Study Reveals Key Mechanisms of a Rare Form of Epilepsy

Article published by MedicalXpress

*Featuring work by CURE Epilepsy Grantees, Drs. Edward Cooper and Jeffrey Noebels

New research is advancing the understanding of KCNQ2 encephalopathy. “KCNQ2 encephalopathy is a rare neurodevelopmental disorder caused by variants in the KCNQ2 gene, which provides the recipe for a type of brain potassium channel,” explains lead author Timothy Abreo, a student in the Genetics and Genomics Graduate Program at Baylor College of Medicine, Houston, Texas, US. “The disorder usually manifests as seizures beginning within days after birth and developmental delays which are lifelong and without effective current treatment.” Newly identified variants in the KCNQ2 gene are hard to assess because not every variant is disease-causing, and the reasons some variants lead to illness have been poorly understood. The research team closely examined a specific genetic variant of the KCNQ2 gene involving a single amino acid change—glycine 256 changed to tryptophan (G256W)—on one copy of the KCNQ2 gene. They examined the structure and pathogenicity of the G256W variant using molecular, cellular, and in vivo approaches and uncovered evidence that G256 helps form a network of hydrogen bonds that serve to stabilize the structure of the pore-forming region of the potassium channel. “Taken together, our study reveals that the presence of KCNQ2 G256W variants affects both molecular and cellular aspects of KCNQ channel activity, including their ion-carrying capacity, expression, and placement within cells,” explains senior author Edward Cooper, Associate Professor of Neurology, Neuroscience, and Molecular and Human Genetics at Baylor College of Medicine. “Selective KCNQ2 openers, which counter the effects of G256W mutations should be tested in additional laboratory models and if effective, in humans with KCNQ2 disease-causing variants,” says Dr. Cooper.

Genotype–Phenotype Associations in Individuals with SCN1A-Related Epilepsies

Article published by Wiley Online Library

A recent study assesses data from a retrospective cohort of 1,018 individuals with SCN1A-related epilepsies, exploring how seizure characteristics, genetic variant type, position, and in silico scores relate to the epilepsy phenotype. Understanding genotype–phenotype associations in SCN1A-related epilepsies is critical for early diagnosis and management. Pathogenic variants in SCN1A, the gene coding for the alpha-1 subunit of the voltage-gated sodium channel, are associated with a range of epilepsy syndromes from relatively mild phenotypes in the genetic epilepsy with febrile seizures plus (GEFS+) spectrum to Dravet syndrome (DS), a severe developmental and epileptic encephalopathy. DS usually presents at approximately five–six months of age with prolonged, febrile and afebrile, hemiclonic or generalized clonic seizures. From age nine months to four years, other seizure types, including myoclonic, absence, and focal seizures, develop. Typical antiseizure medications have limited efficacy, and sodium channel blockers are associated with worse outcomes. From age two years, cognitive, behavioral, and motor development becomes significantly impaired. Epilepsies within the less severe GEFS+ spectrum also present early in life; however, cognitive development is normal. This large cohort study of patients with SCN1A variants provides evidence of associations between gene variant features and phenotype. This includes differences in age at seizure onset associated with different variant types, identification of specific regions within SCN1A associated with specific presentations, and initial status epilepticus as a predictive phenotypic marker for DS.

Study Looks at the Burden of Illness of Lennox–Gastaut Syndrome on Patients, Caregivers, and Society

Article published by Wiley Online Library

In a recent systematic literature review, researchers evaluated the global burden of illness of Lennox-Gastaut Syndrome (LGS) including clinical symptom burden, care requirements, quality of life, comorbidities, caregiver burden, economic burden, and treatment burden. LGS is a rare developmental and epileptic encephalopathy that is estimated to account for 1%–10% of childhood epilepsies. In the study, published articles with predetermined criteria were identified with 113 articles included for review. A high clinical symptom burden of LGS was identified including high seizure frequency and non-seizure symptoms such as developmental delay and intellectual disability, leading to low quality of life and substantial care requirements, with the latter including daily function assistance for mobility, eating, and toileting. Although based on few studies, a high caregiver burden was also identified, which was associated with physical problems including fatigue and sleep disturbances, social isolation, poor mental health, and financial difficulties. Most economic analyses focused on the high direct costs of LGS, which arose predominantly from medically-treated seizure events, inpatient costs, and medication requirements. Drug-resistant epilepsy was common, and many individuals required use of multiple medications and treatment changes over time. In summary, a high burden of LGS on individuals, caregivers, and healthcare systems was identified. The burden may be alleviated by reducing the clinical symptoms. These findings highlight the need for a greater understanding and better definitions for the broad spectrum of LGS symptoms and the development of treatments to alleviate non-seizure symptoms.

