GRIN2A-Related Disorders

Excerpt

Clinical characteristics: GRIN2A-related disorders encompass a broad phenotypic spectrum that includes developmental delay evolving to intellectual disability (DD/ID), epilepsy, speech and language disorders, movement disorders, and neuropsychiatric disorders. Intellect ranges from normal to profoundly impaired. Observed speech disorders include dysarthria and speech dyspraxia, and both receptive and expressive language delays; more mildly affected individuals may display subtly impaired intelligibility of conversational speech. Epilepsy features include seizure onset usually between ages three and six years, focal epilepsy with language and/or global developmental regression, and electroencephalogram (EEG) abnormalities, including continuous spike-and-wave discharges in sleep or very active centrotemporal discharges. Epilepsy is typically focal and ranges from self-limited epilepsy with centrotemporal spikes to developmental and/or epileptic encephalopathies (DEE/EE), including the syndromes of DEE/EE with spike-wave activation in sleep (DEE/EE-SWAS), which include Landau-Kleffner syndrome. Movement disorders occur less frequently and include ataxia, dystonia, and chorea.

Diagnosis/testing: The diagnosis of a GRIN2A-related disorder is established in a proband by the identification of a GRIN2A heterozygous pathogenic variant on molecular genetic testing.

Management: Targeted therapy: In some individuals with pathogenic loss-of-function and null GRIN2A variants, treatment with the N-methyl-D-aspartate receptor (NMDAR) coagonist L-serine was associated with improvements in behavior, development, EEG features, and/or seizure frequency.

Supportive care: Significant speech and language deficits require therapy from a speech-language pathologist. Seizures should be treated with anti-seizure medication (ASM). Multidisciplinary care is recommended by pediatric specialists in the fields of including pediatric epilepsy, movement disorders, speech-language disorders, physical therapy, occupational therapy, feeding and nutrition, behavioral disorders, and genetic counseling.

Surveillance: Developmental surveillance in all affected children; routine monitoring of speech and language by a speech-language pathologist should be considered for all children, particularly those diagnosed before reaching school age.

Agents/circumstances to avoid: In individuals with GRIN2A-related disorders due to pathogenic missense variants activating the NMDAR (i.e., gain-of-function variants), receptor-specific agonists and other activators (e.g., L-serine) should be avoided as this could result in worsening of symptoms. In individuals with pathogenic missense variants inhibiting the NMDAR as well as null variants, NMDA receptor blockers should be used with caution (e.g., memantine, dextromethorphan, ketamine).

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives in order to identify as early as possible those who would benefit from evaluation for speech disorders and/or seizures and institution of treatment.

Genetic counseling: GRIN2A-related disorders are inherited in an autosomal dominant manner. Some individuals diagnosed with a GRIN2A-related disorder have the disorder as the result of a pathogenic variant inherited from an affected parent. Approximately 50% of individuals diagnosed with a GRIN2A-related disorder have the disorder as the result of a GRIN2A pathogenic variant that occurred as a de novo event in the affected individual or, rarely, as a postzygotic de novo event in a mosaic, apparently unaffected parent. Each child of an individual with a GRIN2A-related disorder has a 50% chance of inheriting the GRIN2A pathogenic variant. Once the GRIN2A pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.