CDKL5 Deficiency Disorder: The Early-Onset Seizure Condition Once Grouped With Rett Syndrome

Table of Contents

1. The Gene and Its Protein
2. How the Condition Was Separated From Rett Syndrome
3. Age of Seizure Onset and Seizure Patterns
4. Development and Movement
5. Vision
6. Feeding, Digestion, Sleep and Breathing
7. Differences Between Girls and Boys
8. Diagnostic Criteria as Reported
9. Ganaxolone: The Marigold Trial
10. The FDA Label for Ganaxolone
11. Cannabidiol and Cannabis Products as Reported
12. The Ketogenic Diet as Reported
13. Other Drugs, Devices and Surgery as Reported
14. Gene Therapy and Protein Replacement Research
15. Natural History Studies and Quality of Life
16. What Is Not Known
17. Key Research Papers
18. Connections
19. Featured Videos

The Gene and Its Protein

The gene is cyclin-dependent kinase-like 5, written CDKL5. It sits on the short arm of the X chromosome at position Xp22.13 and has 20 coding exons (Liang 2019). Older papers call it by a former name, serine/threonine kinase 9, or STK9.

The protein it makes is a kinase, an enzyme that attaches phosphate groups to other proteins and so changes how they behave. A 2005 laboratory study showed that the CDKL5 protein phosphorylates itself and helps phosphorylate the Rett syndrome protein MeCP2, and that the two proteins interact (Mari 2005). A 2019 clinical review describes the protein as widely expressed in the brain, mainly in nerve cells, with roles in cell multiplication, the migration of nerve cells, the growth of their long and branching extensions, and the development of synapses (Olson 2019).

The disease-causing changes reported include deletions, truncations that cut the protein short, splice changes and single-letter missense changes. The same review reports that disease-causing missense changes occur only within the kinase domain, the working part of the enzyme, or at splice sites (Olson 2019). A 2024 paper puts the number of reported disease-causing variants at more than 300 (Amato 2024).

In a girl with one working X chromosome and one altered one, each cell silences one of the two X chromosomes. The 2003 report that first tied this gene to disease found the gene is subject to this silencing in ordinary female body cells, and that in two severely affected girls the normal copy was preferentially silenced (Kalscheuer 2003). Most girls with the condition therefore have a mix of cells, some with working protein and some without. A 2025 gene-therapy paper names this mosaic as the reason dosage is a concern, as covered further down (Medici 2025).

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How the Condition Was Separated From Rett Syndrome

The first report came in 2003: two severely affected girls with chromosome rearrangements that broke the STK9 gene, both with early infantile spasms, a profound halt in development and a chaotic brain-wave pattern called hypsarrhythmia (Kalscheuer 2003). A 2022 review dates CDKL5's identification as a cause of human disease to 2004 (Leonard 2022), the year two papers appeared together in one journal issue. One described a family whose daughter's picture overlapped with Rett syndrome, her identical twin with autistic disorder and mild-to-moderate intellectual disability, and a brother with profound intellectual disability and seizures (Weaving 2004). The other reported new missense changes in the kinase domain in children with early infantile spasms and features overlapping Rett and Angelman syndromes (Tao 2004).

In 2005 a study of two patients linked the gene to the "early seizure variant" of Rett syndrome and placed the two proteins in the same molecular pathway (Mari 2005). A 2010 paper proposed clinical criteria for that variant from nine girls: six necessary and eight supportive items, with epilepsy beginning between the first week and 5 months of life, hand stereotypies and severe low muscle tone among the necessary ones (Artuso 2010). The revised Rett syndrome criteria published the same year still used "atypical Rett syndrome (early seizure variant)" as an example label, while noting that children with CDKL5 changes lack some distinctive Rett features, such as the clear period of regression and the intense eye gaze (Neul 2010).

