CDKL5 Disorder

While every child with CDKL5 disorder is different in terms of physical symptoms and developmental milestones met, the condition includes a number of common identifiable features:

• Early onset epilepsy
  • 90 percent of children with CDKL5 disorder will develop seizures before 3 months of age.
  • This commonly includes epileptic spasms, though they may not be the first seizure type.
  • Seizures with multiple distinct phases are common (such as the hypermotor-tonic-spasms sequence).
• Impaired gross motor skills (such as walking)
• Impaired fine motor skills (such as grasping)
• Global developmental delays and intellectual disability
• Impaired language/communication and social skills
• Autistic features (though many children don’t meet formal criteria for autism spectrum disorder)
• Low muscle tone
• Poor eye contact and visual fixation; often with cortical visual impairment (difficulty interpreting vision in the brain, but the eyes are structurally normal)
• Sleep abnormalities
• Swallowing and feeding difficulties
• Growth restriction
• Gastrointestinal reflux and/or constipation
• Scoliosis, hip dysplasia, or other orthopedic complications from low muscle tone
• Development of high muscle tone in the legs over time

Less common features of CDKL5 disorder

• Microcephaly (small head size)
• Subtle characteristic facial features including broad or prominent forehead, large deep-set eyes, and/or full lips.
• Stereotypic movements or movement disorders
• Features overlapping with Rett syndrome and other neurodevelopmental disorders, including cold hands and feet, unexplained laughing or screaming spells, irregular breathing (periods of fast or slow breathing), and teeth grinding.

The disorder is caused by variants in the cyclin-dependent kinase-like 5 (CDKL5) gene. CDKL5 codes for an enzyme that plays an important role in brain development and function. Disease-causing variants in the CDKL5 gene include missense variants (spelling errors in the DNA code causing one amino acid to be substituted for another) and truncations or deletions (a shortened version or missing piece of the gene that can lead to the protein not being made).

CDKL5 is on the X chromosome, one of the sex chromosomes. Females have two copies of the X chromosome and males have one X and one Y chromosome. The majority of children with CDKL5 disorder are girls who have a CDKL5 variant on one X chromosome. However, there are boys who have a CDKL5 variant on their only X chromosome who can show features of the disorder.

For infants being seen for the first time, the CDKL5 diagnosis is most often made after a clinical workup for causes of early life seizures, including genetic testing.

For older children, the diagnosis is likely made in the process of revisiting potential causes for epilepsy and neurodevelopmental disorder, using the same kind of genetic testing.

Evaluation should seek to exclude other causes of early life seizures, such as structural brain changes on imaging and metabolic disorders. Symptoms of CDKL5 disorder overlap with symptoms of various other neurodevelopmental disorders such as:

• Other genetic early life epileptic encephalopathies (including channelopathies such as SCN2A or KCNQ2)
• Rett syndrome (and its early seizure variant)

Genetic tests for CDKL5 variants

Any of the following four methods can establish a diagnosis of CDKL5 disorder:

• Sequencing of the CDKL5 gene or testing for small deletions or duplications within the gene
• Testing for a panel of known epilepsy genes
• Screening with an intellectual disability gene panel
• Chromosomal microarray to evaluate for larger deletions including the CDKL5 gene
• Whole exome sequencing

Testing results should be reviewed with an expert in neurogenetics. Sometimes testing reveals variants in the CDKL5 gene that are not already known to be disease associated (called “variants of uncertain significance”). Such cases may require further workup, such as testing of both parents for the variant. Your doctors will help in determining how likely the variant in the CDKL5 gene is to be responsible for your child’s symptoms.

While there is no currently targeted treatment or gene therapy for CDKL5 disorder, a care plan can be adapted to the needs of each child. With appropriate therapy, we have found that children can do more than you might initially expect.

In many cases, the physical symptoms of CDKL5 can be alleviated and managed with a robust regimen of therapies:

• Occupational therapy
• Speech therapy
• Physical therapy
• Vision therapy
• Augmentative communication

If you are planning a visit, please call ahead so we help plan which specialty teams your child would benefit from seeing during your visit and any other testing that might be helpful. We can also assist you in scheduling appointments with specialists beyond the CDKL5 clinic. 

Seizure treatment for children with CDKL5 disorder

One of the most common features of CDKL5 disorder is seizures that are typically challenging to control. There is no single best anticonvulsant medication or combination for children with CDKL5 disorder, so specialists in Boston Children’s comprehensive Epilepsy Center will work with you and your primary neurologist/epileptologist to choose medications tailored to your child’s needs. The choice is based on seizure type and the drugs’ mechanism of action, potential side effects, and potential for interacting with other medications. 

