CDLK5 deficiency disorder

CDKL5 deficiency disorder (also CDKL5 disorder, STK9) is a rare X‑linked genetic disorder that results in a very early onset of severe, treatment‑resistant seizures and profound impairment of central nervous system (CNS) development. Although the number of diagnosed children and adults is increasing, mutations of the CDKL5 gene still belong among rare genetic disorders. Statistically, the disorder affects girls more frequently; however, when boys are affected, the syndrome usually presents in a more severe form than in females.

Most children with a CDKL5 gene mutation suffer from seizure disorders that are difficult to control with medication. Seizures are of various types and typically begin within the first months of life. These may include infantile spasms, myoclonic seizures, and tonic‑clonic seizures. More than 30 seizure types have been described.

Most children with CDKL5 are unable to walk, speak, or feed themselves independently. Many are wheelchair‑dependent and require continuous assistance in all aspects of daily life. A large proportion suffer from scoliosis, visual impairment, sensory processing difficulties, and various gastrointestinal problems. Fine motor skills are impaired, cortical visual impairment (CVI) is frequently present, and severe intellectual disability is common.

Diagnosis

The CDKL5 gene encodes the CDKL5 protein, which is essential for normal and healthy brain development. Although the precise function of this protein is not yet fully understood, it is known to play a role in regulating the activity of other genes, such as the MECP2 gene (mutations of which cause Rett syndrome).

The CDKL5 protein functions as a kinase, an enzyme that alters the activity of other proteins by attaching oxygen and phosphate groups (phosphorylation) at specific sites. However, researchers have not yet identified all proteins that are influenced by CDKL5.

The exact role of CDKL5 is still unclear, but it plays a crucial role in brain development and is closely linked to the function of the MECP2 protein. In addition, CDKL5 appears to be particularly important during the early weeks of life, as studies show increased expression of the protein in certain regions of the brain during this period.

Diagnosis is typically based on clinical evaluation, followed by genetic testing confirming a mutation in the CDKL5 gene.

Therapy

Great emphasis is placed on early intervention. A multidisciplinary approach is required, involving speech therapists, visual therapists, occupational therapists, and psychologists. Due to frequent abnormalities in muscle tone, rehabilitation and physiotherapy are recommended.

Regular follow‑up by a neurologist is necessary for antiepileptic treatment; in many cases, a combination of three antiepileptic medications is required.

• epileptic seizures (beginning between 1–8 months of age)
• infantile spasms (in approximately 50% of children)
• various types of epilepsy, usually involving myoclonic jerks
• hand stereotypies manifested by clapping, tapping, or putting hands into the mouth
• marked developmental delay
• limited speech development or complete absence of speech
• hypersensitivity to touch, for example intolerance of hair brushing
• insufficient eye contact or, conversely, excessively intense visual interaction
• gastroesophageal reflux (backflow of gastric and/or duodenal contents into the esophagus) and other severe gastrointestinal problems such as reduced intestinal motility (hypomotility, “lazy bowel”)
• constipation
• small feet and cold feet syndrome
• breathing irregularities such as hyperventilation
• teeth grinding (bruxism)
• episodes of laughter or crying without an apparent cause
• low muscle tone (hypotonia)
• very limited ability to use the hands
• presence of certain typical autistic features
• scoliosis
• cortical visual impairment (CVI) or cortical blindness
• apraxia
• feeding and drinking difficulties, such as refusal to eat or drink, including complete refusal of all intake
• fragmented / disrupted sleep
• characteristic features such as side gaze or the habit of crossing one leg over the other
• mental disorder