A New Hope for Genetic Epilepsy Patients: Boosting a Missing Enzyme


Epilepsy is a neurological disorder that affects millions of people around the world. It causes recurrent seizures that can interfere with daily life and pose serious health risks. While there are many types of epilepsy, some are caused by genetic mutations that impair the function of certain enzymes in the brain. One of these enzymes is CDKL5, which is involved in regulating the activity of nerve cells and synapses.

What is CDKL5 deficiency disorder?

CDKL5 deficiency disorder (CDD) is one of the most common forms of genetic epilepsy. It is caused by a mutation or deletion of the CDKL5 gene, which produces the CDKL5 enzyme. This enzyme phosphorylates proteins, meaning it adds an extra phosphate molecule to change their function. CDKL5 is especially important for the development and maturation of the brain, as it affects the formation and stability of synapses, the connections between nerve cells.

CDD affects mainly children, who start having seizures in the first few months of life. They also have severe developmental delays, intellectual disability, and autism-like features. There is no cure for CDD, and the available medications can only manage the symptoms, not the underlying cause.

How can CDKL5 be replaced?

Scientists at the Francis Crick Institute in London have found a new way to potentially treat CDD by boosting the activity of another enzyme that can compensate for the loss of CDKL5. Their research, published in Molecular Psychiatry, was based on studying mice that lack the CDKL5 enzyme. These mice show similar symptoms to human patients with CDD, such as impaired learning and social interaction.

CDKL5 deficiency disorder

The researchers discovered that CDKL5 is not the only enzyme that can phosphorylate a protein called EB2, which is known to be a target of CDKL5. They identified another enzyme, called CDKL2, that can also do the same thing. CDKL2 is present in human neurons, and it can phosphorylate about 15% of the EB2 protein, even when CDKL5 is absent. The researchers hypothesized that increasing the level of CDKL2 in the brain could restore some of the EB2 phosphorylation that is lost due to CDKL5 deficiency, and thus improve the function of the nerve cells and synapses.

What are the implications of this finding?

The finding of a potential way to replace CDKL5 with CDKL2 is a promising step towards developing a targeted therapy for CDD. It suggests that by stimulating the production or activity of CDKL2, it might be possible to correct some of the effects of CDKL5 deficiency on the brain, especially in early development. This could lead to better outcomes for the patients, such as reduced seizures, improved cognition, and enhanced social skills.

However, the research is still in its early stages, and more studies are needed to confirm the role and safety of CDKL2 in CDD. The researchers are now working on testing whether increasing CDKL2 in mice can actually improve their symptoms. They are also collaborating with biotechnology companies to find molecules that can increase CDKL2 for potential new medicines for CDD.

Why is this research important?

This research is important because it sheds light on the molecular mechanisms of CDD, one of the most common and devastating forms of genetic epilepsy. It also opens up new avenues for exploring novel treatments that could target the root cause of the disease, rather than just the symptoms. It is a hopeful sign for the patients and their families, who are eagerly waiting for a breakthrough in the field of epilepsy research.


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