Potential Therapy Targets Brain Deterioration in Children with Rare Genetic Disorders

A groundbreaking study conducted by the Francis Crick Institute and Great Ormond Street Hospital (GOSH)/UCL Great Ormond Street Institute of Child Health has unveiled potential treatments for children suffering from rare genetic conditions affecting blood vessels. These conditions lead to debilitating symptoms such as seizures and hindered development that persist throughout the individual’s life. 

The researchers, through their findings published in the Journal of Investigative Dermatology, have pinpointed calcium-related issues as the root cause of these diseases. They suggest that stabilizing calcium levels in the brain could be pivotal in devising new therapeutic interventions to prevent further brain damage. 

These rare conditions are a result of “mosaic mutations” in the GNAQ or GNA11 genes, leading to a range of disorders, including Sturge-Weber syndrome and Phakomatosis Pigmentovascularis with Dermal Melanocytosis (PPV-DM). Affected individuals exhibit symptoms like seizures, developmental delays, severe headaches, blindness, and facial birthmarks. Although these conditions are congenital, the brain-related symptoms tend to worsen during the early years of life. 

Historically, calcium deposits in the brain, visible as “tramlining” on X-rays, were considered non-specific indicators of brain damage. However, this research challenges that notion. Upon examining 42 children diagnosed with either Sturge-Weber syndrome or PPV-DM at GOSH, the team discovered that a significant 74% had abnormal calcium measurements in their blood, with the calcium deposits in their brains worsening over time. 

Delving deeper into the cellular mechanisms, the researchers identified that an excessive release of calcium within cells was a persistent issue. This led cells to absorb even more calcium from their surroundings through CRAC channels. This chronic calcium imbalance is believed to be the foundation of the clinical symptoms observed in patients. In a bid to rectify this, the researchers tested a novel genetic therapy aimed at silencing the hyperactive gene and a drug designed to block the CRAC channels in lab settings.

Both approaches showed promise in addressing the calcium imbalance, with genetic therapy proving to be more effective. The research team is optimistic that early interventions using the genetic therapy or drugs targeting the calcium pathway could prevent the accumulation of calcium deposits in brain cells, thereby reducing the risk of seizures. 

Veronica Kinsler, a leading figure at the Crick and GOSH/UCL, expressed the profound impact of these findings, emphasizing the potential to transform the lives of children diagnosed with these severe conditions. Additionally, Antonella Perini, president of the Associazione Sindrome di Sturge Weber Italia, highlighted the significance of this research, viewing it as a beacon of hope for patients and their families. 

Journal Reference  

(N.d.). Retrieved from https://www.jidonline.org/article/S0022-202X(23)02604-0/fulltext