CDKL5 is a

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

that provides instructions for making a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

called cyclin-dependent kinase-like 5 also known as serine/threonine kinase 9 (STK9) that is essential for normal brain development. Mutations in the gene can cause deficiencies in the protein. The gene regulates neuronal morphology through cytoplasmic signaling and controlling gene expression. The CDKL5 protein acts as a

kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...

, which is an enzyme that changes the activity of other proteins by adding a cluster of

oxygen Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as wel ...

and

phosphorus Phosphorus is a chemical element with the symbol P and atomic number 15. Elemental phosphorus exists in two major forms, white phosphorus and red phosphorus, but because it is highly reactive, phosphorus is never found as a free element on Ear ...

atoms (a

phosphate In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthophosphoric acid . The phosphate or orthophosphate ion is derived from phospho ...

group) at specific positions. Researchers are currently working to determine which proteins are targeted by the CDKL5 protein.CDKL5 on Genetics Home Reference
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Mutations

Mutations in the CDKL5 gene cause CDKL5 deficiency disorder. CDKL5 Deficiency had been thought of as a variant of Rett's Syndrome due to some similarities in the clinical presentation, but it is now known to be an independent clinical entity caused by mutations in a distinct X-linked gene, and is considered separate from Rett Syndrome rather than a variant of it. While CDKL5 is primarily associated with girls, it has been seen in boys as well. This disorder includes many of the features of classic Rett syndrome (including developmental problems, loss of language skills, and repeated hand wringing or hand washing movements), but also causes recurrent seizures beginning in infancy. Some CDKL5 mutations change a single protein building block (

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

) in a region of the CDKL5 protein that is critical for its kinase function. Other mutations lead to the production of an abnormally short, nonfunctional version of the protein. At least 50 disease-causing mutations in this gene have been discovered. Further confirmation that CDKL5 is an independent disorder with its own characteristics is provided by this study, published in April 2016, which concluded 'There were differences in the presentation of clinical features occurring in the CDKL5 disorder and in Rett syndrome, reinforcing the concept that CDKL5 is an independent disorder with its own distinctive characteristics'. At one time, mutations in the CDKL5 gene were said to cause a disorder called X-linked infantile spasm syndrome (ISSX) or

West syndrome Epileptic spasms is an uncommon-to-rare epileptic disorder in infants, children and adults. One of the other names of the disorder, West syndrome, is in memory of the English physician, William James West (1793–1848), who first described it in ...

. but this research established CDKL5 disorder as a distinct clinical entity.

Animal studies

GSK3β inhibitors in Cdkl5 knockout (Cdkl5 -/Y) mice rescues hippocampal development and learning. Likewise, IGF-1 treatment in CDKL5 null mice restores synaptic deficits.

Therapeutics

Aside from novel therapies with limited availability,

anticonvulsants Anticonvulsants (also known as antiepileptic drugs or recently as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of b ...

are the mainstay of treatment for most affected people. These have limited efficacy, pointing to a strong need to develop new treatment strategies for patients. Some treatments might show efficacy in a relevant proportion of patients, such as valproic acid, vigabatrin, clobazam or sodium channel blockers, as well as ketogenic diet A clinical trial of

Ataluren Ataluren, sold under the brand name Translarna, is a medication for the treatment of Duchenne muscular dystrophy. It was designed by PTC Therapeutics. Medical use Ataluren is used in the European Union to treat people with Duchenne muscular dys ...

for nonsense mutations in CDKL5 and

Dravet Syndrome Dravet syndrome, previously known as severe myoclonic epilepsy of infancy (SMEI), is an autosomal dominant genetic disorder which causes a catastrophic form of epilepsy, with prolonged seizures that are often triggered by hot temperatures or feve ...

has been announced. This same drug was approved by the UK's

National Institute for Health and Care Excellence The National Institute for Health and Care Excellence (NICE) is an executive non-departmental public body of the Department of Health and Social Care in England that publishes guidelines in four areas: * the use of health technologies withi ...

(NICE) for use in treating nonsense mutations in

Duchenne muscular dystrophy Duchenne muscular dystrophy (DMD) is a severe type of muscular dystrophy that primarily affects boys. Muscle weakness usually begins around the age of four, and worsens quickly. Muscle loss typically occurs first in the thighs and pelvis fol ...

. This drug did not show any efficacy in patients with CDKL5 mutations. Finally a CDKL5

protein replacement therapy Protein replacement therapy is a medical treatment that supplements or replaces a protein in patients in whom that particular protein is deficient or absent. There have been significant advances in this treatment. PRT is being tested in clinical tr ...

is in development.

Location

The CDKL5 gene is located on the short (p) arm of the X chromosome at position 22. More precisely, the CDKL5 gene is located from base pair 18,443,724 to base pair 18,671,748 on the X chromosome.

ICD-10

G40.42

References

External links

* *
Cure CDKL5 Disorder
resources for Families and Professionals - based in the UK
International Foundation for CDKL5 Research
- based in the US
CDKL5 Forum
- a professional forum to share current research on CDKL5 and to stimulate peer-group discussion
CDKL5 Foundation Netherlands
- CDKL5 Foundation based in holland for research, information and collaboration {{Portal bar, Biology, border=no EC 2.7.11