The evidence for separation built up in comparison studies:

• A 2008 series of 20 girls found some Rett features, such as slowing of head growth and hand stereotypies, but not the course of near-normal early development followed by regression, nor the characteristic intense eye communication (Bahi-Buisson, Brain 2008).
• A 2013 international database study compared 86 people with CDKL5 changes with 920 females with MECP2 changes. Fewer than one quarter met the criteria for the early-seizure Rett variant. Seizures and sleep disturbance were more common than in the MECP2 group, while regression and spinal curvature were less common. The authors concluded that the condition is separate from Rett syndrome rather than a variant of it (Fehr 2013).
• A 2016 database comparison found epilepsy, digestive problems and sleep abnormalities more common than in Rett syndrome, and scoliosis and breathing problems less common (Mangatt 2016).
• A 2020 head-to-head comparison of 793 people across four related disorders found CDKL5 deficiency disorder the most severely affected group, with the youngest age at seizure onset (2 months). Seizures before the baseline visit were reported in 96.2%, against 47.5% in Rett syndrome. Regression occurred in all Rett participants, at a median of 18 months, but in only 23 to 34% of those with the other disorders (Cutri-French 2020).

It is now classified as a developmental and epileptic encephalopathy (Leonard 2022), a term for severe epilepsies that begin in infancy or childhood with developmental delay (Dudley 2026). More on the MECP2 condition is on the Rett syndrome page.

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Age of Seizure Onset and Seizure Patterns

Early onset is the most consistent finding. In an international database of 204 people, the median age at the first seizure was 6 weeks, with a range from 1 day to 65 weeks (Lim 2017). The 2022 review describes onset generally within the first 2 months (Leonard 2022).

A small 2008 series of 13 children proposed three stages:

• Early epilepsy, starting at 1 to 10 weeks, with frequent convulsive seizures and yet a normal brain-wave recording between seizures in 10 of 13.
• Epileptic encephalopathy with infantile spasms and hypsarrhythmia, seen in all 8 children for whom this stage was recorded.
• At the time of evaluation, 7 were seizure free and 6 had developed hard-to-control epilepsy, 5 of those 6 with tonic seizures and myoclonic jerks (Bahi-Buisson, Epilepsia 2008).

Later and larger work changed that picture somewhat. In a cohort of 92 people, 81% developed epileptic spasms but only 47% of those also had hypsarrhythmia. A previously described sequence of hypermotor movements, tonic stiffening and spasms was seen in 24%, while 56% had seizures with several phases, often tonic stiffening and spasms together. Forty-three percent had a seizure-free period lasting from 1 to more than 12 months, and only 6% were still seizure free at their last visit (Demarest 2019).

A long-term study of 22 people also described three phases, with focal motor seizures in all of them early on, many types of seizure persisting throughout, and myoclonic seizures and spasms lessening in the long-term phase while tonic seizures appeared in the last two phases (Darra 2023). A 2026 study of 152 brain-wave recordings from 48 children under 2 years found the recordings became more abnormal with age. Spasms peaked at 7.5 to 11.5 months and tonic seizures at 6.5 to 14 months, and sequences of tonic seizures followed by spasms were most often seen between 7 and 11 months (Tokatly Latzer 2026). In two of eight children in a small series, recordings of a so-called tonic seizure revealed a tonic phase, then a clonic phase, then a cluster of spasms, which the authors propose as an early diagnostic clue (Melikishvili 2019).

One recent observation is unusual. In a 2026 national survey in China with seizure diaries from 84 people, 47 (56.0%) had significantly fewer seizures during fevers, 27 (32.1%) of those with daily seizures had at least one seizure-free day, and 20 (23.8%) had fewer seizures after the fever passed, for more than 2 weeks in 6 (Wang 2026). Fever brings seizures on in many other childhood epilepsies, as the febrile seizures page describes. This is a single cross-sectional survey based on questionnaires and diaries.

