Lina has CDD. She was not taking
ZTALMY at the
time of this photo.

DIAGNOSIS AND MANAGEMENT
OF SEIZURES IN CDKL5 DEFICIENCY DISORDER (CDD)

Lina has CDD. She was not taking
ZTALMY at the
time of this photo.

Though rare, CDD is one of the
most common genetic epilepsies¹

CDD is a developmental and epileptic encephalopathy (DEE) resulting from pathogenic, or likely pathogenic, mutations in the cyclin-dependent kinase-like 5 (CDKL5) gene, which is essential to neuronal development and function. Early-onset and refractory seizures are a fundamental feature of the disorder.^1-3 Genetic testing for variants of the CDKL5 gene, which is included on standard epilepsy panels, is required for the diagnosis of CDD.^2,4

Estimated incidence of CDD:
1 in 40,000 live births⁵

4th most common pathogenic variant among patients with genetic epilepsy⁶

~4:1 female predominance
Typically more severe in males^2,3

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

REVIEW THE GUIDELINES

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

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 ahead^2,3

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 refractory^3,14

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

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

Patients were prescribed a median of 6 ASMs (range: 0 to 18) over the course of their lives^16✝

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

EFFICACY

SAFETY

DIAGNOSIS AND MANAGEMENT
OF SEIZURES IN CDKL5 DEFICIENCY DISORDER (CDD)

Though rare, CDD is one of the
most common genetic epilepsies¹

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

CDKL5 deficiency disorder has a distinct genetic etiology⁴