CDKL5 Deficiency Disorder

Clinical characteristics: CDKL5 deficiency disorder (CDD) is a developmental and epileptic encephalopathy (DEE) characterized by severe early-onset intractable epilepsy and motor, cognitive, visual, and autonomic disturbances. Movement disorders include chorea, dystonia, and stereotypical hand and leg movements.

Although females are more commonly affected than males (female-to-male ratio is approximately 4:1), the severity of manifestations in heterozygous females and hemizygous males can be equivalent. However, the severity of the phenotype can vary depending on the type and position of the CDKL5 pathogenic variant, pattern of X-chromosome inactivation in females, and presence of postzygotic mosaicism in males or females, who can have mild manifestations.

Diagnosis/testing: The diagnosis of CDD is established in a female proband with suggestive clinical findings and a heterozygous CDKL5 pathogenic variant identified by molecular genetic testing.

The diagnosis of CDD is established in a male proband with suggestive clinical findings and a hemizygous CDKL5 pathogenic variant identified by molecular genetic testing.

Management: Treatment of manifestations: International consensus recommendations for the assessment and management of individuals with CDD have been published. The management of individuals with CDD is complex and requires multiple specialty evaluations; referral to a CDKL5 Center of Excellence may allow families to coordinate care more easily for affected individuals.

Targeted therapy: Ztalmy^® (ganaxolone) is a targeted therapy for the treatment of epilepsy associated with CDD in individuals aged two years and older. This is the first approved treatment for seizures associated with CDD and the first treatment specifically for CDD.

Supportive care: Multidisciplinary care by specialists in the fields of pediatric neurology including pediatric epilepsy, feeding and nutrition, sleep disorders, behavioral disorders, orthopedics, physical therapy, occupational therapy, speech-language disorders, and genetic counseling.

Surveillance: Annual assessments by a medical home / primary care physician and specialists.

Genetic counseling: CDD is inherited in an X-linked manner. Approximately 99% of affected individuals represent simplex cases (i.e., a single occurrence in the family). The majority of individuals who represent simplex cases have the disorder as the result of a de novo germline or (rarely) postzygotic CDKL5 pathogenic variant. Rarely, an individual with CDD has the disorder as the result of a CDKL5 pathogenic variant inherited from a heterozygous or mosaic mother. If the mother of the proband has a CDKL5 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Females who inherit the pathogenic variant will be heterozygous and are at high risk of being affected, although skewed X-chromosome inactivation and the possibility of other attenuating factors may result in a variable phenotype. Males who inherit the pathogenic variant will be hemizygous and will most likely be severely affected. Once the CDKL5 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.