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Development and Movement

Most children have severe developmental delay from birth (Fehr 2013). Low muscle tone, called hypotonia, is one of the key early signs (Bahi-Buisson, Brain 2008). The 2022 review reports that only a quarter of girls and a smaller share of boys learn to walk independently, and it stresses that there is real variation between children, probably related to the genetic change involved (Leonard 2022). Hand stereotypies that severely affect grasping are described (Artuso 2010). Reports on head growth differ: one 2008 series describes slowing of head growth (Bahi-Buisson, Brain 2008), while a small 2010 series found head circumference within the normal range in most children (Artuso 2010).

Movement disorders are reported beyond the epilepsy. Across four United States centres, 35 of 154 individuals (23%) were described as having one, most often choreoathetosis (involuntary writhing movements) in 16, dystonia in 7 and dyskinesia in 4 (Olson 2021, Journal of Neurodevelopmental Disorders). In a Japanese series, involuntary movements were noted in 15 of 29 (Kobayashi 2021).

Behaviour has been less studied. A long-term series of 22 people noted severe behavioural disturbance in 8 and autistic-like features in 14 (Darra 2023). A small 2024 study of 15 people noted some less expected findings, including large head size, congenital digestive malformations and spinal cord abnormalities, in a sample its authors describe as limited (Amato 2024).

Communication and motor skills carry the most weight in a 2025 global severity score built from 206 people aged 3 months to 40 years (Jacoby 2025).

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Vision

Many children have cerebral visual impairment, meaning the eyes themselves may be healthy but the brain does not process what they see in the usual way. It was present in 75% of the 92 people in the 2019 cohort, and it was correlated with reaching fewer developmental milestones (Demarest 2019). The 2022 review reports that the prevalence appears higher than in other developmental and epileptic encephalopathies (Leonard 2022).

In a detailed eye study of 26 children, cerebral visual impairment was diagnosed in all those over 2 years of age. Strabismus was found in 24 and nystagmus in 10. Sharpness of vision was lower than expected for age, improved over the first 3 years, and was higher in children who could get around than in those who could not (Olson, Developmental Medicine and Child Neurology 2021). A study of 46 children found that a higher severity score for cerebral visual impairment went with lower developmental achievement, and proposed it as a possible early marker of severity (Brock 2021).

Vision also interests researchers because it can be measured. In mice lacking the gene, defects in the brain's response to visual signals appeared from about 4 weeks of age and persisted into adulthood, which the authors propose as a biomarker for testing treatments (Mazziotti 2017).

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Feeding, Digestion, Sleep and Breathing

Feeding problems are common. In a 2021 United States cohort, at least 40 of 92 people with available data (43.5%) had a gastrostomy tube, a feeding tube placed through the abdominal wall into the stomach. Of 24 who had a swallow study, 14 (58.3%) showed difficulty swallowing with a risk of food or liquid entering the airway. The same paper cites earlier database figures of 20.7% fed only by tube (Olson 2021, Journal of Neurodevelopmental Disorders). Digestive problems, breathing problems, epilepsy and scoliosis all became more likely with age in the international database (Mangatt 2016).

Sleep disturbance was reported at some point in 61 of 86 individuals (71%) in the 2021 cohort, and 40 of 126 (32%) used sleep medication. Melatonin was the most common, given to 30, of whom 10 reported better sleep (Olson 2021, Journal of Neurodevelopmental Disorders). A sleep-laboratory study of four girls found little dream-stage sleep, frequent waking not caused by breathing pauses or seizures, and low sleep efficiency. Two of the four had episodes of fast breathing followed by pauses in breathing while awake (Hagebeuk 2013).

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Differences Between Girls and Boys

Most people diagnosed are girls. Eighteen of 92 (19%) in the 2019 cohort were male (Demarest 2019), and 79.2% of the children in the Marigold trial were female (Downs 2024). Boys have one X chromosome, so a change present from conception affects the gene's only copy in every cell.

