A rare genetic mutation tied to childhood epilepsy could also be one of the clearest single-gene risk factors yet identified for early-onset schizophrenia and other psychiatric disorders. It’s a claim that – if it survives further scrutiny – could break down the door for more targeted treatment.
Molecular Psychiatry has published an exhaustive international analysis that argues that the so-called “null” variants in GRIN2A dramatically drive up the risk of developing mental disorders in childhood or adolescence.
GRIN2A encodes a subunit of the NMDA receptor, a key molecular gatekeeper of synaptic plasticity and cognition. While earlier studies have established a robust connection between the gene and epilepsy (and other neurodevelopmental disorders) for more than a decade, its role in psychiatric illness – schizophrenia, in particular – remains shrouded in mystery.
The new study suggests that the relationship is, in fact, much stronger (and occurs much sooner) than anyone realized.
A Clear Genetic Signal
The researchers paged through the data of 235 individuals enrolled in a global GRIN registry, more than half of whom received confirmation of their mental health status. Among them, 84 carried GRIN2A “null” variants – mutations that prune back the protein or eliminate it completely.
Nearly one in three of those carriers developed a diagnosable mental disorder.
By contrast, individuals with GRIN2A missense variants – mutations that altered but failed to eliminate the protein’s function – rarely developed psychiatric conditions.
After adjusting for age, sex, and family relationships, the researchers determined that carriers of null variants were more than five times as likely to develop a mental disorder as those with missense mutations. When compared with population-level data from Finland’s national health registries, the differences only became more apparent.
Children boasting GRIN2A null variants showed sharply elevated rates of psychiatric illness long before adolescence. During childhood, GRIN2A null variants accelerated the risk of psychotic disorders nearly 90-fold compared to the general population. GRIN2A null variants also substantially boosted the threat of anxiety and mood disorders.
Earlier Emergence
Unlike schizophrenia in the general population, which normally rears its head in late adolescence or early adulthood, psychiatric symptoms in GRIN2A null carriers instead tend to crop up in childhood. Anxiety and mood disorders can appear as early as elementary school, while psychotic symptoms usually show up in early adolescence.
But maybe more importantly, these mental disorders didn’t always show up alongside the neurological features clinicians expect to see in GRIN2A-related diseases. Half a dozen individuals in the cohort presented with psychiatric illness alone – without intellectual disability, and (in some cases) without epilepsy.
This discovery challenges a long-held belief in psychiatry that severe mental illness almost always stems from many small genetic effects rather than a single powerful mutation.
It’s All About Timing
Most GRIN2A null carriers with psychiatric illness also lived with a history of epilepsy. But the relationship appeared to be more than just comorbidity.
Mental disorders didn’t necessarily occur more frequently in individuals with epilepsy. Timing seemed to make a huge difference. In more than half of cases with detailed data, psychiatric symptoms emerged after epilepsy resolved itself. The age at which seizures tapered off trailed the onset of mental illness. The revelation hints at a shared developmental mechanism rather than a direct causal role for seizures themselves.
But maybe the most compelling part of the study rests in its therapeutic potential.
Four individuals with GRIN2A null variants and notable psychiatric symptoms received the amino acid L-serine, which boosts levels of D-serine. Subsequently, all four showed meaningful clinical improvement, including resolution of hallucinations, remission of paranoid symptoms, improved behavior, or reduced seizure burden.
Biology could be the solution. Loss of GRIN2A reduces the number of functional NMDA receptors at synapses. Enhancing receptor activation with serine-derived co-agonists could (at least somewhat) compensate for that deficit, restoring glutamatergic signaling during critical developmental windows.
Time to Rethink Genetic Testing?
All told, the findings stir up some uncomfortable questions about today’s prevalent diagnostic practices. While genetic testing remains common in pediatric epilepsy and intellectual disability, we don’t often think about it when assessing individuals who present with early-onset psychiatric illness.
The authors argue that this might need to change, especially for children and adolescents with severe or atypical symptoms. For psychiatry, a field long stalled between complex genetics and blunt therapeutics, GRIN2A could be the rare bridge between cause and care.
Further Reading
SGK1 Emerges as Key Driver (and Target) in Depression
Can Teen Body Dissatisfaction Predict Mental Health Problems?