 

Fintepla Safely Reduces Seizures in Children Younger than 2, Study Finds

Article published by Dravet Syndrome News

Treatment with Fintepla (fenfluramine) appeared to be reasonably safe and lower seizure frequency in five children with Dravet syndrome who started on the therapy before they were two years old, scientists in Italy reported. These findings are noteworthy because in the US and European Union, Fintepla is approved for Dravet patients ages two and older. “We demonstrated that [Fintepla] used in patients younger than two years may offer excellent tolerability and a clinically significant reduction in seizure frequency,” the researchers wrote. The researchers highlighted that two of the children showed slight improvements in some measures of cognitive development after starting on Fintepla, in contrast to Dravet’s typical progression where cognitive development slows. Though the scientists stressed that it’s too early to make definitive conclusions, they said their study offers hope that reducing seizures in early life may help to protect cognitive development over time.

High-Powered Magnets on the Brain Help Control Seizures in Dravet Mice

Article published by Dravet Syndrome News

Treatment with a noninvasive procedure called transcranial static magnetic stimulation (tSMS) led to significantly less seizure activity in a mouse model of Dravet syndrome. “Our results show that tSMS, a non-invasive neuromodulatory technique, can reduce the number, duration, and severity of [seizures] in a mouse model of Dravet,” researchers wrote in the study. tSMS involves applying a powerful magnetic field to the skull. While it’s not known exactly how this affects brain activity, there is evidence suggesting it can reduce the overactivation of brain cells that can occur in people with Dravet syndrome causing seizures. “We believe that tSMS is emerging as an affordable, simple, safe and promising therapy for Dravet patients, alone or complementing the partial effectiveness that has been obtained with other treatments,” the researchers wrote. The researchers conducted two sets of experiments altering the amount of tSMS given, as well as a sham procedure. Results showed mice had fewer and shorter seizures while undergoing active tSMS; total time spent in seizures was reduced by about 72%. In the second set of experiments that utilized multiple rounds of tSMS, treated mice had about 86% less seizure activity. The researchers said these data could provide a useful benchmark for future work aiming to translate this approach into a treatment for people.  

Newer Antiseizure Medications (ASMs) Show Effectiveness in Dravet Syndrome

Article published by Dravet Syndrome News

Newer antiseizure medications (ASMs) for children and adolescents with Dravet syndrome reduced seizure frequency by at least 50% in clinical trials, according to a pooled analysis of study data. The recent study also compared the benefits and safety of such therapies, each of which is approved in the U.S. for patients ages two and older. Dravet syndrome is a severe epileptic brain disease in which symptoms typically emerge in the first year of life. It is characterized by hard-to-treat, lifelong seizures, intellectual disability, behavior disturbances, sleep disorders, and walking problems. With the approval of new ASMs in recent years, the management of Dravet-related seizures has changed. To better understand the overall impact of these changes, a team led by researchers in Italy pooled available evidence to evaluate the efficacy and tolerability of these newer ASMs. A database search revealed eight placebo-controlled trials that included 680 pediatric participants. Of these, 409 were randomly assigned an active add-on treatment, while 271 received a placebo. Add-on treatments included Diacomit® (stiripentol), Epidiolex® (cannabidiol), Fintepla® (fenfluramine), and the experimental therapy soticlestat. Diacomit® was associated with a 100% reduction in seizure frequency compared with the placebo, while Epidiolex® was linked to a lower rate of adverse events than Diacomit® and Fintepla®. The data gathered in this study will allow healthcare providers “to have reliable data and enable discussion with caregivers of people with [Dravet syndrome] about the expected outcomes” of these medications, the team wrote.

 

CURE Epilepsy Update November 2023

Greetings Epilepsy Community,

We are in the midst of Epilepsy Awareness Month and Thanksgiving is only a few short days away. There is much to update you on!

