What is CDKL5 Deficiency Disorder

CDKL5 is a rare X-linked genetic disorder that results in early onset, difficult to control, seizures, and severe neuro-developmental impairment. CDKL5 is classed as a rare disease, however more and more children and indeed adults are being diagnosed every day.

The CDKL5 gene provides instructions for making a protein that is essential for normal brain development. Although little is known about the protein’s function, it may play a role in regulating the activity of other genes, including the MECP2 gene (or Rett Syndrome). The CDKL5 protein acts as a kinase, which is an enzyme that changes the activity of other proteins by adding oxygen and phosphate atoms (a phosphate group) at specific positions. Researchers have not yet determined which proteins are targeted by the CDKL5 protein.

Most children affected by CDKL5 suffer from seizures that begin in the first few months of life. Most cannot walk, talk or feed themselves, and many are confined to wheelchairs, dependent on others for everything. Many also suffer with scoliosis, visual impairment, sensory issues and various gastrointestinal difficulties. As time has gone on it appears that there might be other symptoms that play a role in the condition.

This is the current list of the most common symptoms, however it is important to note that not every child will have what is listed, and therefore there appears to be a wide spectrum in terms of the severity of some children, from moderately affected to profoundly affected.

  • Epileptic seizures starting in the first 8 months of life.
  • Infantile spasms (in about 50%)
  • Many different types of epilepsy usually including myoclonic jerks
  • Hand stereotypies in the form of hand clapping, tapping, movements or mouthing
  • Marked developmental delay
  • Limited or absent speech
  • Hypersensitivity to touch, for example dislike of hair brushing
  • Lack of eye contact or poor eye contact, but may have intensive eye interaction
  • Gastro‐esophageal reflux, and other severe gastrointestinal problems such as low gut motility
  • Constipation
  • Small, cold feet
  • Breathing irregularities such as hyperventilation
  • Grinding of the teeth
  • Episodes of laughing or crying for what appears to be no reason
  • Low/Poor muscle tone
  • Very limited hand skills
  • Some autistic‐like tendencies
  • Scoliosis
  • Cortical Visual Impairment (CVI), aka “cortical blindness”
  • Apraxia
  • Eating/drinking challenges, such as refusal to eat and drink, as well as giving up altogether
  • Interrupted sleep
  • Characteristics such as a sideways glance, and habit of crossing legs

History of CDKL5

resizedimage407158 CDKL5 in X chromosome

The story of CDKL5 begins with Rett Syndrome, which was first described in 1966 by Andreas Rett, an Austrian paediatrician. By the 1980’s the characteristics of the syndrome had been firmly established. Affected children typically have normal development for the first 6 to 18 months of life, followed by arrest and then regression of their development. A number of typical clinical features then develop including loss of motor and cognitive function, loss of communication ability, spinal problems (scoliosis), epilepsy and characteristic stereotypic hand movements. Subsequent studies showed that in the majority of cases, Rett Syndrome was caused by mutations in a gene on the X-chromosome known as the MECP2 gene.

In 1998, a new gene was identified in the Xp22 region of the X-chromosome. A number of genetic conditions had previously been mapped to this region. The new gene was initially called the STK9 (Serine- Threonine Kinase) gene. In 2003, a study was published that linked disruption in this gene to infantile spasms and mental retardation. The STK9 gene subsequently became known as CDKL5, which stands for Cyclin- Dependant Kinase-Like 5.

In 2004, separate case-studies were published by Dr. John Christodoulou and Dr. Vera Kalsceuer on mutations in CDKL5 producing severe neurodevelopmental disorder and mental retardation. These papers concluded that mutations in the CDKL5 gene gave rise to a phenotype (observable characteristics) that overlapped with Rett Syndrome. Over the next few years, further studies appeared from around the world including the UK, Italy, China and France. CDKL5 is now becoming recognised as a distinct condition in its own right.

Genes and mutations – what causes CDKL5?

To understand how a mutation can cause a condition like CDKL5, it is necessary to first understand how a normal gene works. A gene is composed of a chain of bases or base-pairs, and is a master plan for producing a protein, which is just a chain of amino acids. The gene can be thought of like a sentence, which has words that are made up of letters, with spaces between the words. A gene is made up of exons (the words) and introns (the spaces). The CDKL5 gene contains 24 exons, of which 21 provide the code for the protein. The base-pairs of the gene are effectively the letters, and the order of the base-pairs is essential to the formation of the protein. Every 3 base-pairs codes for an amino acid, which make up the protein, and if the order is corrupted by a mutation then the protein probably won’t be made properly and therefore won’t function properly. Examples of how mutations affect the gene are shown below using sentences.

One type of mutation is a deletion where a letter (base) is deleted and everything after that shifts along one place. So…….

The long and winding road
Deletion of a gives
The long ndw inding road!

Another type of mutation is a translation….

It’s been a hard day’s night and I’ve been working like a dog
A Translocation might give
It’s been a hard day’s dog and I’ve been working like a night

Although each sentence has been affected in a different way, the overall effect in each case is to alter the meaning of what was intended. Another CDKL5 mutation that has been described is a substitution, where one letter (base) is replaced by another, again altering the meaning of the sentence, or…. the meaning of the gene. This is how mutations work.

What is the CDKL5 protein and what does it do?

resizedimage359162 cdkl5

CDKL5 stands for Cyclin-Dependant Kinase-Like 5. A kinase is a protein that “energizes” other proteins into action, and there are about 500 kinases in the body. One particular group of kinases only become active when linked to another protein called Cyclin. They are therefore known as a Cyclin-Dependant Kinases (CDK) and they have an important role in the “cell cycle” whereby a single parent cell divides into 2 daughter cells. The CDKL5 gene codes for a protein that acts “Like” a Cyclin-Dependant Kinase, and there are 5 known CDKL proteins. CDKL1-4 are also involved with brain development in some way.

The CDKL5 gene is copied to produce a chain of amino acids that make up the CDKL5 protein. Biochemical factors and forces cause the protein chain to convolute into a 3-D structure. The CDKL5 protein is divided into 2 regions, the catalytic or kinase domain, and the C-terminal domain. The kinase domain is the main functional part of the protein but it is also clear from recent studies that the C-terminal also has an important role to play in the regulation of the function of the CDKL5 protein.

The exact role of the CDKL5 protein is not yet known but it has an important role in brain development and is also closely linked with the function of the MeCP2 protein associated with Rett Syndrome. Furthermore, it appears that the CDKL5 protein may be particularly important for brain development from the first few weeks of life onwards, when studies have shown its increasing presence within certain areas of the brain.

Does it matter which part of the CDKL5 gene the mutation affects?

resizedimage224142 keyWe don’t know yet! The function of the protein depends on its 3- D structure, which in turn depends on the correct sequencing of amino acids. A protein kinase can be thought of like a keywith a functional part (where the cuts are made that fit into the lock), and the part you hold (the bow). If the bow is broken, then it might work but not so well. However, if the cuts are wrong, or the key is just broken past the shoulder then the key is unlikely to work at all.

A mutation in the CDKL5 gene might have a similar sort of effect, in that, if it affects the part of the protein where the “cuts” are (the kinase domain) then this might have more of an effect than if the “bow” part of the protein is affected (in the C- terminal domain). It remains to be established whether or not such a relationship exists.