Recessive Loss of PI4K2A Function Causes a Developmental and Epileptic Dyskinetic Encephalopathy with Prominent Orolingual Dyskinesia.

Background: Biallelic loss-of-function variants in PI4K2A have been associated with a neurodevelopmental disorder characterized by seizures and movement disorders, including orofacial dyskinesia. However, only 4 cases have been reported. Orolingual dyskinesia-defined as involuntary movements of the mouth and tongue-is observed in various pediatric neurodevelopmental disorders (NDD) but remains under-recognized.

Objectives: The aims were to highlight orolingual dyskinesia as a core feature of PI4K2A-related disorder (PI4K2A-RD) and explore its presence across other NDDs.

Methods: We described two new families with PI4K2A-RD and reviewed the clinical features of four previously reported cases. A focused literature search was also conducted to identify other neurogenetic conditions associated with orolingual dyskinesia.

Results: All individuals with PI4K2A deficiency exhibited orolingual dyskinesia, along with developmental delay, movement abnormalities, and variable seizures. The literature review confirmed frequent underreporting of this feature in NDDs.

Conclusions: Orolingual dyskinesia is a relevant but under-recognized clinical sign in PI4K2A-RD and other neurogenetic conditions, with potential diagnostic value. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.