Some highlights from our incredibly busy month so far . . . We kicked off November with Epilepsy Awareness Day at Disneyland, which was fantastic! There were many, many opportunities for families to gather information on treatments, advancements, and support services. We moderated an inspiring session on a new regenerative cell therapy in development for mesial temporal lobe epilepsy, recorded two episodes of Seizing Life, and showcased board member Kelly Cervantes’ new book Normal Broken. The following week, I had the privilege of attending the Isaiah Stone Foundation Golf Tournament in Oklahoma City and joining them in increasing awareness of the prevalence and impact of epilepsy while raising funds and enjoying a beautiful day. We also supported our CURE Epilepsy Champions running the NYC Marathon and celebrated the first annual Jeavons Syndrome Awareness Day.  And just this week, we participated in a Congressional Briefing by the bipartisan Epilepsy Caucus in Washington DC. All of this and it is only the middle of November!

As we prepare to celebrate Thanksgiving next week and the blessings that we have in our lives, I want to take a moment and thank you. Thank you for opening and reading this CURE Epilepsy Update. Thank you if you have been a CURE Epilepsy Champion or have run with Team CURE Epilepsy in a marathon. Thank you for following us on social media and helping spread epilepsy awareness as well as the need for more epilepsy research with your network. Thank you to SK Life Science for their generosity in matching all of the donations made during Epilepsy Awareness Month up to $50k. Thank you for choosing to support CURE Epilepsy on Giving Tuesday. Thank you for sharing our vision to live in a world without epilepsy. Thanks to all of you, we are closer now than we have ever been before.

Have a wonderful Thanksgiving holiday!

With gratitude,


In this CURE Epilepsy Update, please find information on:


Epilepsy Awareness Month

This Epilepsy Awareness Month, CURE Epilepsy is highlighting the journey 1 in 26 people will go through at some point in their lifetime — the epilepsy journey. We’ve already uncovered the first and second points along the journey. Check out the event page for resources on Starting the Epilepsy Journey and Working Towards a Diagnosis, and check back every Monday during Epilepsy Awareness Month for a new point to be uncovered with additional resources.

See the Epilepsy Journey

 

 


Giving Tuesday Save the Date

Giving Tuesday, a global day of giving, is just around the corner. You can easily add the event to your calendar for ease below, or you can donate early now! Thanks to the generosity of SK Life Science, all donations through Epilepsy Awareness Month will be matched up to $50,000! Donate today and you can double your impact.

Donate Now

 

 

 

Add Giving Tuesday to your calendar now!

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Recap of the First-Ever Jeavons Syndrome Awareness Day

As part of the work that CURE Epilepsy is doing to jump-start conversations on Jeavons syndrome, we were excited to launch an annual awareness day this year on November 13 to draw attention to this little-researched rare epilepsy.  Learn more about Epilepsy with Eyelid Myoclonia (EEM), formerly known as Jeavons syndrome, on the event page or read a personal story of a young woman with Jeavons syndrome here.

 

Learn More

 


What’s New from the Seizing Life® Podcast

Epilepsy in Women: Challenges, Concerns, and Considerations

 

Dr. Elizabeth Gerard, epileptologist and Director of the Women with Epilepsy Program at Northwestern Medicine’s Comprehensive Epilepsy Center, about the unique concerns specific to women living with epilepsy. From puberty to menstruation, contraception, pregnancy, and menopause, we explore managing epilepsy through all stages of a woman’s life.

Watch or Listen

 

 

NYC Marathoner Achieves Seizure Control and Runs for Epilepsy Research

 

Kelly speaks with Peter Burpee, who experienced absence epilepsy in childhood and tonic-clonic seizures in his teen years. Peter has gained seizure control and just ran for Team CURE Epilepsy in the NYC Marathon to raise money for epilepsy research.

Watch or Listen

 

 

Watch these and all of our upcoming Seizing Life episodes here.


Epilepsy Awareness Month Sale in the CURE Epilepsy Store

 

Enjoy 20% off all orders over $50 during Epilepsy Awareness Month in the CURE Epilepsy Store! Sale ends December 1.

 

 

 

Shop Sale


Please mark your calendar for the following key dates in the epilepsy community:

  • January 1 – December 31, 2023 – CURE Epilepsy’s 25th Anniversary
  • November – Epilepsy Awareness Month
  • December 1-7 – Infantile Spasms Awareness Week

 

1 in 26 individuals will be impacted by epilepsy in their lifetime.
Each person has their own story.

