Complex CDKL5-Related Disease Cases Require Coordinated Care

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By Sumit Parikh, MD, and Elia Pestana Knight, MD

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Mutations in the cyclin-dependent kinase-like 5 (CDKL5) gene lead to a characteristic infant-onset epileptic encephalopathy and neurodevelopmental disorder known as CDKL5-related disease.

The initial presentation of the disease in infants (Table 1) includes:

  • Early-onset seizures beginning in the first three months of life.
  • Seizures that often but not always become refractory to many antiepileptic drugs.
  • Multiple seizure types that can change as the patient gets older.
  • Delayed neurocognitive development without a history of regression.
  • Other manifestations such as poor social interaction, stereotypic hand movement, severe hypotonia, visual disturbances, feeding difficulties, dysphagia and autonomic changes.
  • No specific facial dysmorphic features.

Table 1. Symptoms present in children with CDKL5-related disease.


Types of Seizures and EEG Patterns

Seizures in patients with CDKL5-related disease present as early as the neonatal period. Seizure types may change across the life span of these patients. The initial presentation in almost half of patients includes early-onset infantile spasms with or without other associated seizures. Other associated seizure types include focal motor, tonic, myoclonic, apneic and complex motor with oral automatisms.

As these children become older, a variety of mixed seizures can be seen, including myoclonic, tonic, absence and complex partial seizures. Generalized tonic-clonic seizures are frequent and common. Epileptic spasms persist in some patients. Often seizures are long, lasting more than five minutes. Seizures are often highly refractory to anti-epileptic treatment, but honeymoon periods after the introduction of a new anti-epileptic drug have been described.

No specific EEG pattern has been associated with CDKL5-related disease. EEG abnormalities seem to change with age and seizure types. The initial EEG can be interpreted as normal, but a hypsarrhythmia pattern (Figure 1) often becomes a prominent finding once infantile spasms begin (Figure 2). Focal, multifocal, diffuse or generalized sharp waves can also be seen on initial EEGs. Ictal findings are dependent on the seizure type. Abnormalities of the background rhythm are a common finding in these patients and are present in all patients as they become older.

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Figure 1. Sample of video EEG recording showing hypsarrhythmia. Patient is a 4-year-old male with seizures since age 2½ months, severe neurodevelopmental delay, visual impairment, swallowing dysfunction, gastroesophageal reflux and a gastric tube placed for feeding. Since seizure onset, he has had daily clusters of infantile spasms and tonic seizures that have persisted despite treatment with phenobarbital, rufinamide, topiramate, levetiracetam, valproic acid and the ketogenic diet. He has a confirmed pathogenic mutation in the CDKL5 gene.



Figure 2. Sample of video EEG recording showing ictal pattern during epileptic spasms in the same patient.


Screening and Etiology

CDKL5-related disease is a dominant X-linked condition that should be considered for any child with an early-onset epileptic encephalopathy, especially when infantile spasms begin prior to 3 months of age. The condition presents in both males and females. The yield of CDKL5 testing in children with an early-onset epileptic encephalopathy is around 5 percent for males and 14 percent for females. A CDKL5 gene mutation can be found in as many as 31 percent of females with Rett syndrome-like features and negative MECP2 test results.

CDKL5-related disease occurs due to mutations in the cyclindependent kinase-like 5 gene on the X chromosome. Patients with the condition were only first identified in the early 2000s, and clinical testing became available as of late 2000. Scientific knowledge regarding the disease’s pathophysiology is still rudimentary, although we know that the gene is primarily expressed in the brain and expression overlaps that of MECP2 (the gene involved in Rett syndrome) during neuronal maturation. CDKL5 and MECP2 may belong to the same neurodevelopmental pathway.

The Importance of a Multidisciplinary Team

The understanding of the clinical phenotype of CDKL5-related disease is improving but remains general and incomplete, with notable phenotypic variability. Symptoms include varying degrees of refractory epilepsy and developmental disability. There is notable variability in the severity of the epilepsy and developmental disability from patient to patient. At least one patient without epilepsy has been identified. The natural history of the condition is not yet known. The condition is considered rare but is likely underidentified, and its true incidence is not yet known.

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The International Foundation for CDKL5 Research (IFCR) is establishing centers of excellence across the country, with each housing a multidisciplinary clinic to improve clinician familiarity with this condition and to provide a standard of care for patients and families. Such centers can better ascertain how the condition unfolds, allowing their researchers to study the natural progression of the disease.

Cleveland Clinic Children’s began the third such clinic in the United States in 2014. Patients are evaluated by multiple providers, including dedicated specialists in epilepsy, neurogenetics, genetic counseling, gastroenterology, rehabilitation medicine, orthopaedics, pulmonology, cardiology, ophthalmology, gynecology and physiotherapy. A social worker also is available.


Dr. Parikh is a pediatric neurologist and staff member of Cleveland Clinic’s Center for Pediatric Neurology, where he directs the Multidisciplinary CDKL5 Syndrome Clinic and the Neurogenetics, Metabolic and Mitochondrial Disease Program.

Dr. Pestana Knight is a pediatric neurologist and staff member of Cleveland Clinic’s Epilepsy Center.