CDKL5-deficiency disorder (ORPHA:505652)
A rare genetic neurodevelopmental disorder characterized by early-onset drug-resistant seizures and severe neurodevelopmental impairment with major motor development delay.
Epidemiology
CDKL5-related epileptic encephalopathy has an estimated birth prevalence of 1/42,400 in the UK (Scotland). It affects predominantly females with a sex ratio of 12:1
Clinical description
Presentation is of severe seizures with onset in the first six months of life (often within the first 3 months or even the first few weeks after birth), hypotonia, poor eye contact and poor neurocognitive development. Severe hypotonia can be present before seizure onset, as well as irritability, excessive crying, drowsiness, and poor sucking. Seizures are usually difficult and include epileptic spasms, myoclonic seizures, tonic seizures and tonic-clonic seizures. At the beginning EEG might not reveal significant epileptiform abnormalities, however over time abundant and multifocal epileptiform discharges are evident. During the disease course a seizure free period might be observed, this is also reported as ''honey-moon period''. The neurological outcome is poor as most affected individuals cannot walk and many are confined to a wheelchair. Communication strategies are restricted to elementary non-verbal communication. Patients do not develop autonomy to feed themselves. Subtle dysmorphic facial features include a prominent/broad forehead, deep-set eyes, a well-defined philtrum, and everted lower lip, possibly associated with tapered fingers and hallux valgus. Stereotypies are common. Some may have scoliosis, visual impairment, gastrointestinal difficulties, and sleep problems. Epilepsy is drug-resistant and most of patients continue with active epilepsy.
Etiology
The disorder is caused by mutations or deletions in the cyclin-dependent kinase-like 5 (CDKL5, Xp22.13) gene situated in the X chromosome. CDKL5 is a kinase predominantly expressed in the brain. Deficiency in CDKL5 leads to neurodevelopmental alterations.
Diagnostic methods
Diagnosis is suspected in patients with early onset epilepsy with a severe developmental delay and with a poor response to anti-epileptic drugs. Genetic identification of CDKL5 alterations confirms diagnosis.
Differential diagnosis
Differential diagnosis includes developmental epileptic encephalopathies (DEE) with early onset seizures and West syndrome. Molecular testing of the CDKL5 gene should be considered in cases DEE, West syndrome.
Genetic counseling
The pattern of inheritance is X-linked. The risk of recurrence in affected families is low since the pathogenic mutations occur de novo in most cases; however, some cases of parental mosaicism have been reported.
Management and treatment
There is no medication currently approved for the specific treatment of this disorder. Management is symptom-based and requires a multidisciplinary approach. Anticonvulsant medications and ketogenic diet is used for the management of seizures. Non-pharmacological management includes physical, occupational, visual and speech therapy.
Prognosis
Life expectancy is unknown due to underdiagnosis in adults, but adult patients are known. Prognosis is poor with severe psychomotor deficits and intractable seizures remaining into adulthood. Autonomy is never reached.

                            Last update: 
                            November 2019


                            - Expert reviewer(s): 
                            Pr Helen CROSS | EpiCARE* - Pr Reetta KÄLVIÄINEN | EpiCARE* - Pr Rima NABBOUT | EpiCARE* - Pr Nicola SPECCHIO | EpiCARE*


                                * European Reference Network