NORD gratefully acknowledges Dr. Helen Leonard, Telethon Kids Institute, Perth, Australia; Prof. John Christodoulou, NSW Centre for Rett Syndrome Research, Children's Hospital at Westmead, Sydney, Australia; and Dr. Katheryn Elibri Frame, International Foundation for CDKL5 Research, for assistance in the preparation of this report.
Synonyms of CDKL5
- CDKL5 deficiency
- CDKL5 disorder
CDKL5 is a rare X-linked genetic disorder that results in severe neurodevelopmental impairment and early onset, difficult to control seizures. CDKL5 stands for cyclin-dependent kinase-like 5, and is a gene located on the X chromosome.
Most of the children affected by the CDKL5 disorder suffer from seizures that begin in the first few months of life. Most cannot walk, talk or feed themselves, and many are confined to a wheelchair. Some may have scoliosis, visual impairment, gastrointestinal difficulties, respiratory and sleep problems.
CDKL5 mutations were initially thought to be specifically associated with the Hanefeld variant of Rett syndrome, where early onset seizures are a prominent feature. However, the profile (phenotype) of the CDKL5 disorder has been expanded to include early epileptic seizures and later onset intractable seizure disorders commonly including myoclonus without clinical features of Rett syndrome. More recent studies suggest that the predominant characteristic associated with CDKL5 mutations is the so-called epileptic encephalopathy, the onset of severe seizures in the first six months of life (often within the first 3 months), and poor subsequent neurocognitive development and commonly the presence of repetitive hand movements (stereotypies).
CDKL5 mutations have been found in children diagnosed with infantile spasms, West syndrome, Lennox-Gastaut syndrome, Rett syndrome, and autism. The full spectrum of the CDKL5 disorder is unknown at this time. It is possible that there are affected individuals who have mild symptoms and no seizures.
The first report associated with an abnormality of the CDKL5 gene was in a child with a congenital eye problem known as retinoschisis, severe intellectual disability and seizures. This patient had a deletion of the end of the CDKL5 gene, which overlaps with the end of the RS1 gene, the latter being associated with the eye abnormality in this patient. Subsequently, disruption of the CDKL5 gene due to X:autosome translocations was reported in two patients with X-linked infantile spasm syndrome (ISSX). The identification of the association between CDKL5 mutations and Rett syndrome followed. Weaving et al reported a rare family in which one of identical twin sisters had atypical Rett syndrome with early onset seizures, while the other twin had autism and intellectual disability, but did not have Rett syndrome. They had a brother who had severe neonatal onset epileptic encephalopathy. Another female with atypical Rett syndrome and early onset seizures and a different CDKL5 mutation, was also reported by this group. Tao, et al reported two cases with a similar presentation and different mutations of the CDKL5 gene.
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