PACS2-related Developmental and Epileptic Encephalopathy 66

PACS2 is a neonatal-onset developmental and epileptic encephalopathy characterized by seizures beginning in the first days of life, variable developmental delay, hypotonia and behavioral features. Posterior-fossa or cerebellar vermis abnormalities are frequent but not universal. More info
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Genetics

Usually caused by a de novo heterozygous PACS2 variant, most commonly c.625G>A, p.Glu209Lys. Recurrence is generally low but parental mosaicism must be considered.

Molecular Mechanism

PACS2 regulates membrane-cargo trafficking, endoplasmic-reticulum-mitochondrial contacts, calcium flux, apoptosis and autophagy. Pathogenic variants near the autoregulatory region appear to alter cargo interactions, but the precise disease mechanism is not yet fully resolved.

Therapy

Treatment is symptomatic with antiseizure medication and developmental, feeding and rehabilitation support. Seizure burden may lessen with age in some patients, but neurodevelopmental outcome remains variable and no targeted therapy is established.

CCP Activity

CCP is developing and characterizing a variant-appropriate PACS2 model. The program integrates neonatal phenotyping specifically neurodevelopmental outcomes followed by adult comprehensive phenotyping.

Mouse Models

  • PACS2(E209K)