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.

• epileptické záchvaty (začínajú medzi 1-8 mesiacom života)
• infantilné spazmy (u cca 50% detí)
• rôzne typy epilepsie, zvyčajne zahŕňajúce myoklonické zášklby
• stereotypie rúk prejavujúcich sa tlieskaním, ťukaním, strkaním si rúk do úst
• výrazné oneskorenie vo vývoji
• obmedzená forma reči, resp. jej úplná absencia
• hypersenzitivita na dotyk, napríklad neznášanlivosť česania vlasov
• nedostatočný očný kontakt alebo naopak príliš intenzívna zraková interakcia
• gastroezofagálny reflux (spätný návrat žalúdočného, príp. i dvanástnikového obsahu do pažeráka) a ďalšie závažné gastrointestinálne problémy ako napr. nízka motilita čriev (lenivé črevá)
• zápcha
• nohy menšieho vzrastu a syndróm studených nôh
• dýchacie nezrovnalosti ako napr. hyperventilácia
• škrípanie zubami (bruxizmus)
• epizódy smiechu, resp. plaču bez zjavnej príčiny
• nízky svalový tonus (hypotonus)
• veľmi limitovaná schopnosť používať ruky
• niektoré typické autistické črty
• skolióza
• kortikálne poškodenie zraku (Cortical Visual Impairment- CVI), resp. kortikálna slepota
• apraxia
• problémy s jedením/pitím, ako napr. odmietanie jesť a piť, ako aj odmietanie úplne všetkého
• prerušovaný spánok
• charakteristické znaky ako napr. bočný pohľad alebo zvyk prehadzovať si nohu cez nohu
• mentálna porucha