PACS2-related DEE66: closing a three-decade diagnostic odyssey through electro-radio-genetic correlation and precision therapy

Abstract

Case Presentation: A 28-year-old female from Maceió, Brazil, presented with drug-resistant early-onset epilepsy beginning at three months of age. Initial seizures consisted of focal motor events associated with cyanosis and episodic nystagmus. During childhood, she exhibited a high seizure burden, with frequent seizure clusters and episodes requiring hospital admission, with partial stabilization after age seven.Despite trials of multiple anti-seizure medications (Carbamazepine, Lamotrigine, Levetiracetam, and Valproate), seizure control remained inadequate, fulfilling criteria for drug-resistant epilepsy, with significant neuropsychiatric adverse effects, notably persistent mood instability and irritability. In adulthood, she developed chronic occipital headaches and recurrent focal impaired awareness seizures. Global neurodevelopmental delay and moderate intellectual disability were present.Brain MRI revealed rhombencephalosynapsis, characterized by trans-hemispheric continuity of the cerebellar hemispheres and vermian hypoplasia, associated with midbrain elongation. Bilateral hippocampal malrotation and adjacent cortical abnormalities suggestive of focal cortical dysplasia/polymicrogyria were also identified. Serial imaging (2017–2024) confirmed structural stability. EEG demonstrated diffuse slowing and multifocal epileptiform discharges with occipital predominance, showing topographic concordance with cortical malformations.Whole-exome sequencing identified a pathogenic de novo heterozygous variant c.625G>A (p.Glu209Lys) in the PACS2 gene, confirming Developmental and Epileptic Encephalopathy 66 (DEE66). Following initiation of cannabidiol (CBD 100 mg/mL), the patient achieved her best clinical baseline, with reduced seizure frequency and marked improvement in mood stability compared to previous treatments. Discussion: DEE66 is an ultra-rare disorder, with fewer than 150 cases reported since 2018, caused by gain-of-function mutations in the PACS2 gene, which regulates intracellular Ca²⁺ homeostasis. The p.Glu209Lys variant leads to neuronal hyperexcitability.The triad of rhombencephalosynapsis, midbrain dysmorphism, and hippocampal malrotation represents a distinctive neuroimaging signature that should prompt targeted genetic testing.This case highlights a precision medicine approach, in which the molecular mechanism supports the use of cannabidiol, known to modulate neuronal excitability and calcium dynamics. The favorable clinical response reinforces its potential role in rare genetic epileptic encephalopathies.Additionally, this case underscores a diagnostic delay of nearly three decades, emphasizing the importance of recognizing specific neuroimaging patterns even in adulthood. Final Comments: Recognition of this electro-radiological pattern is essential for directing genetic investigation. Even in adulthood, etiological diagnosis through exome sequencing can end the diagnostic odyssey, enable precision therapy, and improve quality of life in drug-resistant epilepsy.