GRIA2-Related Neurodevelopmental Disorder

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.