Read Nora’s Story

 

CURE Epilepsy Update October 2023

Greetings Epilepsy Community,

I hope that you are all enjoying the cooler temperatures, fall activities, and at least where we are, spectacular fall foliage. The end of the year is a very busy time for the epilepsy community, and this year is no different. In October alone, we have hosted a special New York City event, a Hamilton raffle, two Treatment Talks, and many CURE Epilepsy Champion events. On a personal note, my son is a CURE Epilepsy Champion and ran the Chicago Marathon for us last year. This weekend, he will be running the Marine Corps Marathon in Washington DC to raise funds for post-traumatic epilepsy research, which is important for our wounded veteran community. It will be a special race for him as he is a 1stLt in the Marine Corps. You can support his run here. As a CEO and a proud mother, I am honored to have each and every one of you supporting us as we continue our mission to find a cure for epilepsy.

As we enter the final months of our 25th anniversary year, we are undertaking exciting strategic planning and visioning on the next chapter for the organization. As we think about how to update our messaging and improve our website, we would appreciate your participation in an anonymous five-to-ten-minute brand and website survey. Thank you in advance for helping us serve the epilepsy community in ways that continually evolve to meet new needs!

Finally, as many of you know, Sudden Unexpected Death in Epilepsy (SUDEP) Action Day took place last week. It is an important day within our community to both increase education and raise awareness among those unfamiliar with this devastating and often not talked about outcome. Since CURE Epilepsy pioneered the first SUDEP research almost 20 years ago, we have funded initiatives that study why SUDEP occurs and how it can be prevented. Just as I look forward to a day when we have a world without epilepsy, I look forward to a time when no individual passes away due to SUDEP. Until that day comes, I encourage you to review our SUDEP Action Day resources and share them with your family and friends. Doing so might save a life.

With a commitment to inspire hope and deliver impact.


In this CURE Epilepsy Update, please find information on:


Brand and Website Survey

We want your feedback! Please complete this short survey about our communications and website to help us evolve and improve our resources.

Take Survey

 

 

 

 


Over $275,000 Raised for Future Research Thanks to Hamilton Unplugged!

Thank you to everyone who was in The Room Where It Happened on Monday, October 23 for Hamilton Unplugged! With your help, we raised over $275,000 for critical epilepsy research. Guests enjoyed a phenomenal performance by Miguel Cervantes and his Broadway friends, including never-before-seen musical mashups, hilarious behind-the-scenes stories from the Hamilton stage, and more.

 

 

 


Thank You to Our CURE Epilepsy Champions

Thank you to our recent CURE Epilepsy Champions who have helped us raise critical epilepsy research funds and who are getting us closer to completion of the 25th Anniversary Champions Challenge – raising $425K for 25 years! Kris Sadens ran, biked, and swam in honor of his son Silas and the 10-year anniversary of Silas’ diagnosis, by participating in the Chicago Triathlon. Erin Monast, her daughter Reagan, and her family hosted the second annual Reagan’s Run, a 5K and 1-mile fun run in Eastern Pennsylvania. Champions also got out their golf clubs from coast to coast to raise funds and awareness for epilepsy in two separate events. The 5th annual Commish Open, in memory of Aiden Nichols Long, was held on September 27 in Maryland and the 3rd annual Epilepsy Awareness Golf Tournament honoring Colton Grothe and Joey Hart in Willamette Valley Oregon was held on October 9.

If you would like more information about the Champions Challenge or hosting your own unique fundraising event, click here. Every participating Champion host will receive a free raffle entry for one trip for a family of four to Epilepsy Awareness Day 2024 at Disneyland California, including airfare, hotel, epilepsy expo, and park tickets. Also, every Champion host who raises over $1,000 will receive a CURE Epilepsy Treasure Pack, with merchandise to help show your CURE Epilepsy pride.

Become a CURE Epilepsy Champion


CURE Epilepsy Discovery: Leading the Charge on Research and Awareness of Sudden Unexpected Death in Epilepsy

In our latest CURE Epilepsy Discovery, we showcase CURE Epilepsy’s work within the SUDEP space. Over the past 25 years, CURE Epilepsy has funded transformative science and significantly furthered awareness of SUDEP, and we will continue to prioritize this important area of research going forward in hopes of eventually preventing this tragic outcome. Read about some of the research and projects we have funded.

