Neurodevelopmental disorder due to a frameshift mutation in the gene: a case report.

Background: Pathogenic variants in , encoding the GluN2A subunit of the N-methyl-D-aspartate receptor (NMDAR), are increasingly recognized as causes of neurodevelopmental disorders, particularly within the epilepsy-aphasia spectrum. However, presentations without clinical seizures-especially those initially manifesting as isolated ataxia-are rarely reported. We describe a previously unreported frameshift variant associated with early-onset ataxia, delayed-onset electrographic abnormalities, and favorable response to immunotherapy.

Case Description: A 23-month-old boy presented with subacute gait ataxia following a viral illness. Neuroimaging, cerebrospinal fluid analysis, and an extensive autoimmune panel were unremarkable. Initial immunotherapy with high-dose corticosteroids and intravenous immunoglobulin (IVIG) led to transient improvement. Five months later, he developed recurrent ataxia, speech regression, drooling, and global developmental delay, still without overt seizures. Video electroencephalogram (EEG) revealed electrical status epilepticus during slow-wave sleep (ESES) with a spike-wave index exceeding 85%. Trio-based whole genome sequencing identified a novel heterozygous frameshift variant in (c.1717delG, p.Val573Phefs*16), predicted to result in loss of all transmembrane domains. Repeat immunotherapy produced significant clinical improvement, including restored ambulation, cessation of drooling, enhanced speech output, and marked reduction in epileptiform discharges. The patient remained seizure-free during the reported treatment period. Notably, his mother, a carrier of the same variant, reported only a brief history of childhood seizures with minimal residual speech disturbance.

Conclusions: This case expands the phenotypic spectrum of -related disorders to include early isolated ataxia and delayed electrographic epilepsy in the absence of clinical seizures. It highlights the diagnostic value of early genetic testing in atypical neurodevelopmental syndromes and suggests that immunotherapy may confer clinical and electrophysiological benefits, even in presumed NMDAR loss-of-function states. Integration of genomics, neurophysiology, and immune-modulating strategies may inform future precision therapies for -associated encephalopathies.