While one drug may work for a period of time, the nature of the seizures may change, so it may be appropriate to change medications. Thus, finding the best treatment approach for your child over time will require careful team work. The CDKL5 clinic team can offer advice and experience. 

Many anticonvulsants have come out on the market over the past couple of decades.

If seizures are refractory (not responding to the usual medications), your doctor may also consider other treatments such as steroids and/or Intravenous Immunoglobulin (IVIG)

If medications are not effective, other treatment options include the following. Your child would require detailed clinical evaluation before we would try these treatments.

• Ketogenic diet
• Implantation of a vagus nerve stimulator (VNS), which delivers small pulses of electricity to the vagus nerve running along the neck to the brain
• Corpus callosotomy, an operation in which the major fibers that connect the two halves (hemispheres) of the brain are cut

Children with CDKL5 disorder are not typically candidates for focal surgery (removing a part of the brain causing seizures) or laser surgery. This is because CDKL5 disorder affects the brain broadly, rather than in a specific location.

Nutritional and gastrointestinal care in CDKL5 disorder

Treatment for feeding and swallowing dysfunction may include the following, and are adapted for each child:

• Feeding therapy
• Thickening of liquids
• Gastrostomy tubes

Medications may be appropriate for management of reflux or constipation.

Nutrition evaluations to address difficulties with weight gain are also important.

Orthopedic treatments in CDKL5 disorder

Children who develop orthopedic complications from low muscle tone may be helped by braces, such as ankle-foot-orthoses, hand splints, or scoliosis braces, depending on specific needs. Surgical treatments may also be required if orthopedic complications are severe.

Sleep and behavioral disturbances

Some children with CDKL5 disorder will benefit from dedicated sleep or behavioral assessments. While behavioral management and environment adaptations are always the first approach, medications are sometimes needed. Some children may have sleep breathing problems that contribute to daytime behavior concerns. You may be asked to complete a sleep questionnaire to determine if a dedicated sleep clinic visit is appropriate.

Vision care in CDKL5 disorder

Some children with CDKL5 will need glasses to correct their vision, and some will have a misalignment of the eyes, known as strabismus. During your visit, treatment options for this condition will be discussed together with recommendations for services for promoting visual development, such as working with a teacher trained in cortical visual impairment (a teacher of the visually impaired or TVI).

Cardiac evaluations

While heart rhythm problems are not a known clinical sign/symptom of CDKL5 disorder, we suggest yearly electrocardiograms (EKGs) because of some clinical overlap of CDKL5 with Rett syndrome and other early life epilepsy syndromes with known risk for cardiac arrhythmias.

While there is currently no specific treatment for CDKL5 disorder, the multidisciplinary CDKL5 Clinic can create a care plan to match your child’s needs and help her reach her full potential, as well as resources and help in connecting with community and educational services.

Our physicians and therapists are experienced in treating children with CDKL5 and come from a variety of specialties, including:

• Neurology (including epilepsy, neurogenetics, behavioral neurology, and sleep)
• Gastroenterology, nutrition, and feeding
• Genetics
• Neuro-ophthalmology
• Orthopedics

Our team, in turn, is learning from patients and their families and is conducting ongoing clinical and laboratory research studies with the goal of improving care for this rare condition. Read about CDKL5 research at Boston Children’s.

Please call our clinic coordinator at 617-355-8994.

While there is no known cure for CDKL5 disorder, the CDKL5 Clinic and its affiliated researchers are working hard to develop treatment options. To set the stage for clinical treatment trials in the future, we are seeking to better understand the disorder’s natural progression and the complications that children can experience. Our laboratory research on the effects of the CDKL5 mutation will help guide these trials as well.

Two observational studies at Boston Children’s Hospital’s CDKL5 Clinic are actively gathering information about the genetic variations that may contribute to the disorder and the clinical features that are associated with those variants. These studies are optional and are not required for care at the clinic. If you have questions about participating in our CDKL5 research studies, please contact the study coordinators at 617-355-5230 or by email at CDKL5@childrens.harvard.edu.

Boston Children’s Translational Neuroscience Center and F.M. Kirby Neurobiology Center have upcoming studies to better understand the biology of CDKL5 disease and its effects on visual processing. Read about laboratory research on CDKL5.

Additional translational studies may be available soon. Please ask our team (617-355-5230 or via email).

• Fehr S; et al. There is variability in the attainment of developmental milestones in the CDKL5 disorder. J Neurodev Disord 2015; 7:2. DOI: 10.1186/1866-1955-7-2
• Fehr S; et al. The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy. Eur J Hum Genet 2013 Mar; 21: 266–73.
• Olson HE, Poduri A. CDKL5 mutations in early onset epilepsy: Case report and review of the literature. J Pediatr Epilep 2012: 1:151-9.

See more research publications on CDKL5.