Read this Discovery

 

 


Treatment Talks on Seizure Emergencies and Childhood Absence Epilepsy Now Available

Two new Treatment Talks were recently released! In the Treatment Talk Diagnosis, Treatment, and Prognosis of Childhood Absence Epilepsy, viewers learn about absence epilepsy, including how it is diagnosed, current treatments available for childhood absence epilepsy, the prognosis for those diagnosed with childhood absence epilepsy, and some of the current research that is occurring in the field. In our Treatment Talk Seizure Emergencies: Delivery Methods and Treatment Options, viewers learn about seizure emergencies, the different delivery options that are available for current rescue medications, and how the recent medications on the market have become more convenient and effective treatment options for seizure emergencies.

 

Watch Childhood Absence Epilepsy Treatment Talk

Watch Seizure Emergencies Treatment Talk


What’s New from the Seizing Life® Podcast

Infantile Spasms Diagnosis and Treatment Journey Inspires Children’s Book

 

Kate Kostolansky shares her daughter Charlotte’s infantile spasms journey and explains how these experiences inspired a children’s book designed to help newly-diagnosed families and those around them better understand infantile spasms.

Watch or Listen

 

 

Searching for Answers, Providing Support, and Understanding Grief After the Death of a Child

 

In observance of SUDEP Action Day on October 18, we spoke with Dr. Richard Goldstein, Associate Professor of Pediatrics at Harvard Medical School, about the program he directs conducting research into both Sudden Unexpected Death in Pediatrics (SUDP) and the grieving process of bereaved parents.

Watch or Listen

 

 

Watch these and all of our upcoming Seizing Life episodes here.


The CURE Epilepsy Store

 

Check out the CURE Epilepsy Store to get apparel or accessories to raise epilepsy awareness in time for Epilepsy Awareness Month!

 

 

 

Shop Now


Please mark your calendar for the following key dates in the epilepsy community:

  • January 1 – December 31, 2023 – CURE Epilepsy’s 25th Anniversary
  • October 31- November 1 – Epilepsy Awareness Day at Disneyland
  • November – Epilepsy Awareness Month
  • November 13 – Jeavons Syndrome Awareness Day
  • December 1-7 – Infantile Spasms Awareness Week

 

1 in 26 individuals will be impacted by epilepsy in their lifetime.
Each person has their own story.

Hear Dylan’s Story

 

Epilepsy Research News: September 2023

This issue of Epilepsy Research News includes summaries of articles on:

 

 

The Cerebellum as a Source of Generalized Convulsive Seizures

A recent study provides new insights into how convulsive seizures happen, implicating a “circuit” in the brain, specifically a connection of neurons between the cerebellum and thalamus, in driving convulsive seizures. To investigate the importance of this circuit in causing seizures, the team utilized a technique called optogenetic imaging to record the activity of neurons in the brain before, during, and after convulsive seizures. The team found that a group of neurons in a specific area of the thalamus called the ventral posteromedial nucleus were initiating convulsive seizures. The team then found that neurons in the cerebellum that connect to this area of the thalamus not only significantly contribute to the seizures, but that blocking activity from the cerebellum to the thalamus blocked seizures from occurring. The team noted that the findings not only deepen the understanding of how seizures originate but also create the possibility of targeting this cerebellum-thalamus circuit to treat convulsive seizures.

Learn More

 

Examining the Benefit of Rapid Genome Sequencing for Infantile Epilepsy

A recent study shows that rapid genome sequencing (a process that looks for changes across the entire genome) can provide a rapid diagnosis of genetic mutations and influence clinical care of infants with new-onset epilepsy. As part of this study, researchers sequenced the genomes of 100 infants with unexplained seizures along with their parents to better understand the potential diagnostic value of this approach for infantile epilepsy. The researchers found that across all children enrolled in the study, 43% received a diagnosis within weeks, and that diagnosis impacted the medical outcomes in nearly 90% of those cases, guiding treatment options for over half. This study provides an initial framework for further investigation of the long-term benefits of early genetic diagnosis in infants, and the potential use of targeted “precision” treatments that are specific to an infant’s genetic diagnosis.

