Clinical Guidance

While genotype-phenotype correlations are emerging , there are two caveats regarding ascertainment: (1) the frequency of recurrent CDKL5 pathogenic variants is relatively low; and (2) measurements of severity with sufficient granularity to differentiate clinical severity have only recently become available. CDKL5 pathogenic variants causing CDD are typically loss-of-function variants ; however, duplications and missense gain-of-function variants associated with different, and often milder, neurologic manifestations have been reported. Phenotypes associated with nonsense alterations throughout the protein appear equally severe, suggesting that truncating variants located within the terminal region of the gene may be less severe .

Source: GeneReviews — "CDKL5 Deficiency Disorder"

Diagnostic Criteria

For the purposes of this GeneReview, the terms "male" and "female" are narrowly defined as the individual's biological sex at birth as it determines clinical care . Diagnostic criteria for CDKL5 deficiency disorder (CDD) have been proposed .

Suggestive Findings

CDD should be suspected in females and males with motor and cognitive developmental delays and epilepsy with onset in the first year of life (developmental delays and early-onset epilepsy constitute the minimal clinical diagnostic criteria proposed by ). Note: (1) Although females are more commonly affected than males with this X-linked disorder, the severity of manifestations in affected females and males can be equivalent.

Source: GeneReviews — "CDKL5 Deficiency Disorder"

Differential Diagnosis

Table 3. Developmental and Epileptic Encephalopathies in the Differential Diagnosis of CDKL5 Deficiency Disorder

Management Guidelines

International consensus recommendations for the assessment and management of individuals with CDKL5 deficiency disorder (CDD) have been published (full text). The management of individuals with CDD is complex and requires multiple specialty appointments; referral to a CDKL5 Center of Excellence may allow families to more easily coordinate care for affected individuals (to date, ten CDKL5 Centers of Excellence have been established in the United States).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CDD, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

CDKL5 Deficiency Disorder: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Constitutional

| Measurement of OFC, length, weight | • Smaller OFC is assoc w/ severity of disorder.1

• Poor weight gain can reflect nutritional status.

Neurologic

| Eval of epilepsy by neurologist or epileptologist | • EEG to assess EEG background, epileptiform activity, seizure type correlate w/clinical semiology

• Prolonged video EEGs may be required to characterize spells of unclear etiology or rule out subclinical status epilepticus.

Eval of movement disorders | To characterize movement disorder, if present, ascertain effect on gross fine motor skills

Ophthalmologic/

Vision

| Ophthalmologist | Assess for visual acuity, abnormal ocular movement, refractive errors, strabismus

Source: GeneReviews — "CDKL5 Deficiency Disorder"

Therapies Under Investigation

Several therapies have been investigated or are ongoing for CDD including the following:

• Soticlestat/TAK935 (NCT03694275)

• Ataluren (NCT02758626)

• Fenfluramine (NCT03861871, NCT05064878)

• Canabidiol

• Ketogenic diet

• Vagal nerve stimulation

• Protein and gene replacement therapies have been proposed.

Clinical trials and registries assessing natural history and outcome measures are ongoing (NCT05558371, NCT05373719, NCT04486768). Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Source: GeneReviews — "CDKL5 Deficiency Disorder"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended. In general, annual assessments by a medical home/primary care physician and specialists are needed.

Table 7.

CDKL5 Deficiency Disorder: Recommended Surveillance

System/Concern | Evaluation | Frequency

Constitutional

| Measurement of OFC, length, weight | Annually, or more frequently as required for mgmt

Neurologic

| Monitor those w/seizures as clinically indicated. | At each annual visit

Assess for new manifestations such as seizures, changes in tone, movement disorders. | At each visit

Feeding

| • Measurement of growth parameters

• Eval of nutritional status safety of oral intake

• Eval of feeding time

Development

| Monitor developmental progress educational needs.

Neurobehavioral/

Psychiatric

| Assessment for sleep, anxiety, ADHD, ASD, aggression, self-injury

Gastrointestinal

| Monitor for feeding, nutrition, constipation, GERD.

Respiratory

| Monitor for evidence of aspiration respiratory insufficiency.

Musculoskeletal

| • Physical medicine, OT/PT assessment of mobility, self-help skills

• Assessment of large joint mobility (e.g., hip surveillance)

• Clinical eval of spine

• Spine radiograph as needed to identify progressive scoliosis

• Referral to orthopedist if Cobb angle 45 degrees for consideration of surgical correction

| At each annual visit

Family/Community

| Assess family need for social work support (e.g., palliative/respite care, home...

Source: GeneReviews — "CDKL5 Deficiency Disorder"