Driving research forward in CASK disorders

Led by Professor James Hodge, University of Bristol. This project uses CASK fly models to understand how CASK mutations affect movement, sleep and seizures, and to investigate the cellular mechanisms behind these problems. The researchers have identified specific cell types involved in CASK-related behaviours and found changes in cell survival and calcium signalling. They are now developing more detailed models carrying different CASK variants and testing ways to restore CASK function.

Long-term goal: to develop a practical, low-cost drug-screening platform to identify potential treatments for CASK disorders. Funded by CASK Research Foundation. This project requires further funding.

Led by paediatric neurologist Dr Sam Amin. A UK-wide clinical registry and CASK biobank to better understand prevalence and systematically collect clinical and biological data. Families will be invited to contribute samples (blood/saliva) to enable biomarker discovery — crucial for tracking disease progression and assessing treatment effects in trials.

This study focuses on a key question: Do CASK changes make human brain cells less active, and can we safely boost that activity again? The team will grow human brain cells in the lab and measure how well they "talk" to each other. They will look at:

• How active the cells are at rest
• How they respond when encouraged to fire more, using gentle light-based stimulation
• Whether a specific signalling protein called GluN2B can help restore activity when it is added back into cells that have CASK changes

GluN2B is important because it helps brain cells strengthen their connections — something children need for learning, memory, and development.

The researchers will also test medicines that block GluN2B to confirm whether this protein is truly involved in the communication problems they see. This helps make sure the results are reliable and not caused by something else.

This project will not create a treatment right away, but it answers a crucial question that must come first: Is GluN2B a good target for future therapies in CASK disorders? If boosting GluN2B improves brain-cell activity in the lab, it could guide the development of gene therapies; medicines that strengthen brain-cell communication; new approaches to support learning and development. Even if GluN2B does not fix the problem, the results will still help researchers rule out the wrong pathways and focus on the right ones — saving time and accelerating progress.

Co-funded by CASK Research and University of Southampton. This study will investigate CASK missense mutations — changes to a single DNA letter that alter one part of the CASK protein rather than stopping the protein from being made altogether. The researchers will create patient-derived cells (iPSCs) from boys with CASK missense mutations and use these cells to 1) understand how the mutation is affecting the cell, 2) test FDA approved drugs to see if they can improve the cell's functions.

Although the initial work will focus on boys, the findings should be relevant to both males and females with CASK missense mutations. Studying males makes the effects of a missense mutation easier to identify because they have only one copy of the CASK gene, whereas females have two copies and a healthy copy can potentially mask some of the effects of the altered gene. If a drug is found to improve the function of CASK affected by a particular missense mutation, it should theoretically also be relevant to females with missense variants affecting the same part of the gene.

Importantly, the potential benefits may extend beyond missense mutations. If the researchers identify drugs that can improve the function of CASK within cells, these treatments could potentially also help children who have a non-functioning copy of CASK, like many of our children with MICPCH.

A PhD starting in October 2026 led by Dr Cayuso. The project will generate novel zebrafish models using CRISPR/Cas9 genome editing and uncover how CASK mutations lead to neural and craniofacial defects by studying the behaviour of different cell types during brain development. Funded by the University of Portsmouth.

Led by Dr Karen Low, the GenROC study hopes to improve understanding of how rare genetic syndromes affect the way children grow, their physical health and their development. It also aims to work with parents to understand new ways clinicians and parents can work together to improve their knowledge (such as through social media). This study looked at the real-life experiences of children in the UK who have a CASK gene mutation. Parents shared detailed information about their child's development, health, behaviour, education, and how caring for their child affects family life. Doctors also provided clinical information. This study is awaiting publication.

Following a publication by Dr Tabuchi, CASK Research is exploring how to translate this knowledge into treatment. Dr Tabuchi discovered that JNK-IN-8 prevents cell death in certain brain cells in mice artificially lacking CASK. JNK-IN-8 itself isn't a drug candidate, but CASK Research has identified compounds with existing safety profiles and licenced drugs that could be repurposed. These have been tested in vitro and the team is exploring next steps. To financially support Dr Tabuchi's work, email info@caskresearch.org.

In 2022 our founder Laura Hattersley advocated for greater focus on epilepsy in CASK. Motivated by her daughter's prolonged diagnostic journey and multiple misdiagnoses, she approached Dr Asim Shahid at New York-Presbyterian Brooklyn Methodist Hospital. Dr Shahid pledged his support and has since initiated a US study focused on identifying biomarkers for epilepsy in CASK. A French team supported by Association Enfants CASK France is developing a complementary study. Together these efforts represent important progress towards better understanding, diagnosing and treating epilepsy within the CASK community.