Penetrance

GRIN2A-related disorders show high penetrance and variable expressivity. In families of mildly affected individuals, carriers of the familial pathogenic GRIN2A variant have been observed who were less severely or very rarely not known to be affected .

Source: GeneReviews — "GRIN2A-Related Disorders"

Diagnostic Criteria

Suggestive Findings

A GRIN2A-related disorder should be considered in a proband with the following suggestive clinical findings and family history.

Clinical findings

Source: GeneReviews — "GRIN2A-Related Disorders"

Differential Diagnosis

Genetic epilepsy syndromes. GRIN2A-related epilepsy phenotypes cannot be distinguished from other epilepsy-aphasia syndromes (EAS), apart from the ongoing subtle speech abnormalities that persist into adult life in those with GRIN2A pathogenic variants. GRIN2A-related infantile-onset developmental and epileptic encephalopathy (DEE) has no distinguishing features from other genetic causes. Note: While GRIN2A pathogenic variants can be associated with EAS, the majority of individuals with EAS do not have an identified genetic cause. A number of copy number variants (CNVs) have been associated with EAS in individual cases.

Source: GeneReviews — "GRIN2A-Related Disorders"

Management Guidelines

No clinical practice guidelines for GRIN2A-related disorders have been published.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with GRIN2A-related disorders, the evaluations summarized (if not performed as part of the evaluation that led to diagnosis) are recommended.

Table 4.

GRIN2A-Related Disorders: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Constitutional

| Assessment of overall growth incl weight, height, head circumference |

Development

| Developmental assessment | • To incl motor, adaptive, cognitive, speech-language eval

• Evaluate for early intervention need for special education.

• Assess for developmental regression across all areas.

Epilepsy

| Neurologic eval | • EEG

• Careful clinical history to identify seizures

• In infancy childhood, sleep-deprived or sleep EEG w/monitoring to capture sleep, as this is essential to identify DEE-SWAS

Speech language disorders

| Consultation w/speech-language pathologist | Assessment for dyspraxia, dysarthria, language impairment

Movement disorders/

Musculoskeletal/

Activities of daily living

| Orthopedics/ physical medicine rehab/ PT OT eval | In severe DEE cases, consider eval for:

• Gross motor fine motor skills;

• Mobility, ADL, need for adaptive devices;

• Need for PT (to improve gross motor skills) /or OT (to improve fine motor skills).

Neurobehavioral/

Psychiatric

| Neuropsychiatric eval | • Screening for behavior concerns incl sleep disturbances...

Source: GeneReviews — "GRIN2A-Related Disorders"

Clinical Guidance

In individuals with GRIN2A-related disorders due to pathogenic missense variants activating the N-methyl-D-aspartate receptor (NMDAR), receptor-specific agonists and other activators (e.g., L-serine) should be avoided, as this could result in worsening of symptoms . In individuals with GRIN2A-related disorders due to pathogenic missense variants inhibiting the NMDAR as well as null variants, receptor-specific blockers should be used with caution (e.g., memantine, dextromethorphan, ketamine).

Source: GeneReviews — "GRIN2A-Related Disorders"

Therapies Under Investigation

Several treatments are now under investigation in individuals with GRIN2A pathogenic gain-of-function (GOF) variants:

Source: GeneReviews — "GRIN2A-Related Disorders"

Surveillance Guidelines

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

Table 7.

GRIN2A-Related Disorders: Recommended Surveillance

System/Concern | Evaluation | Frequency

Development

| Monitor developmental progress educational needs. | At each visit

Neurologic

| • Assess for new manifestations such as seizures, changes in tone, movement disorders, regression

• Assess for more subtle seizure types that many not have been recognized.

Speech language disorders

| Routine monitoring of speech language by speech-language pathologist should be considered, particularly in childhood. Parents should be asked by all clinicians about loss of understanding or regression in spoken language skills.

Neurobehavioral/

Psychiatric

| Assess for behavioral disorders (particularly ADHD ASD) mental health issues (particularly anxiety, mood, psychotic disorders).

Musculoskeletal/

Activities of daily living

| Physical medicine (particularly in childhood), OT/PT assessment of mobility, self-help skills depending on childs phenotype

Family/Community

| Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).

ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy

Source: GeneReviews — "GRIN2A-Related Disorders"