Early reports of boys were sparse: only 10 had been described by 2013, when a diagnostic laboratory added 8 from sequencing 266 boys (Mirzaa 2013). A 2021 review counted 45 published boys and added 5 more (Siri 2021). Reported differences include:

• Severity: boys with the condition have been reported as more severely affected. A Japanese series of 29 found boys had lower motor attainment and more brain shrinkage on imaging (Kobayashi 2021), and a review of 166 published cases along with 4 new ones reached a similar conclusion (Liang 2019).
• Sleep and breathing: boys were more vulnerable to these problems in the international database (Mangatt 2016).
• Mosaicism: when the change arises after conception, so that only some cells carry it, the effects may be milder (Siri 2021).
• Not every feature differs: in the 92-person cohort, spasms, seizure-free periods and cerebral visual impairment were not associated with sex (Demarest 2019).

Whether the pattern of X-chromosome silencing explains differences between girls is unsettled. One 2008 series found severity did not correlate with it (Bahi-Buisson, Brain 2008), while a 2021 review lists it among the factors believed to contribute (Siri 2021).

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Diagnostic Criteria as Reported

The diagnosis today rests on genetic testing plus the clinical picture. In 2019 minimum criteria were proposed by clinicians at specialist centres (Olson 2019). As restated in a 2021 paper from the same network, they are:

• a pathogenic or likely pathogenic variant in CDKL5,
• epilepsy beginning within the first year of life, and
• motor and cognitive developmental delays (Olson 2021, Journal of Neurodevelopmental Disorders).

Earlier clinical clues in the literature include early epilepsy with a normal recording between seizures together with severe low muscle tone. One screening study found CDKL5 changes in about 10% of girls with early, severe seizures or spasms, or with a Rett-like picture and early seizures (Bahi-Buisson, Brain 2008). Paroxysmal fast activity over the back of the head and sequential seizures are described as not specific to the condition but highly suggestive of it (Tokatly Latzer 2026).

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Ganaxolone: The Marigold Trial

Ganaxolone is a neuroactive steroid. The Marigold trial, reported in 2022, is described by its authors as the first controlled trial in this condition (Knight 2022). It was funded by the drug's developer.

• Design: randomised, double-blind and placebo-controlled, at 39 clinics in 8 countries. Eligible participants were aged 2 to 21 years with a disease-causing or probably disease-causing CDKL5 variant and at least 16 major motor seizures per 28 days. Major motor seizures meant bilateral tonic, generalised tonic-clonic, bilateral clonic, atonic, or focal to bilateral tonic-clonic seizures.
• Treatment: ganaxolone or placebo was added to existing care for 17 weeks. The maximum dose the trial gave was 63 mg/kg per day for those weighing 28 kg or less, or 1800 mg per day for those weighing more.
• Participants: 101 were randomised, 50 to ganaxolone and 51 to placebo, with a median age of 6 years. The primary analysis covered 100.
• Main result: the median change in 28-day major motor seizure frequency was −30.7% with ganaxolone (interquartile range −49.5 to −1.9) and −6.9% with placebo (−24.1 to 39.7), p=0.0036. The estimated median difference between groups was −27.1% (95% confidence interval −47.9 to −9.6).
• Harms: adverse events occurred in 86% on ganaxolone and 88% on placebo, and serious adverse events in 12% and 10%. Somnolence, fever and upper respiratory infections occurred in at least 10% on ganaxolone and more often than on placebo. Two patients (4%) on ganaxolone and four (8%) on placebo left the trial. There were no deaths in the double-blind phase.

Beyond seizure counts, a further analysis of the same trial found lower manic or hyperactive scores and lower compulsive behaviour scores on ganaxolone than on placebo. Daytime sleepiness scores were similar. Quality-of-life scores were 2.6 points higher with ganaxolone, a difference that was not statistically significant (Downs 2024).

