Individuals with unexplained epilepsy should be offered genetic testing regardless of age7

Genetic testing in epilepsy is largely performed through epilepsy gene panels and exome sequencing, in which CDKL5 is one of the high-yield genes.4

Recent guidelines from the National Society of Genetic Counselors strongly recommend comprehensive, multigene testing for individuals with unexplained epilepsy, without limitation of age. Exome sequencing (ES) and genome sequencing (GS) or multigene panels (MGP) are strongly recommended as first-tier tests. An MGP should have a minimum of 25 genes and include copy number analysis.7

These guidelines were endorsed by the American Epilepsy Society (AES).7


CDKL5 deficiency disorder has a distinct genetic etiology4

Previously classified as an atypical form of Rett syndrome because of its overlapping phenotype, CDD is a recently recognized disorder.4

Timeline showing the history of CDKL5 research, from identification in 2004, to receiving an unique ICD-10-CM code in 2020 Timeline showing the history of CDKL5 research, from identification in 2004, to receiving an unique ICD-10-CM code in 2020

Genetic testing is essential for diagnosing DEEs with overlapping phenotypes.10 DEEs are a heterogenous group of severe epilepsies with several shared characteristics11:

Early onset and treatment‐resistant epilepsy

Frequent interictal epileptiform
discharges on EEG

Multiple seizure types

Developmental slowing or regression

Identification of underlying genetic etiology in DEEs has direct implications on patient care. This has included avoiding, stopping, or initiating specific antiseizure medications (ASMs) or a ketogenic diet and even halting plans for surgery in the presence of a specific genetic diagnosis.12

Early diagnosis can help families and care teams plan ahead2,3

As with other DEEs, intractable seizures in infancy are typically the first overt symptom of CDD and signal the need for genetic testing, including the CDKL5 gene. A confirmed diagnosis of CDD is critical for decision-making about antiseizure medications and other interventions for overall CDD management.1,2,13

Minimum diagnostic criteria for CDD2*

Onset of epilepsy within the first year of life

Presence of pathogenic or likely pathogenic variant in the CDKL5 gene

Motor and cognitive developmental delays

Common clinical characteristics2

  • Early-onset and refractory epilepsy
  • Severe global developmental delay
  • Intellectual disability
  • Hypotonia
  • Cortical visual impairment (CVI)
  • Sleep disturbance
  • Dyskinetic movements
  • Autonomic and breathing disturbances
  • GI disturbances (reflux, constipation)
  • Dysphagia

*Minimum diagnostic criteria for CDD is from expert opinion of Olson et al (2019).

Clinical hallmarks of disease1

Hypermotor-tonic-spasms sequence (HTSS) or HTSS-like seizures were seen in 57% of patients with CDD

CVI was seen in at least 75% of patients with CDD

Seizures persist throughout the patient journey
and are often refractory3,14

Seizures associated with CDD remain a lifelong concern that must be managed alongside the constellation of other symptoms and comorbidities. Patients typically cycle through multiple ASMs with limited response.14-16

The burden of seizures in CDD

Daily seizures

Despite a majority taking at least 2 ASMs, patients experienced a median of 2 seizures a day17*

Treatment failure

Patients were prescribed a median of 6 ASMs (range: 0 to 18) over the course of their lives16✝

Rarely seizure-free

Fewer than half of patients with CDD experienced >2 months of sustained seizure freedom17*

*Data from the International CDKL5 Patient Registry on 172 individuals with CDD, with a median age of 5 years, per caregiver report.17

✝︎Study analyzed 177 individuals with CDD, with a median age of 8.1 years.16

Explore the efficacy


Learn about the safety




  • Somnolence and Sedation: ZTALMY can cause somnolence and sedation. In a clinical study somnolence and sedation appeared early during treatment and were generally dose related. Other CNS depressants, including opioids, antidepressants, and alcohol, could potentiate these effects. Monitor patients for these effects and advise them not to drive or operate machinery until they have gained sufficient experience on ZTALMY to gauge whether it adversely affects their ability to drive or operate machinery.



ZTALMY is indicated for the treatment of seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) in patients 2 years of age and older.




The most common adverse reactions (incidence of at least 5% and at least twice the rate of placebo) were somnolence (38%), pyrexia (18%), salivary hypersecretion (6%), and seasonal allergy (6%).


Cytochrome P450 inducers will decrease ganaxolone exposure. Avoid concomitant use with strong or moderate CYP3A4 inducers; if unavoidable, consider a dosage increase of ZTALMY, but do not exceed the maximum recommended dosage.



ZTALMY contains ganaxolone, a Schedule V controlled substance (CV). Advise patients of the potential for abuse and dependence. It is recommended that ZTALMY be tapered according to the dosage recommendations unless symptoms warrant immediate discontinuation.

Please see full Prescribing Information.


  1. Demarest ST, Olson HE, Moss A, et al. Epilepsia. 2019;60(8):1733-1742.
  2. Olson HE, Demarest ST, Pestana-Knight EM, et al. Pediatr Neurol. 2019;97:18-25.
  3. Jakimiec M, Paprocka J, Śmigiel R. Brain Sci. 2020;10(2):1-9.
  4. Leonard H, Downs J, Benke TA, Swanson L, Olson H, Demarest S. Lancet Neurol. 2022;21(6):563‐576.
  5. Symonds JD, Zuberi SM, Stewart K, et al. Brain. 2019;142(8):2303-2318.
  6. Mei D, Parrini E, Marini C, Guerrini R. Mol Diagn Ther. 2017;21(4):357-373.
  7. Smith L, Malinowski J, Ceulemans S, et al. J Genet Couns. 2023;32(2):266-280.
  8. International Foundation for CDKL5 Research. Accessed March 24, 2023.
  9. Mingorance A, Jaksha A, Smart T, et al. Loulou Foundation; International Foundation for CDKL5 Research. Published June 17, 2020. Accessed May 24, 2023.
  10. Ortega-Moreno L, Giráldez BG, Soto-Insuga V, et al. PLoS One. 2017;12(11):e0188978.
  11. Bayat A, Bayat M, Rubboli G, Møller RS. Genes. 2021;12(7):1051.
  12. Sheidley BR, Malinowski J, Bergner AL, et al. Epilepsia. 2022;63(2):375-387.
  13. Mangatt M, Wong K, Anderson B, et al. Orphanet J Rare Dis. 2016;11(1):39.
  14. Bahi-Buisson N, Bienvenu T. Mol Syndromol. 2012;2(3-5):137-152.
  15. Müller A, Helbig I, Jansen C, et al. Eur J Paediatr Neurol. 2016;20(1):147-151.
  16. Olson HE, Daniels CI, Haviland I, et al. J Neurodev Disord. 2021;13(1):1-11.
  17. Fehr S, Wong K, Chin R, et al. Neurology. 2016;87(21):2206-2213.