February 2026 Research Update

In a small group of girls with CDKL5 deficiency disorder, adding highly purified cannabidiol (CBD) was linked to a strong drop in seizures early on, but this benefit became much less consistent by 12 months. [1]

At 3 months, most participants had their motor seizures reduced by more than half, and caregivers and clinicians also reported overall improvement around that time. By 6 months fewer children met the same seizure-reduction mark, and by 12 months only a small minority still did, suggesting the seizure response may fade for many people over longer follow-up. [1]

Side effects were common in this report but were not considered serious, and one person stopped CBD due to a skin rash. The study also measured CBD blood levels, but it did not establish a clear way to use those levels to predict who would keep benefiting over time. [1]

This adds to the picture that CBD can be linked to meaningful seizure reduction for some people with CDKL5 deficiency disorder, especially in the first few months, while longer-term seizure control may be harder to sustain. Because this was an open-label study in 9 girls and did not include a comparison group, it cannot show how much of the change was due to CBD versus other factors, but it helps clarify what families and researchers might watch for in longer studies: early response, whether it lasts, and tolerability. [1]

This month, several early studies tested different ways to reduce brain network overactivity or replace CDKL5 function, but all of them were done in laboratory or animal models rather than in people. Together, they point to multiple possible paths for future therapies, while also showing that delivery and model-specific differences remain major challenges. [2] [3] [4]

In patient-derived mini-brain tissue (cortical organoids), a gene therapy strategy designed to let treated cells share CDKL5 with nearby cells produced broader improvements than standard CDKL5 delivery. The organoids showed stronger recovery of cell survival, nerve cell markers, and electrical network activity with the secretable Igk-TATk-CDKL5 approach, although the therapy still reached only limited regions of the organoids. [2]

In a Cdkl5 knockout mouse model, researchers focused on KCC2, a protein involved in keeping brain signaling balanced, and found signs of reduced KCC2 activity during early development. Treating young mice with the KCC2 activator OV350 reduced infantile spasms, and mice treated early were later reported to have lower seizure susceptibility and better thinking and behavior measures as adults. [3]

A separate mouse study tested seizures triggered by sound and found that loud sound stimulation caused very severe seizures in many Cdkl5 knockout males, while most heterozygous females survived the same challenge. The same report also observed spontaneous seizures in only a subset of knockout mice during long-term video-EEG monitoring, highlighting that seizure patterns can vary even within a single model. [4]

These findings mainly matter as early research because they were not tested in people with CDKL5 deficiency disorder. They help clarify which biological targets and delivery strategies might be worth testing next, such as approaches that spread CDKL5 function beyond directly treated cells or approaches that aim to rebalance brain excitation and inhibition through KCC2. What remains uncertain is whether these benefits in organoids or mice would translate to improvements in seizures or development in patients, and what the safest and most effective timing and delivery methods would be. [2] [3] [4]

This month added a clearer, more detailed explanation of how CDKL5 may support learning-related connections between brain cells, and what might go wrong when CDKL5 is altered. The work points to CDKL5 helping organize key synapse proteins into small clusters that allow synapses to strengthen, and disease-linked changes can disrupt this clustering. [5]

In lab experiments, CDKL5 was reported to form droplet-like clusters (called liquid-liquid phase separation) and to cluster together with PSD95, a scaffolding protein at excitatory synapses. This clustering helped recruit Kalirin7 and supported dendritic spine enlargement, a process related to synapse strengthening, while disease-associated mutations interfered with cluster formation. [5]

This is basic science, so it does not change diagnosis or treatment now, but it helps explain the "why" behind some CDKL5-related brain differences. By tying CDKL5 mutations to a specific problem in how synapses organize and adapt, it gives researchers a more concrete set of steps to target or measure in future therapy development. What remains uncertain is how directly these synapse changes connect to day-to-day symptoms in people and whether fixing this process would improve seizures or development. [5]

A small hospital-based report reinforced that CDKL5 deficiency disorder often begins with seizures in infancy and is linked with significant developmental challenges, while also suggesting some differences between girls and boys in certain behaviors. The overall pattern was severe, hard-to-control epilepsy and broad developmental impact across both sexes in this cohort. [6]

In 12 children, seizures started on average around 6 months, with tonic seizures and epileptic spasms being common early types, and many children later fit patterns such as West syndrome or Lennox-Gastaut syndrome. Brain imaging often showed changes such as volume loss or white matter lesions, and the report described substantial developmental impairment, with repetitive motor behaviors and regression reported more often in females than males. [6]

This kind of study matters most for understanding what CDKL5 deficiency disorder can look like in real-world care, rather than testing a new therapy. It helps clarify that early-onset epilepsy and major developmental needs were common in this group, and it raises the possibility of sex-related differences in features like repetitive movements or loss of skills. What remains uncertain is how well these patterns apply to all families, because the cohort was small and came from a single center. [6]