Of the 101, 88 (87.1%) entered an open-label extension in which everyone knew they were receiving the drug. There was no control group in this stage. At 2 years, 50 people had data, and their major motor seizures were down by a median of 48.2% from the original baseline. When missing data were estimated, the figure was 43.8% by one method and 27.4% by another. At that point 23 of 50 had reductions of at least 50%, and 12 of 50 had reductions of at least 75%. Thirty-seven stopped the drug: 13 for lack of benefit, 12 withdrawn by a caregiver, 10 for an adverse event, 1 by physician decision and 1 death judged unrelated to the drug. Serious adverse events were recorded in 28 (31.8%), including seizure in 6, pneumonia in 5, acute respiratory failure in 3, aspiration pneumonia in 3 and dehydration in 3 (Olson 2024).

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The FDA Label for Ganaxolone

The United States Food and Drug Administration approved ganaxolone oral suspension on 18 March 2022. The indication is seizures associated with CDKL5 deficiency disorder in patients 2 years of age and older. The label rests on one trial, Marigold. Its efficacy table gives a median change of −31% with ganaxolone and −7% with placebo. The label's main safety statements are:

• Sleepiness: somnolence and sedation occurred in 44% on ganaxolone and 24% on placebo, appeared early and were generally dose-related. Other nervous-system depressants, including opioids, antidepressants and alcohol, can add to the effect.
• Other common reactions: somnolence 38% against 20%, fever 18% against 8%, upper respiratory infection 10% against 6%, excess saliva 6% against 2%, and seasonal allergy 6% against 0%.
• Suicidal thoughts: a warning carried by antiseizure medicines as a class, based on pooled analyses of 199 trials of 11 other drugs (adjusted relative risk 1.8).
• Stopping: the label describes gradual withdrawal because of the risk of more seizures and of status epilepticus, a prolonged seizure that is a medical emergency.
• Interactions: inhibitors of the UGT enzymes, such as valproic acid, may raise blood levels, and strong or moderate CYP3A4 inducers lower them.
• Food: a high-fat meal raised peak levels three-fold and total exposure two-fold compared with fasting.
• Pregnancy and young brains: no human pregnancy data are available. Animal studies found harm to development in mice and rats. Widespread nerve-cell death was seen in 7-day-old rats, at exposures lower than those of children at the maximum human dose. The label states that safety and effectiveness below 2 years of age have not been established.
• Abuse potential: ganaxolone is a Schedule V controlled substance.

The label states that the precise way ganaxolone works in this condition is unknown. Its anti-seizure effect is thought to come from strengthening signalling at the gamma-aminobutyric acid type A receptor, the brain's main calming pathway. The trial's maintenance dose was 21 mg/kg three times a day for those weighing 28 kg or less and 600 mg three times a day for those weighing more, always with food. A registry entry describes a small planned open-label study in children from 6 months to under 2 years, listed as not yet recruiting (NCT05249556).

Sources: ganaxolone oral suspension prescribing information, DailyMed and FDA application record NDA 215904.

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Cannabidiol and Cannabis Products as Reported

No randomised, placebo-controlled trial of cannabidiol in this condition appeared in the searches behind this page. What exists is open-label or observational:

• Expanded-access study, 2018: 55 patients with four rare epilepsies, 20 of them with CDKL5 deficiency disorder, received highly purified cannabidiol. Across all four groups, convulsive seizures fell by a median of 51.4% at week 12 and 59.1% at week 48. Figures for the CDKL5 group alone are not given in the abstract. Fifteen (27%) withdrew by week 144, 9 for lack of benefit and 4 for side effects. The authors rate it as class III evidence and call for placebo-controlled trials (Devinsky 2018).
• Single-centre study, 2026: nine girls and young women received purified cannabidiol, at a median dose of 15.6 mg/kg per day, for up to a year. A reduction of more than 50% was seen in 8 of 9 at 3 months, 6 of 9 at 6 months and 1 of 8 at 12 months, so the effect faded. Five had adverse events, none serious, and one stopped for a skin rash (Perulli 2026).
• Caregiver survey, 2021: of 312 caregivers, 82 (26%) described use of a cannabis product, usually cannabidiol. Of 70 who rated the effect, 54% reported lasting improvement and 16% temporary improvement. Yet actual seizure frequency and number of medications did not differ between current users and non-users, or before and after starting. The authors note the limits of unblinded self-assessment (Dale 2021).

