# Neurodevelopmental disease-causing variants in choline kinase CHKA gene couple phosphatidylcholine synthesis to oxidative stress damage and disease etiology

## TL;DR

This study explores how mutations in the CHKA gene lead to neurological disorders by disrupting lipid synthesis and increasing oxidative stress.

## Contribution

The study reveals a novel link between CHKA variants, lipid metabolism, and oxidative stress in neurodevelopmental disease.

## Key findings

- CHKA variant fibroblasts show impaired phospholipid and triacylglycerol synthesis.
- CHKA deficiency is associated with elevated ROS and lipid peroxidation.
- Mitochondrial uncoupling reduces oxidative stress in CHKA patient cells.

## Abstract

Biallelic variants in CHKA, which encodes the first enzyme in the CDP-choline pathway for the synthesis of phosphatidylcholine, cause an inherited disorder characterized by epilepsy, microcephaly, and intellectual disability. How a deficiency in CHKA activity manifests these neurological symptoms is poorly understood. In this study, we investigated patient-derived fibroblasts with CHKA missense variants to elucidate the molecular and biochemical mechanisms underlying the associated pathologies. CHKA variant fibroblasts exhibited impaired phospholipid and triacylglycerol synthesis, altered mitochondrial morphology and function, elevated reactive oxygen species (ROS) levels, and increased lipid peroxidation, suggesting a mechanism by which defective CHKA activity leads to lipid damage. Treatment with FCCP, a mitochondrial uncoupler, reduced ROS levels and attenuated lipid peroxidation in CHKA patient fibroblasts, suggesting a potential approach to therapeutic intervention.