To describe a patient with ASXL3 mutation presenting with behavioral dysregulation and new-onset seizures, whose combativeness likely reflected subclinical seizures that improved with levetiracetam, and to discuss associated metabolic abnormalities. 

Bainbridge–Ropers syndrome, caused by de novo mutations in ASXL3, first described in 2013. The ASXL3 protein function as a regulator of chromatin through histone methylation. It is expressed in multiple tissues, with highest expression in the insula, cingulate gyrus, and amygdala, characterized by global developmental delay, hypotonia, feeding difficulties, and behavioral disturbances. Seizures have been described but remain poorly defined. 

An 18-year-old male with a de-novo ASXL3 mutation confirmed in 2014 presented with profound developmental delay, hypotonia, wheelchair dependence, and feeding difficulties requiring GJ tube placement. He exhibited episodes of combativeness and staring off. At age 18, he experienced his first generalized tonic–clonic seizure. CT head was unremarkable. EEG obtained months later due to poor tolerance, demonstrated intermittent generalized slowing. Despite the known risk of behavioral worsening with levetiracetam, initiation of the drug led to improvement in agitation and staring, suggesting these symptoms reflected ictal or peri-ictal hyperexcitability in cortical or limbic network circuits rather than primary psychiatric dysfunction.

Concurrent metabolic evaluation revealed abnormalities in amino acid utilization, including dysregulated serine, methionine, and tyrosine metabolism, with elevated alpha-amino-N-butyric acid, findings might indicate emerging mitochondrial dysfunction. ASXL3 deficiency is thought to impair histone-mediated transcriptional regulation, disrupting amino acid pathways and leading to oxidative stress and energy imbalance, which contributes to both behavioral instability and seizure susceptibility.

This case highlights that behavioral symptoms in Bainbridge–Ropers syndrome may reflect subclinical or subtle seizures. Early recognition may enable earlier diagnosis and treatment. Concurrent amino acid and mitochondrial abnormalities further support a metabolic contribution to epileptogenesis, underscoring the need for systematic studies to clarify the prevalence and mechanisms of seizure activity in this disorder.