What Is CDKL5 Deficiency Disorder?

CDKL5 deficiency disorder (abbreviated to CDD) is a rare genetic disease that is characterised by changes (termed “mutations”) in the cyclin-dependent kinase-like 5 (full name for CDKL5) gene. The condition is classified as a “developmental epileptic encephalopathy” – in simpler terms, CDD patients suffer from significant damage to the brain, resulting in frequent seizures in newborns and infants, severe developmental delay, and lifelong disabilities.

Although the disorder is considered rare, it is also classed as one of the most common genetic conditions which results in severe childhood seizures. 1 in 40,000 – 60,000 live births have mutations in the CDKL5 gene, and symptoms of CDD can typically start in the first 3 months of life and can even begin within the first few hours or days.¹

As CDD was first identified in 2004, this disorder is considered relatively new; in this article, we will explain what has been discovered so far about this genetic disorder. Although a cure has not yet been found for the condition, this article will also outline the current treatments and management for CDD and describe the steps researchers are taking to improve the treatment and quality of life of patients.

Why is the CDKL5 gene so important?

To understand why mutations in the CDKL5 gene lead to such severe consequences, we must first understand the important function of the gene in the healthy development of the brain. The CDKL5 gene holds instructions to produce an essential protein, termed the “CDKL5 kinase1”. This kinase controls key changes in proteins found in the brain, known as “phosphorylation events”. What occurs in these events is that a part of the CDKL5 kinase termed the “phosphate group”, is transferred to other proteins in the brain.² This phosphorylation event essentially acts like a switch: the CDKL5 kinase, adding this phosphate group to other brain proteins, switches them on, allowing them to carry out crucial tasks involved in the development of the brain. In particular, the CDKL5 kinase and its phosphorylation events are essential in neuronal ( brain cell) formation, growth and maturation, as well as the functioning of synapses; connections between neurons which allow them to communicate with each other and form a robust network.³

When mutations occur in the CDKL5 gene, such as in CDD patients, the genetic instructions to create the CDKL5 kinase are altered, meaning that the kinase can no longer be produced correctly. This results in no CDKL5-dependent phosphorylation events happening in the brain, meaning that proteins which rely on these events to be “switched on” can no longer perform their function and aid the development of the brain, neurons and synapses. Examples of types of mutations the CDKL5 gene can undergo and cause disease include missense mutations³ (which is when there are “spelling errors” in the DNA code of the gene, meaning there is an error in the instructions to create the CDKL5 kinase) and frameshift mutations³ (which is when a piece of code of the gene is deleted, or an entirely new code is added to the gene, changing the entire structure of CDKL5). When CDKL5 undergoes these types of mutations, it is defined as a “non-functional gene”, as it has lost the function of providing those crucial instructions to make its kinase.

In other CDD patients, the CDKL5 gene can be completely deleted, and the same consequences as with a non-functional CDKL5 gene occur: no CDKL5 kinase is made, and no CDKL5-dependent phosphorylation events occur in various brain proteins, negative impacting brain development³

Regardless of whether the CDKL5 mutation present in a CDD patient is non-functional or absent, they are usually not inherited from the parents; instead, these mutations happen spontaneously in the patient³ This type of mutation is termed “de novo” (Latin for “new”).

CDD is an X-linked disease: what does this mean?

The CDKL5 gene is located on the X chromosome, which is one of the sex chromosomes containing essential genes found in all cells in the body. CDD is classed as an “X-linked dominant disorder”, as the mutation that causes the disease is located on the X chromosome.  

Due to the fact that the disease is an X-linked disorder, CDD is four times more prevalent in people assigned female at birth (AFAB) than people assigned male at birth (AMAB). 

AFABs have two X chromosomes in all their cells, whereas AMABs have one X and one Y chromosome in all their cells. If AMAB has a CDKL5 gene mutation, then all their cells will contain the mutation in their X chromosomes, as they only have one copy of the X chromosome in their cells. This indicates that they would have no normal copies of the CDKL5 gene in their body, and no functional CDKL5 kinase could be made to aid the development of their brain.⁴ This means that any AMAB with CDD often unfortunately die in the womb or experiences a much more severe version of CDD that often leads to death by the age of 20.⁵

In the case of AFAB, as they have two X chromosomes if a CDKL5 mutation occurs in one of the chromosomes, the other one remains normal. Another important feature of AFAB is a process called “X inactivation”, which consists of one of the two X chromosomes becoming permanently inactivated in all cells of the foetus except the egg cells. This process occurs to ensure that AFAB, like AMAB, only has one active copy of the X chromosome in its cells. X inactivation occurs randomly, meaning there is a varied distribution of both copies of the X chromosome being active within the body. Taking this into account for CDD, AFAB patients only have a percentage of their cells containing the active X chromosome where the CDKL5 gene mutation resides. Hence, some normal brain development can occur due to the presence of the functioning X chromosome distribution.⁴ This means that AFAB CDD patients do survive in the womb and live long enough to experience CDD symptoms and be diagnosed. 

