CDKL5 deficiency disorder (CDD) is a rare genetic disorder caused by pathogenic variants in the gene CDKL5.
Signs and symptoms
The symptoms of CDD include early infantile onset refractory epilepsy; hypotonia; developmental, intellectual, and motor disabilities, with little or no speech; and cortical visual impairment. Patients usually present first with seizures within the first months of life, followed by infantile spasms which progress to epileptic seizures that are largely refractory to treatment. Development of gross motor skills, such as sitting, standing, and walking, is severely delayed, along with restricted fine motor skills. About one-third of affected individuals can ambulate with assistance, but most CDD patients rely on wheelchairs. Additional features include repetitive hand movements (stereotypies), such as clapping, hand licking, and hand sucking; tooth grinding (bruxism); disrupted sleep; feeding difficulties; gastrointestinal problems including constipation and gastroesophageal reflux. Some patients show irregular breathing.
Cause
CDD is caused by pathogenic variants in the gene CDKL5. This gene provides instructions for making a protein (cyclin-dependent kinase-like 5) that is essential for normal brain development and function. The CDKL5 protein is widely expressed in the brain, predominantly in nerve cells (neurons), with roles in cell proliferation, neuronal migration, axonal outgrowth, dendritic morphogenesis, and synapse development. Inheritance Pattern: the CDKL5 gene is located on the X chromosome but nearly all known pathogenic mutations are de novo, rather than being inherited from an affected mother or father; the profound neurodevelopmental disabilities of CDD patients makes it extremely unlikely they would have children. There is one reported case of an inherited CDKL5 mutation; a mother carried a CDKL5 mutation on one X chromosome, but was high functioning and showed only mild cognitive impairment. The mother's mutant CDKL5 allele was skewed in its X-inactivation, being expressed in only 20% of circulating lymphoblasts. However, her daughter, who was diagnosed with CDD, expressed the mutant in 50% of her circulating lymphoblasts. Females: a mutation in one of the two copies of the CDKL5 gene in each cell causes the disorder. Males: a mutation in the only copy of the gene causes the disorder.
Diagnosis
For the clinical diagnosis of CDKL5 Deficiency Disorder, minimal diagnostic criteria have been established, including motor and cognitive delays, epilepsy with onset within the first year of life, and the presence of a pathogenic or likely-pathogenic mutation of the CDKL5 gene. While initial diagnosis is based mostly on clinical suspicion, definitive diagnosis requires confirmation by genetic testing. The first presentation of epileptic seizures within the first few months of life would suggest a possible diagnosis of CDD. Initial clinical testing for differential diagnosis may include MRI and CSF testing for structural or infectious etiologies; however, CDKL5 is now widely included in DNA sequence-based molecular diagnostic gene panels or infantile epilepsy for more rapid and precise diagnosis. Note: many adolescents and young adults may have CDD but were never tested since such tests were not available when they were infants. Therefore, epilepsy panels for CDD and other genes should be considered in such individuals.
A diagnostic ICD-10 code has been assigned to CDKL5 deficiency disorder: G40.42 (since 2020).
Treatment
Antiseizure medications (ASMs) are used to manage seizures; however, in most cases, control is partial or transient. Commonly used ASMs include valproic acid, clobazam, vigabatrin, felbamate, steroids, and lamotrigine for seizures, although comprehensive data are limited for the efficacy and safety of ASMs in CDD; medications for infantile spasms include ACTH, prednisolone, and vigabatrin for infantile spasms. Clinical trials support the efficacy some new ASMs. Currently, there are no specifically approved therapeutics for the symptoms of CDD, although clinical trials for the treatment of CDD symptoms are currently underway, as both phase 2 and phase 3 studies. Medications to control GI and sleep disturbances are often prescribed. Therapies, including physical, occupational, and vision therapy, are recommended. Specialized diets, such as the ketogenic diet, have been reported to help manage seizures, though the effect is often partial and transitory.