Clinical characteristics.

The clinical phenotype of GRIA2-related neurodevelopmental disorder (GRIA2-NDD) comprises global developmental delay, cognitive and language impairment with poor or absent speech in almost all individuals, and varying combinations of tone abnormalities at birth, early-onset developmental and epileptic encephalopathy, complex movement disorders with or without epilepsy, and neurobehavioral and/or psychiatric disorders. Some affected individuals have normal early development followed by variable regression with impaired social and/or language skills. About half of individuals are nonverbal. Several individuals are unable to walk, and several have gait abnormalities, including gait dyspraxia and ataxia. Nearly half of affected children develop seizures including early-onset tonic-clonic, focal, and focal to bilateral tonic-clonic seizures, most of which are refractory to treatment. Some children present with movement disorders, including chorea, dystonia, and dyskinesia.

Diagnosis/testing.

The diagnosis of GRIA2-NDD is established in a proband with suggestive findings and a heterozygous pathogenic variant in GRIA2 identified by molecular genetic testing.

Management.

Treatment of manifestations: There is no cure for GRIA2-NDD. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in neurology, developmental pediatrics, speech-language therapy, otorhinolaryngology, sleep disorders, orthopedics / physical medicine and rehabilitation, physical therapy and occupational therapy, feeding therapy, gastroenterology, ophthalmology, hearing impairment, and medical genetics and genetic counseling.

Genetic counseling.

GRIA2-NDD is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Risk to future pregnancies is presumed to be low as the proband most likely has a de novo GRIA2 pathogenic variant. There is, however, a recurrence risk (~1%) to sibs based on the possibility of parental germline mosaicism. Given this risk, prenatal and preimplantation genetic testing may be considered.

Suggestive Findings

GRIA2-NDD should be considered in a proband with the following clinical and brain MRI findings and family history.

Clinical findings

• Developmental delay (DD) and/or intellectual disability (ID) (present in all individuals)

AND any of the following features presenting in infancy or childhood:

• Body tone abnormalities
  • Congenital-onset abnormal muscle tone (generalized hypotonia or hypertonia)
  • Feeding difficulties during infancy associated with abnormal muscle tone
• Epilepsy. Early-onset and typically treatment-resistant focal and/or generalized seizures
• Movement disorders. Several types of movement disorders may occur including gait dyspraxia, ataxia, choreoathetoid movements, and dystonia.
• Neurobehavioral and/or psychiatric disorders
  • Autism spectrum disorder, attention-deficit/hyperactivity disorder, repetitive behaviors, obsessive-compulsive findings, inappropriate laughing/screaming spells, aggressive or self-injurious behavior
  • Stereotypies (including hand wringing, hand clapping, mouthing, and rubbing automatisms)
• Other features
  • Microcephaly (or deceleration of head growth)
  • Cerebral visual impairment, broadly defined here as bilateral visual impairment due to non-ocular causes (i.e., based in the brain) in the presence of normal pupil reactivity
  • Skeletal abnormalities (scoliosis, spinal fusion, femoral anteversion)
  • Hypothyroidism
  • Sleep apnea

Note: The constellation of findings may occasionally resemble MECP2 disorders with findings of stereotypic hand movements (including hand wringing, hand clapping, mouthing, and rubbing automatisms), gait abnormalities (including gait dyspraxia and inability to walk), microcephaly (or deceleration of head growth), and motor/sensory abnormalities (including abnormal muscle tone and hypersensitivity).

Brain MRI findings. Brain MRI is usually normal; however, two out of 33 affected individuals are reported to have delayed myelination and nonspecific white matter changes and/or cerebellar atrophy characterized by prominent vermian involvement (see Salpietro et al [2019], Figure 2).

Family history. Because GRIA2-NDD is typically caused by a de novo pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family).