The process of X inactivation also plays a role in the severity of the disease – if AFAB has a higher percentage of the active X chromosome containing the mutation in their body, then their symptoms will be more severe, whereas if AFAB has a smaller percentage of the active X chromosome containing the mutation, symptoms will be less severe.⁴

Symptoms of CDD

Symptoms in most CDD patients are present by the age of 3 months. However, it is also common for CDD newborns to show symptoms within the first hours, days or weeks after birth. The latest that symptoms start to show is 2 years of age. Life expectancy is difficult to estimate for many CDD patients, as the disease is relatively recently outlined. However, the oldest people reported to have CDD are over 60 years old, and there are many cases of CDD patients in their mid-30s and 20s. Hence, the disease is not necessarily fatal. However, it can be debilitating due to the various symptoms a patient can endure.

The following sections will provide details of the range of symptoms of CDD:

Seizures and epilepsy

The most common symptoms in CDD patients are seizures- this tends to be the first identifiable symptom within the first few months of life. Most CDD infants and children are subject to 1 – 5 seizures every day, and they are difficult to control with medication. These seizures can also occur during sleep, leading to severe sleep disruption in affected children. The types of seizures CDD patients face vary; the most common types include:

• Generalised tonic-clonic seizures – Also known as “grand mal seizures”, this type of seizure is what most people imagine when they hear the word “seizure”. The “tonic” part of the seizure is characterised by continuous limb and neck stiffening, leading to a sustained irregular posture of the body, which typically results in the person falling to the floor. The “clonic” part consists of rhythmic jerking of the body and tremors of the extremities of the body (hands and feet).
• Tonic seizures – Seizures which consist of abnormal contractions of the muscles and stiffening of the body.
• Epileptic spasms – Tonic seizures of the arm, leg and head, which typically only last a couple of seconds.

Some CDD patients experience a variety of seizure types all within one day, whereas other patients experience only one type of seizure at a time, and this singular type can change over time. This makes the disease incredibly variable and difficult to control.

Cognitive and motor impairments

The cognitive and motor development of a CDD patient is severely impaired and delayed. Examples of deficits include:

• Limited development of gross motor skills (actions which involve whole body movement) – examples include sitting, standing, and walking. Only a third of CDD patients are able to walk independently.⁶
• Limited development of fine motor skills (actions which involve using the small muscles in hands and wrists) – examples include holding a pen, getting dressed, and brushing teeth.
• Severe intellectual disability.
• Absent or limited speech.

Physical features

The typical hallmark physical features of CDD patients include the following:

• Decreased / low muscle tone (known as hypotonia).
• Broad, prominent forehead.
• Large, deep-set eyes, which often lead to visual impairment. A distinctive feature of CDD patients includes the inability to focus their eyes to a specific spot (known as eye fixation.⁷   
• Widely-spaced teeth.
• Enlarged philtrum (the space between the nose and the upper lip of the mouth).
• Microcephaly (abnormally small head size).
• Scoliosis.

Other symptoms

Other common symptoms that CDD patients can experience include:

• Problems with feeding. In fact, around 1 in 5 children affected by CDD use a feeding tube.⁶
• Problems with grinding their teeth excessively.
• Various gastrointestinal problems – including constipation, reflux, and excessive air swallowing, which in turn amplify issues with feeding.

How is CDD diagnosed?

A child is suspected to have CDD if they suffer from early onset seizures, as well as distinct delays in their development. When this is the case, they are referred to see a child neurologist, who will assess the following:

• Symptoms of the child.
• Family history – On some rare occasions, multiple siblings from the same family can be affected by CDD, indicating that either parent could have a small number of cells which contain a CDKL5 mutation, which was then passed to their children (this is known as “parental mosaicism¹”)
• Physical examination.

