Mutations in the CDKL5 gene, previously known as STK9,¹ can result in a wide variety of symptoms and disorders. Common symptoms in those with CDKL5 mutations include early seizures and severe intellectual disability, failure to develop appropriate motor skills, hypotonia, hand stereotypies, infantile spasms, persistent epilepsy and autism.² Studies have shown that the CDKL5 gene likely plays an upstream role in the same molecular pathway as MECP2, which is associated with Rett Syndrome, by mediating its phosphorylation. Mutations in CDKL5 have been associated with atypical variants of Rett Syndrome (RTT), and with X-linked Dominant Infantile Spasm Syndrome (ISSX2).³

RTT is a severe, progressive neurologic disorder, characterized by apparently normal development in the first 6-18 months, followed by rapid regression in intelligence, language and motor skills, and development of streotypic hand movements and autistic characteristics.

Atypical variants of Rett Syndrome include Infantile Spasm syndrome, also known as West syndrome or the Hanefeld variant. Due to lack of function of the protein associated with CDKL5, symptoms often include severe infantile spasms, profound global developmental arrest, hypsarrhythmia and severe mental retardation.⁴

Infantile Spasm Syndrome (ISSX) affects 2 to 5 individuals per 10,000 births. Symptoms linked to mutations in the CDKL5 gene account for mental retardation and seizures in all cases, hypotonia and hand stereotypes in 85%, and epilepsy, infantile spasms, and autism in 75% of patients. Approximately 17% of patients diagnosed with ISSX have a CDKL5 mutation.⁷

Boys with mutations in CDKL5 present with symptoms of severe encephalopathy and early-onset intractable epilepsy.⁵ CDKL5 mutations are X-linked dominant, and the majority of mutations are de novo.