Establishing the Diagnosis

The diagnosis of GRIA2-NDD is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in GRIA2 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variant" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous GRIA2 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Note: Single-gene testing (sequence analysis of GRIA2, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

Clinical Description

The clinical phenotype of GRIA2-related neurodevelopmental disorder (GRIA2-NDD) comprises global developmental delay, cognitive and language impairment with poor or absent speech in almost all individuals, and varying combinations of tone abnormalities at birth, early-onset developmental and epileptic encephalopathy, complex movement disorders with or without epilepsy, and neurobehavioral and/or psychiatric disorders.

Some affected individuals have normal early development, followed by variable regression with impaired social and/or language skills. About half of individuals are nonverbal. Several individuals are unable to walk, and several have gait abnormalities, including gait dyspraxia and ataxia.

Nearly half of affected children develop seizures including early-onset tonic-clonic, focal, and focal to bilateral tonic-clonic seizures, most of which are refractory to treatment. Some children present with movement disorders, including chorea, dystonia, and dyskinesia.

Neurobehavioral and/or psychiatric disorders can include autism spectrum disorder, obsessive-compulsive findings, hyperactivity, inappropriate laughing/screaming spells, repetitive behaviors, and stereotypic movements.

Several individuals have either microcephaly or head growth deceleration during infancy.

To date, 33 individuals, ranging in age from three months to 31 years, have been reported with a pathogenic variant in GRIA2 [Salpietro et al 2019, Zhou et al 2021, Cai et al 2022, Coombs et al 2022, Huang et al 2022, Ji et al 2022, Latsko et al 2022]. The information in Table 2 and the description that follows are based on these reports.

Tone abnormalities at birth. Muscular hypotonia was present in three individuals. Spasticity, including muscular hypertonia, that was non-progressive was present in some individuals.

Developmental delay (DD) and intellectual disability (ID) ranging from moderate to severe were present in all reported individuals. Most individuals had delays in gross motor milestones, and several individuals never acquired the ability to walk independently.

All affected individuals had delays (or regression) of speech and language development, and in most cases they could only speak a few intelligible words.

Neurobehavioral and/or psychiatric disorders. Several individuals had autism spectrum disorder and attention-deficit/hyperactivity disorder. Some had repetitive behavior patterns, impaired social interaction, inappropriate laughing/screaming spells, aggressive or self-injurious behavior, and stereotypies (including hand wringing, hand clapping, mouthing, and rubbing automatisms).

Findings resembling MECP2 disorders. Between ages two and six years, 16 children (both male and female, in equal numbers) developed several features that resembled Rett syndrome (i.e., low muscle tone, stereotypic hand movements, gait abnormalities) as well as developmental stagnation in which development slows down or stops altogether; abnormal sleep rhythm; and irregular breathing pattern with frequent episodes of hyperventilation.

Epilepsy. Fifteen of 33 individuals had seizures with median age of onset around age three months (range: 1-15 months). Common seizure types included tonic-clonic seizures, myoclonic seizures, and infantile spasms. Fever was a common trigger. Twelve individuals displayed multiple seizure types over time.

Among the 15 individuals with seizures, epilepsy could be classified as generalized onset in three, focal onset in five, and of unknown onset in seven. Known electroclinical epilepsy syndromes included epileptic spasms syndrome and developmental and epileptic encephalopathy.

Seizures were controlled with standard anti-seizure medications in only two of 12 individuals.

EEG features included polyspikes, slow spike-and-wave, and bilateral temporal non-synchronized epileptic activity.

Movement disorders were observed in two individuals who presented with dyskinesia, dystonia, and choreiform movements.