Learn More

 

Large Genetic Study Provides Insights on Why Epilepsy Develops and Potential Treatments

The largest genetic study of its kind has discovered specific changes in our DNA that increase the risk of developing epilepsy. The research advances our knowledge of why epilepsy develops and may inform the development of new treatments for the condition. The researchers identified 26 distinct areas in our DNA that appear to be involved in epilepsy. This included 19 which are specific to a particular form of epilepsy called genetic generalized epilepsy. They were also able to identify 29 genes within these DNA regions that probably contribute to epilepsy. The researchers also showed that many of the current medications for epilepsy work by targeting the same epilepsy risk genes that were highlighted in the study. Furthermore, based on their data, the researchers were able to propose some potentially effective alternative drugs. The researchers noted that these discoveries, only achieved through international collaboration, help us to better understand the genetics of this type of epilepsy and potential treatments.

Learn More

 

Preventive Epilepsy Treatment with Vigabatrin Does Not Improve Neurocognitive Development in Infants with Tuberous Sclerosis Complex (TSC)

In new study results, researchers found that administering the preventive epilepsy treatment vigabatrin (Sabril ®) prior to seizure onset did not improve neurocognitive outcomes in TSC infants at two years of age. In the original results, this study (known as the PREVeNT trial) showed that preventative treatment delayed the start and lowered the number of infantile spasms in infants with TSC. This study enrolled 84 infants with TSC between 2016 and 2020, who had been diagnosed with TSC either through prenatal testing, physical examination, or genetic testing, but had yet to have any seizures. Infants who developed a specific EEG biomarker that indicates a risk of developing seizures were then placed in two groups, one receiving preventative vigabatrin treatment and one receiving a placebo. In this new study, the researchers found that infants who received vigabatrin still had drug-resistant epilepsy at 24 months, that focal seizures remained prominent in the infants, and there was no benefit in cognitive outcomes. The researchers state that these findings indicate the need to develop more effective therapies to treat cognitive and behavioral dysfunction in TSC.

Learn More

 

Advances in Cannabidiol (CBD) for Epilepsy Treatment and Prevention

A series of recently published articles details new breakthroughs in the field of medical cannabinoids for epilepsy and seizure disorders. Two publications review the effectiveness of CBD, a compound found in cannabis, in treating epilepsy and seizures. Another publication in the series describes the results of a meta-analysis (a type of study that reviews and combines the results of multiple other studies) to determine the overall effectiveness and safety of CBD treatment in children with genetic epilepsies such as Dravet syndrome, Lennox-Gastaut syndrome, and Tuberous Sclerosis Complex. This analysis revealed that CBD was effective in managing these genetic epilepsies, albeit with an increase in adverse events such as diarrhea, somnolence, sedation, and potential drug interactions. A separate publication showed potential effects of CBD as a prevention against seizures that are similar to those associated with temporal lobe epilepsy. Together, these publications provide information on the use of CBD in the treatment of epilepsy and open up the possibility of utilizing CBD in individuals at risk for developing epilepsy.

Learn More

CDKL5-Mediated Developmental Tuning of Neuronal Excitability and Concomitant Regulation of Transcriptome

Abstract found on PubMed

Cyclin-dependent kinase-like 5 (CDKL5) is a serine-threonine kinase enriched in the forebrain to regulate neuronal development and function. Patients with CDKL5 deficiency disorder (CDD), a severe neurodevelopmental condition caused by mutations of CDKL5 gene, present early-onset epilepsy as the most prominent feature. However, spontaneous seizures have not been reported in mouse models of CDD, raising vital questions on the human-mouse differences and the roles of CDKL5 in early postnatal brains. Here, we firstly measured electroencephalographic (EEG) activities via a wireless telemetry system coupled with video-recording in neonatal mice. We found that mice lacking CDKL5 exhibited spontaneous epileptic EEG discharges, accompanied with increased burst activities and ictal behaviors, specifically at postnatal day 12 (P12). Intriguingly, those epileptic spikes disappeared after P14. We next performed an unbiased transcriptome profiling in the dorsal hippocampus and motor cortex of Cdkl5 null mice at different developmental timepoints, uncovering a set of age-dependent and brain region-specific alterations of gene expression in parallel with the transient display of epileptic activities. Finally, we validated multiple differentially expressed genes (DEGs), such as glycine receptor subunit 2 and cholecystokinin, at the transcript and/or protein levels, supporting the relevance of these genes to CDKL5-regulated excitability. Our findings reveal early-onset neuronal hyperexcitability in mouse model of CDD, providing new insights into CDD etiology and potential molecular targets to ameliorate intractable neonatal epilepsy.