Akademik Veri Yönetim Sistemi
Epilepsy Research, cilt.224, 2026 (SCI-Expanded, Scopus)
Introduction: PRUNE1-related disorders present diverse neurological manifestations, including developmental delay, congenital brain malformations, and epilepsy. Despite their frequency and often refractory nature, PRUNE1-related seizures have received insufficient attention. Methods: Five Turkish patients carrying the homozygous c.316G>A (p.Asp106Asn) variant in the PRUNE1 gene were evaluated through retrospective review of clinical data, including neurological assessments, neuroimaging, and treatment responses. To explore the functional consequences of the mutation, computational structural analyses were performed using the AlphaFold2 model and PDBeFold server, followed by PyMOL-based evaluation of the DHH motif and its role in ion coordination. We also reviewed PRUNE1-related disorders with a focus on seizure characteristics and treatment responses. Results: Among 62 cases, including the five presented here, seizures were reported in 79%, with epileptic spasms the most common type. EEG evaluations revealed a spectrum of epileptic activities and diffuse slowing of the background activity, underscoring heterogeneous electrographic abnormalities. Treatment responses varied, with drug-resistant epilepsy observed in 47% of cases. To elucidate the functional impact of the identified mutations, we examined the DHH motif's role in ion coordination using structural biology approaches. Our findings indicate that mutations within the DHH motif of PRUNE1 interfere with manganese ion binding, resulting in diminished enzymatic activity, neuronal dysfunction, and hyperexcitability, contributing to seizures. Discussion: PRUNE1-related disorders show diverse neurological features, with seizures—particularly epileptic spasms—being the most common. Drug resistance remains a major challenge, underscoring the need for improved therapeutic strategies. Mutations in the DHH motif impair manganese binding and enzymatic activity, linking molecular dysfunction to epileptogenesis and highlighting potential targets for future interventions.