103 Leipzig, Germany
ed.gizpiel-inu.nizidem@reztalp.darnok
twitter.com/platzer_k

Ilona Krey, MD
Institute of Human Genetics
University of Leipzig Medical Center
Philipp-Rosenthal-Str. 55
04103 Leipzig, Germany
ed.gizpiel-inu.nizidem@yerk.anoli
twitter.com/ilona_krey

Johannes R Lemke, MD
Institute of Human Genetics
University of Leipzig Medical Center
Philipp-Rosenthal-Str. 55
04103 Leipzig, Germany
ed.gizpiel-inu.nizidem@ekmel.sennahoj
twitter.com/lemke_johannes

GRI Registry at the Institute of Human Genetics (ed.gizpiel-inu.nizidem@NIRG)

The authors (Konrad Platzer, Ilona Krey, and Johannes Lemke) are available to help clinicians evaluate variants of uncertain significance in GRIN2D (and all other NMDAR subunit genes) and, if appropriate, can initiate functional testing in the Center for Functional Evaluation of Rare Variants at Emory University, Atlanta, Georgia, USA.

The authors are actively involved in clinical research regarding individuals with GRIN disorders (GRIN1, GRIN2A, GRIN2B, and GRIN2D). They would be happy to communicate with persons who have any questions regarding diagnosis of GRIN disorders or other considerations (e.g., variants in GRIN genes not yet associated with a mendelian disorder: GRIN2C, GRIN3A, and GRIN3B).

The authors are also interested in hearing from clinicians treating families affected by developmental and epileptic encephalopathy in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

Revision History

• 28 July 2022 (bp) Review posted live
• 20 May 2022 (kp) Original submission

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