A 2019 review describes evidence specific to this condition as limited, with anecdotes and one open-label trial, and notes public interest driven by reports of "miraculous cures" (Dale 2019). Cannabis derivatives had been tried by over a third of the 2021 United States cohort (Olson 2021, Journal of Neurodevelopmental Disorders).

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The Ketogenic Diet as Reported

The ketogenic diet is a medically supervised, very high-fat, very low-carbohydrate diet used for hard-to-control epilepsy. About half of people in large cohorts have tried it (Lim 2017; Olson 2021, Journal of Neurodevelopmental Disorders). All the evidence is retrospective, with no randomised trial.

• Family-reported database, 2017: 104 of 204 people had used the diet, for a median of 17 months. Of 69 for whom changes in seizures were reported, 61 (88%) improved. Nearly one third (31.7%) had side effects. Only 32% remained on it, and lack of long-term benefit was the main reason for stopping (51%). The authors state that its side-effect profile calls for supervision by a pediatric neurologist and a specialist dietitian (Lim 2017).
• Meta-analysis, 2022: 12 retrospective studies with 193 people gave a "definite" responder rate of 18.0% and a "clinical" responder rate of 50.5%. Only one study reported side effects, in 18 of 23, mainly constipation and vomiting (Zhang 2022).
• Retrospective series, 2016: across any antiseizure drug or the diet, the share of 39 patients with more than a 50% reduction in seizures was 69% at 3 months, 45% at 6 months and 24% at 12 months (Müller 2016).

The pattern across these reports is a response that is often real at first and frequently does not last. The 2022 review reports "some benefit" from ketogenic diets and vagus nerve stimulation (Leonard 2022).

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Other Drugs, Devices and Surgery as Reported

Most of what follows is uncontrolled and small. Ataluren is the exception, and it was negative.

• Standard antiseizure drugs: in one large cohort, 2-week response ranged from 14 to 48%, and sustained 3-month response from 5 to 36%. No single drug was associated with better control (Olson 2021, Journal of Neurodevelopmental Disorders). In the 39-patient series, the highest early response rates were reported for felbamate (3 of 3), vigabatrin (8 of 25), clobazam (4 of 17) and valproate (7 of 34). Twelve patients (31%) had worse seizures on at least one drug (Müller 2016).
• Worsening with drugs: a Japanese series recorded worsening with lamotrigine, potassium bromide and levetiracetam. No drug produced seizure freedom on its own, and adrenocorticotropic hormone was the most effective treatment in that series (Kobayashi 2021).
• Sodium channel blockers: in a retrospective series of 19 with epilepsy, 6 (31.6%) responded to drugs such as oxcarbazepine, carbamazepine or lacosamide, and 3 non-responders worsened (Aledo-Serrano 2021).
• Vigabatrin with zonisamide: 5 of 8 in a small series responded to the combination (Melikishvili 2019).
• Fenfluramine: in six people, tonic-clonic seizures fell by a median of 90% among the five who had them, and no heart valve disease or pulmonary hypertension developed (Devinsky 2021). There was no control group. A phase 3, placebo-controlled trial with 87 participants is registered as active and not recruiting, with no posted results and an estimated primary completion in November 2027 (NCT05064878).
• Soticlestat: in an open-label pilot study, the 12 people with this condition had a median change in motor seizures of −23.6% (Demarest 2023).
• Ataluren: this drug is meant to read through premature stop signals in a gene. In a placebo-controlled crossover trial including 8 children with stop-signal variants, it was not effective for seizures, cognition, movement, behaviour or quality of life (Devinsky, Annals of Clinical and Translational Neurology 2021). The authors note the small size and short treatment phase.
• Vagus nerve stimulation: 38 of 222 individuals in the database (17.1%) had used it. Seizure control improved in 25 of 36, after a median of 73 days. Three stopped early because of side effects, and medication numbers did not fall (Lim 2018).
• Surgery: functional hemispherectomy and corpus callosotomy are recorded in a few people, in numbers too small to judge (Olson 2021, Journal of Neurodevelopmental Disorders).

