What is CDKL5 Deficiency Disorder?

What is CDKL5 Deficiency Disorder?

CDKL5 Deficiency Disorder (CDD) is a rare neurological condition in young children resulting in seizures and severe developmental delay. CDD is caused by 'mistakes' in a gene on the X-chromosome called CDKL5. The genetic association was only identified in 2005. 

Who does it affect?

CDD affects between one in 40,000 and one in 60,000 people. Worldwide, roughly 1500 patients have been diagnosed with CDD, but because many affected individuals may be undiagnosed or misdiagnosed, it is believed that the actual number is likely quite higher.

A genetic 'mistake' in CDKL5 is very rarely inherited from a person's parents. However, there are some families with more than one affected child, even when the parents  are not carriers of CDKL5 mutations, and do not have any symptoms. 

What are the symptoms?

A characteristic feature of CDD is seizures that begin in early infancy or even at birth, with CDD impacting nearly all aspects of everyday function. Symptoms can range in terms of severity, with some getting worse over time, including:

  • Intellectual disability (usually severe)
  • Limited mobility and low muscle tone
  • Limited use of hands
  • Lack of eye contact and visual impairment
  • Inability to speak
  • Constipation
  • Irregular sleep

What causes CDD?

CDD is caused by 'mistakes' in the Cyclin Dependent Kinase like 5 (CDKL5) gene, which provides the instructions for making a protein called CDKL5. In the majority of affected individuals, the genetic errors in CDKL5 are spontaneous.

CDD is an X-linked disorder which means that the CDKL5 mistake causing CDD is carried on the X chromosome.  

In girls with CDD, one of their X chromosomes has a faulty copy of the CDKL5 gene, whereas the other X chromosome has a working copy of the CDKL5 gene, which may lessen the negative effect of the faulty gene on the other X chromosome. Because boys have only one X chromosome, if it has a CDKL5 mistake, the CDD is usually even more severe.

What are the gaps in research we are trying to fill?

We know the CDKL5 protein is vital for normal brain development and function but the challenge we face is that we do not really know what the CDKL5 protein does inside brain cells. Because we do not know much about CDKL5 function, it's much harder to develop targeted therapies for CDD. Controlling seizures remains a major challenge for CDD because they are difficult to control with current medications. Therefore, there is an urgent need to advance our understanding of CDD biology so that we can find better therapies that could significantly improve development in CDD sufferers.

What research is taking place now?

We have a highly skilled team of researchers using complementary pioneering techniques to unravel CDKL5 function in a bid to find new and effective therapies for this currently untreatable disorder.

We are using skin cells from CDD patients, which we then reprogram into stem cells. We then 'train' these cells to become brain cells and use these cells to identify novel brain-specific critical pathways regulated by CDKL5. The ultimate aim of this is to identify new and effective treatments for children with CDD. 

Author:
Dr Nicole Van Bergen is a Senior Research Fellow based in the Brain and Mitochondrial Research Group at MCRI. In this role she coordinates the CDKL5 stem cell research program at MCRI. Nicole also has a keen interest in functional validation for new genes associated with childhood neurological conditions. Nicole was recently awarded the CDKL5 Junior Research Award, and has received funding from the Foundation for Children for her research.

Reference: 

  • Weaving, L.S., et al., Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation. Am J Hum Genet, 2004. 75(6): p. 1079-93.
  • Tao, J., et al., Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene are associated with severe neurodevelopmental retardation. Am J Hum Genet, 2004. 75(6): p. 1149-54.
  • Olson, H.E., et al., Cyclin-Dependent Kinase-Like 5 Deficiency Disorder: Clinical Review. Pediatr Neurol, 2019.
  • Howden, S.E., et al., Simultaneous Reprogramming and Gene Correction of Patient Fibroblasts. Stem Cell Reports, 2015. 5(6): p. 1109-1118.
  • Van Bergen, N.J., et al., Mutations in the exocyst component EXOC2 cause severe defects in human brain development. J Exp Med, 2020. 217(10).
  • Van Bergen, N.J., et al., Deficiencies in vesicular transport mediated by TRAPPC4 are associated with severe syndromic intellectual disability. Brain, 2019. 143(1): p. 112-130
  • Van Bergen, N.J., et al., NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses. Brain, 2019. 142(1): p. 50-58.