Other findings

• Feeding difficulties. During early infancy, two children had swallowing difficulties leading to impaired feeding, choking, and regurgitation, requiring gastrostomy tube placement.
• Growth. Progressive microcephaly was observed in four out of 29 individuals, where occipitofrontal circumference (OFC) was more than two standard deviations below the mean, with deceleration of head growth usually during early infancy.
• Ophthalmologic findings. Impaired visual interaction due to abnormal communication during the first few months of life has been noted in several affected individuals. Two individuals had cerebral vision impairment with abnormal ocular motility and (usually intermittent) strabismus.
• Prognosis. It is unknown whether life span in GRIA2-NDD is abnormal.
  Two infants died before age six months with sudden unexplained death in epilepsy (patients 17 and 20 in Salpietro et al [2019]). Within the first two months of life, these infants had tonic or clonic seizures associated with breathing difficulties and no response to several anti-seizure medications.
  One reported female with tonic seizures beginning at age eight years, moderate ID/DD, no Rett-like features, and normal brain imaging is alive at age 31 years (patient 23 in Salpietro et al 2019]), demonstrating that survival into adulthood is possible when the phenotype is milder. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.

Genotype-Phenotype Correlations

No clear genotype-phenotype correlations have been identified to date in GRIA2-NDD. However, strong correlations have been observed between two specific recurrent pathogenic variants and the phenotypes of the affected individuals (see Table 7).

• The pathogenic variant p.Ala639Ser, which affects a conserved alanine residue proximal to the SYTANLAAF domain essential for channel gating, was present in two infants who died before age six months with sudden unexplained death in epilepsy (patients 17 and 20 in Salpietro et al [2019]). Within the first two months of life, these infants had tonic or clonic seizures associated with breathing difficulties and no response to several anti-seizure medications. EEGs showed a multifocal spike and/or burst suppression-like pattern. Brain MRI showed cortical and/or cerebellar atrophy.
• The pathogenic variant p.Val647Leu was present in three children with developmental and epileptic encephalopathy and overlapping electroclinical features (polyspikes, slow spike-and-wave, and bilateral temporal non-synchronized epileptic activity) (patients 16, 18, and 21 in Salpietro et al [2019]).

Of note, the pathogenic variant p.Ala643Val, reported to date in one individual, is the only GRIA2 pathogenic variant observed to cause gain of function (rather than loss of function) of the ligand-gated AMPAR receptor (which is encoded by GRIA2) [Coombs et al 2022] (see Table 7). In addition, the anti-seizure medication perampanel (the only approved anti-seizure medication that blocks the AMPAR receptor) improved behavior, mood, alertness, and fine motor control in this individual [Coombs et al 2022]. Of note, the individual was also treated using a modified Atkin diet with medium chain triglyceride oil supplementation, which might have contributed to the reduction in the disease manifestations [Neal et al 2009, Chang et al 2013].

Prevalence

The prevalence of GRIA2-NDD in the general population is 0.0000084 for de novo variants [Gillentine et al 2022].

To date, 33 individuals with GRIA2-NDD from Europe, North America, and Asia have been reported.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with GRIA2-NDD, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

There is no cure for GRIA2-NDD.

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Evaluation of Relatives at Risk

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

Therapies Under Investigation

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

GRIA2-related neurodevelopmental disorder (GRIA2-NDD) is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• All probands reported to date with GRIA2-NDD whose parents have undergone molecular genetic testing have the disorder as a result of a de novo GRIA2 pathogenic variant.
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform 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 (gonadal) cells only.
    * A parent with somatic and germline mosaicism for a GRIA2 pathogenic variant may be mildly/minimally affected.

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

• If a parent of the proband is known to have the GRIA2 pathogenic variant identified in the proband, the risk to the sibs of inheriting the variant is 50%.
• If the GRIA2 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 possibility of parental germline mosaicism [Rahbari et al 2016].

Offspring of a proband. Individuals with GRIA2-NDD are not known to reproduce; however, many are not yet of reproductive age.