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Gene Therapy and Protein Replacement Research

All the published results below come from animals or cells grown in the laboratory. None is a result in a child.

• Protein replacement, mouse study (2018): researchers fused the CDKL5 protein to a TAT peptide, which helps proteins enter cells. In mice lacking the gene, infused or injected protein restored aspects of brain development, memory, breathing pattern and visual responses (Trazzi 2018).
• Gene therapy, mouse study (2022): a virus-delivered gene made a version of the protein that cells release and neighbouring cells can take up, an approach called cross-correction. Male mice lacking the gene improved more than those given the native gene (Medici 2022).
• Gene therapy, mouse study in females (2025): because most patients are girls with a mix of cells, adding protein raises a question about too much in cells that already make it. In heterozygous female mice the same approach improved behaviour and brain structure, with no adverse effects seen in the brain, heart or other organs examined (Medici 2025).
• Gene therapy, human cell study (2026): in small brain-like organoids grown from patients' cells, the same approach reduced abnormal over-excitability. Cell multiplication and cell death were restored only with the secreted version (Medici, Frontiers in Bioengineering and Biotechnology 2026).
• Base editing, human cell study (2026): a molecular tool that changes a single DNA letter corrected one nonsense change in cells derived from a patient, and restored the protein in nerve cells grown from them (Chai 2026). The authors note about half of reported variants are point mutations of this general kind.

A search of ClinicalTrials.gov on 6 November 2026 for CDKL5 together with gene therapy, adeno-associated virus, antisense, or gene or protein replacement listed no interventional gene-therapy or protein-replacement trial for this condition. A registry search can miss a study or a trial still being planned, and it says nothing about future plans.

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Natural History Studies and Quality of Life

The International CDKL5 Disorder Database, set up in 2012 and built largely on information from families, accelerated clinical understanding (Leonard 2021, Epilepsy Research). A registered International CDKL5 Clinical Research Network is listed as recruiting, with an estimated 1,000 participants (NCT05558371).

In 2018, 129 of 160 families of children older than 3 years returned a quality-of-life questionnaire. Inability to sit, to use the hands and to communicate had the greatest adverse effect on quality of life. Children using three or more seizure medicines scored lower than those on one or none, and quality of life also differed by geographical region. The authors write that comprehensive care and support for both the child and the family have important roles in helping families thrive (Leonard 2021, Epilepsy Research).

Because seizure counts miss much of what matters to families, researchers have built measures for this condition. The CDKL5 Clinical Severity Assessment covers movement, communication and vision through clinicians, and seizures, behaviour, alertness and feeding through caregivers. It was evaluated with 148 and 198 participants (Saldaris 2024). A later global severity score was developed from those measures and related scales (Jacoby 2025).

Few long-term figures exist for adults. The 2025 severity-score study included people up to 40 years old (Jacoby 2025). A 2026 review on genetic developmental and epileptic encephalopathies in adulthood reports that many people now live into adulthood but that this period remains poorly characterised (Dudley 2026). A 2026 meta-analysis of trials across such conditions gives an overall mortality estimate of 8.76 per 1000 person-years and sudden unexpected death in epilepsy of 4.32 per 1000 person-years. The authors warn these figures may be underestimates, and they give no separate result for CDKL5 deficiency disorder (Moro 2026).

