CDKL5. This is the Epilepsiome page on CDKL5, a gene for a severe, early onset encephalopathy. CDKL5 encephalopathy was initially considered to be part of the Rett Syndrome spectrum, but has since be recognized as a separate entity. It is one of the most common causes for severe genetic epilepsies.
Here are the most recent blog posts on CDKL5
- CDKL5 – this is what you need to know in 2015
- Publications of the week: CDKL5, KIF1A, and familial cortical tremor
- Sequencing for developmental disorders on a national level – the DDD(UK) study
- The OMIM epileptic encephalopathy genes – a 2014 review
- New epilepsy genes involved in epigenetics – a survey
In a nutshell. In 2015, CDKL5 is one of the most common causes of genetic epilepsies. The classical picture of CDKL5 encephalopathy is characterized by early onset seizures frequently starting before the age of three months. The epilepsy frequently progresses to Infantile Spasms and epileptic encephalopathy. The CDKL5 protein is a kinase involved in both regulation in the cytoplasm and the nucleus with many, largely unknown downstream targets. Given that the CDKL5 gene is located on the X chromosome, males are typically more severely affected than females.
Phenotype – Epilepsy. CDKL5 encephalopathy is an early onset epileptic encephalopathy where seizures usually manifest before the 3 months of age. CDKL5 is located on the X chromosome and the vast majority of patients are girls. Affected boys often have a more severe phenotype. The epilepsy in patients with CDKL5 encephalopathy has been suggested to occur in three typical stages including early epilepsy with focal seizures in the first stage at the age of 4 weeks to 6 months, followed by epileptic encephalopathy with Infantile Spasms in infancy and early childhood as the second stage and tonic seizures and late myoclonic epilepsy in childhood as the third stage. Seizures are usually refractory to antiepileptic medication and there is currently no clear consensus regarding the best treatment regimen. Movement disorders (hand-wringing stereotypy, chorea and ballisms) are also a reported feature.
Phenotype – Physical. Prior to the onset of seizures, patients typically present with muscular hypotonia and delayed gross motor development. In one study of 109 females and 18 males, 75% of females had attained sitting by 5 years, 25% had attained independent walking, 25% of males had attained independent sitting by 15 months, and only 1 (6%) of the males had attained independent walking. There is some suggestion that patients with CDKL5 have some subtle but shared dysmorphic features including a broad forehead, deep-set eyes, full lips and tapered fingers.
Phenotype – Development. The development of patients with CDKL5 encephalopathy has been investigated in smaller case series and some larger studies. More than 90% of patients with CDKL5 encephalopathy have profound developmental delay. Approximately one fourth of patients with CDKL5 encephalopathy gain the ability to walk independently by the age of 5 years or use single words. However, most patients with CDKL5 encephalopathy do not attain these skills. Historically, our concept of CDKL5 encephalopathy is derived from clinical criteria that were used for Rett Syndrome, as patients with CDKL5 encephalopathy may developed stereotypic hand movements that are seen in Rett Syndrome. However, CDKL5 encephalopathy is currently recognized as a separate clinical entity. Importantly, the regression seen in Rett Syndrome is typically not seen in patients with CDKL5 encephalopathy who have delayed development from birth.
Genetics. CDKL5 encephalopathy is due to haploinsufficiency of the CDKL5 gene coding for cyclin-dependent kinase-like 5. In earlier publications, this protein was also called serine/threonine protein kinase 9 (STK9). The gene is located on Xp22.13. Various genetic alterations including deletions, truncating mutations, and missense mutations have been described in patients with CDKL5 encephalopathy and these changes typically arise de novo. Initially, the gene was identified through translocations in two girls with a phenotype that was referred to as X-linked Infantile Spasms.
As of 2015, several hundred patients with CDKL5 encephalopathy have been reported and more than 200 pathogenic mutations are found in ClinVar. It was initially thought that a CDKL5 encephalopathy is extremely rare and severe in males given the X-chromosomal inheritance, but there are increasing reports of de novo CDKL5 mutations in boys with epileptic encephalopathies. The phenotype in boys is considered more severe.
Genotype-phenotype analyses have occurred however no consistent relationship has been observed. The observation that identical twin girls were discordant for phenotype, emphasizes the putative role of other genetic, epigenetic or environmental factors Mutations in the c-terminus (exons 19-21; codon >938) are thought to have minor or no significance and that pathogenicity should not be attributed to variants in this region.
Mechanism. The mechanism how mutations in CDKL5 lead to an epileptic encephalopathy remains poorly understood. The CDKL5 protein works as a kinase and phosphorylated proteins both in the cytoplasm and in the nucleus and many of the targets and downstream effects are not known yet. It is thought that absence of one functional copy of CDKL5 may lead to a domino effect on the downstream targets, resulting in a broad range of transcriptional abnormalities.
Therapeutics. A small number of reports describe therapeutic response in patients with CDKL5-related EE. Most recently, long-term efficacy of AEDs and KGD were retrospectively evaluated in 39 patients. Resistance to therapy was characteristic, with bromide and felbamate having the highest responder rates at 12 months (20% and 33% respectively).
Community. In contrast to many other rare epileptic encephalopathies, there is much clinical data out there on CDKL5 encephalopathy. For example, the CDKL5 community provides the CDKL5 Disorder International Registry Database that currently has more than one hundred patients included. Other locus-specific databases include Leiden University Medical Center and RettBase.