Other family members. Given that all probands with GRIA2-NDD reported to date have the disorder as a result of a de novo GRIA2 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 GRIA2 pathogenic variant. There is, however, a recurrence risk (~1%) to sibs based on the possibility of parental germline mosaicism [Rahbari et al 2016]. Given this risk, prenatal 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

The AMPA-type glutamate receptors (AMPARs) are ligand-gated cation channels, expressed in both neurons and glia, that mediate most of the fast excitatory transmission in the central nervous system [Hansen et al 2021]. AMPARs have also been implicated in the development and maintenance of synaptic plasticity (including both long-term potentiation and depression; reviewed in Isaac et al [2007] and Cull-Candy & Farrant [2021]) and synaptogenesis [Ashby & Isaac 2011, Kwon & Sabatini 2011]. As such, genetic alterations in the genes that encode AMPAR subunits such as GRIA2 likely cause neurodevelopmental disorders via a disruption of more than just excitatory transmission.

Mechanism of disease causation. A range of disease-associated variants have been identified across GRIA2 that can produce either loss or gain of receptor function.

GRIA2 variants such as nonsense, frameshift, or truncating variants may lead to a loss of function via haploinsufficiency.

• Missense GRIA2 variants may cause disease through several mechanisms. In vitro patch clamp studies have shown that missense variants can lead to changes in a range of receptor properties such as kinetics (i.e., deactivation and desensitization) and pharmacology (i.e., glutamate potency), among others [Salpietro et al 2019, Coombs et al 2022]. It is currently unknown how these changes might affect broader synaptic function and circuit/network functions and development.
• The specific GRIA2 missense variant p.Ala643Val exhibits gain of function, with greatly slowed deactivation, markedly reduced desensitization, and increased glutamate sensitivity [Coombs et al 2022].

Author Notes

Allan Bayat and Henry Houlden are shared last authors.

Dr Stephanie Efthymiou, Dr Vincenzo Salpietro, and Ms Elisa Rumbos Siurana are actively involved in clinical research regarding individuals with GRIA2-related neurodevelopmental disorder (GRIA2-NDD) and are working on characterizing the functional effects of GRIA2 variants using in vitro electrophysiology methods. They would also be happy to communicate with persons who have any questions regarding diagnosis of GRIA2-NDD or other considerations.

Contact information: ku.ca.lcu@uoimyhtfe.s (Stephanie Efthymiou), ku.ca.lcu@orteiplas.v (Vincenzo Salpietro), ku.ca.lcu@71.anaruis.asile (Elisa Rumbos Siurana)

Web page: www.neurogenetics.co.uk/meet-the-team

The team led by Dr Allan Bayat is also actively involved in research regarding all GRIA genes: GRIA1, GRIA2, GRIA3, and GRIA4. They are also using in vitro electrophysiology methods to functionally evaluate the effects of all GRIA missense variants.

Their aims are to deep-phenotype GRIA-related disorders, to find new genotype-phenotype correlations, to identify clinical biomarkers suggestive of loss- or gain-of-function variants, and to explore the role of perampenal as precision therapy for individuals with gain-of-function variants.

Dr Bayat would be happy to communicate with persons who have any questions regarding diagnosis of GRIA-NDD or other considerations. Contact him to inquire about potential functional evaluation of all GRIA variants of uncertain significance. No tissue samples are needed for functional testing.

Contact information: abaya@filadelfia.dk or bayabayabayat@hotmail.com

Web page: epi-care.eu/collaborative-genetic-research

Dr Vincenzo Salpietro is also interested in hearing from clinicians treating families affected by GRIA2-NDD in whom causative variant has been identified through molecular genetic testing.

Contact Dr Stephanie Efthymiou and Ms Elisa Rumbos Siurana to inquire about review of GRIA2 variants of uncertain significance.

Acknowledgments

This work was supported by the SYNAPS Study group funded by the Wellcome trust. Ms Elisa Rumbos Siurana's current functional investigations are funded by a Joint Sparks-Great Ormond Street Hospital for Children research program. Dr Allan Bayat is funded by a BRIDGE – Translational Excellence Programme grant funded by the Novo Nordisk Foundation, grant agreement number: NNF20SA0064340.

Revision History

• 11 January 2024 (bp) Review posted live
• 5 July 2023 (ab) Original submission

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