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What Is Not Known

• How many people have it: a prospective national cohort of young children with epilepsy in Scotland estimated an incidence of 1 per 42,400 live births, based on only 4 children (95% confidence interval 0.805 to 5.59 per 100,000) (Symonds 2019). Other population figures were not found in the records reviewed.
• Lifespan: the records reviewed for this page gave no reliable survival figure specific to this condition.
• Lasting effect of seizure treatment: Marigold ran 17 weeks. Its extension had no control group and lost many participants by 2 years, so long-term effect rests on weaker evidence. Whether lowering seizure counts changes development is not shown by these data.
• Treatment in infancy: seizures start in the first weeks of life, while ganaxolone's label starts at 2 years. Safety and effectiveness below that age have not been established.
• Which treatment suits which child: no head-to-head trial was found, and the 2021 United States cohort found no specific drug associated with better seizure control.
• Genotype and severity: the 2016 database study and the 92-person cohort found no clear relationship with broad mutation groups for many features, while other papers report truncating variants or kinase-domain changes as more severe (Mangatt 2016; Demarest 2019; Siri 2021).
• Whether gene or protein replacement works in people: no human results were found. The right dose in girls with a mix of cells is an open question that the 2025 mouse study began to address.
• Why fever lowers seizures in some: the 2026 survey raises this question, and the mechanism is not established.

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Key Research Papers

1. Kalscheuer VM, Tao J, Donnelly A, Hollway G, Schwinger E, Kübart S, Menzel C, Hoeltzenbein M, Tommerup N, Eyre H, Harbord M, Haan E, Sutherland GR, Ropers HH, Gécz J. Disruption of the serine/threonine kinase 9 gene causes severe X-linked infantile spasms and mental retardation. Am J Hum Genet. 2003;72(6):1401-11. PubMed PMID: 12736870
2. Weaving LS, Christodoulou J, Williamson SL, Friend KL, McKenzie OL, Archer H, Evans J, Clarke A, Pelka GJ, Tam PP, Watson C, Lahooti H, Ellaway CJ, Bennetts B, Leonard H, Gécz J. Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation. Am J Hum Genet. 2004;75(6):1079-93. PubMed PMID: 15492925
3. Tao J, Van Esch H, Hagedorn-Greiwe M, Hoffmann K, Moser B, Raynaud M, Sperner J, Fryns JP, Schwinger E, Gécz J, Ropers HH, Kalscheuer VM. Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene are associated with severe neurodevelopmental retardation. Am J Hum Genet. 2004;75(6):1149-54. PubMed PMID: 15499549
4. Mari F, Azimonti S, Bertani I, Bolognese F, Colombo E, Caselli R, Scala E, Longo I, Grosso S, Pescucci C, Ariani F, Hayek G, Balestri P, Bergo A, Badaracco G, Zappella M, Broccoli V, Renieri A, Kilstrup-Nielsen C, Landsberger N. CDKL5 belongs to the same molecular pathway of MeCP2 and it is responsible for the early-onset seizure variant of Rett syndrome. Hum Mol Genet. 2005;14(14):1935-46. PubMed PMID: 15917271
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1. CDKL5 deficiency disorder — PubMed
2. Ganaxolone and CDKL5 — PubMed
3. CDKL5 and cerebral visual impairment — PubMed
4. CDKL5 gene therapy — PubMed

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Connections

• Genetics
• Rett Syndrome — the MECP2 condition this one was once grouped with.
• Angelman Syndrome — another genetic condition with overlapping features noted in early reports.
• Epilepsy — the broader condition and its mechanisms.
• Dravet Syndrome — another severe genetic epilepsy of early life, studied alongside this one in several trials.
• Febrile Seizures — seizures brought on by fever, in contrast to the reduction reported here.
• Ketogenic Diet — the diet tried by about half of people with this condition.
• Seizures and Epilepsy Animation — an interactive view of what happens during a seizure.

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