The following steps after the initial examination include a series of tests to officially diagnose CDD:

• MRI brain imaging is done to assess any non-specific abnormalities in the brains of suspected patients.
• Electroencephalography (EEG) test – Done to assess epilepsy in suspected patients.
• Genetic testing – These examinations include taking a sample of either blood, skin, tissue, or hair and assessing whether the patient has any mutations in their CDKL5 gene and changes in their CDKL5 kinase.

It is crucial that all suspected patients undergo genetic testing, as this is the only examination that is used to officially diagnose CDD. This is because CDD symptoms can often overlap with symptoms from other neurological diseases, such as the X-linked neurological disorder Rett syndrome.⁸ Rett syndrome is also typically characterised by cognitive and motor problems, seizures, and gastrointestinal dysfunction. However, unlike CDD, 95% of Rett syndrome cases are caused by mutations in another gene: methyl-CpG-binding protein 2 (MECP2).⁸ Hence, genetic testing is crucial to distinguish CDD from other similarly-presenting disorders, to make sure the patient is getting the most effective treatment plan.

Treatment and management for CDD

As there is no cure for CDD, the current treatment plan for the disease is based on the symptoms the patient is experiencing and requires a multidisciplinary approach (a combination of several therapies).

Seizure management

With 90% of CDD patients experiencing severe epileptic fits, a lot of focus is placed on how to help CDD patients minimise the frequency and severity of their seizures. Over the past couple of years, a new anti-seizure medication, named Ganaxolone, has been approved in the US and the European Union as the first anti-seizure medication for CDD, as it has been found to significantly reduce the frequency of major seizures related to CDD.⁹ CDD children aged 2 years and above can take this medication orally three times a day in order to control their seizures. The UK is also currently reviewing this drug as a medication for CDD, with a decision expected to be made by November 2023.

Other medications that is currently used to manage seizure symptoms in CDD patients include non-specific anti-epileptic medication. The medication used is patient-dependent: dependent on the types of seizures the patient is experiencing, the potential side effects of the medication, and whether the administration of the drug could interact with and affect any other medication the patient may be on. Therefore, it is important that the nature of a patient’s seizures and how they change over time is monitored to find the best treatment plan.

However, it is common that CDD seizures do not respond well to anti-epileptic medication. When this is the case, other treatments are used instead:

• Ketogenic diet – This diet consists of a high-fat, low-carbohydrate, moderate-protein intake. For 80+ years, this diet has been found to be effective in treating epileptic fits that cannot be controlled with drugs or surgery.¹⁰
• Vagus nerve stimulation – This type of treatment sends little pulses of electricity to the vagus nerve (which is the nerve that runs from the neck to the brain). This stimulation can not only help minimise seizures but also improve patient behaviour.¹¹
• Surgery – Surgery for CDD patients is used as a “last resort” treatment if all of the above do not seem to work in controlling their seizures. The most common type of surgery CDD patients can undergo is the corpus callosotomy surgery, which consists of splitting the part of the brain called the corpus callosum, a bundle of important nerves that connect the two sides of the brain.¹²

Non-pharmaceutical management of other symptoms

For all other symptoms, these are mostly treated with non-pharmacological management. The following list are the common therapies used to treat the other physical symptoms of CDKL5 patients:

• Physical therapy/physiotherapy 
• Occupational therapy
• Visual therapy
• Speech and language therapy 
• Sleep behavioural assessments
• For patients with complications in standing up sitting, or moving, appropriate braces can be given (for example, scoliosis braces, ankle-foot-orthoses, and hand splints)

Ongoing research initiatives for CDD

Research into the nature and history of CDD and how to effectively treat its symptoms is far from complete. Due to this, there are numerous organisations founded to help fight CDD, all of which contribute funding to studies which aim to improve understanding of the disease and find effective treatments.

One of the main organisations driving the ongoing research is the International Foundation for CDKL5 Research, which is determined to find better therapeutics for CDD patients. The following are examples of clinical trials that are currently being carried out:

• GEMZ Study – This clinical trial is assessing whether the medication fenfluramine hydrochloride can minimise seizures in CDD patients aged between 2 and 35.
• The Pacific Study – The pharmaceutical company Longboard Pharmaceuticals is evaluating the safety and tolerability of the oral drug LP352 as a potential medication to diminish drug-resistant seizure frequency in development epileptic encephalopathy patients, including CDD patients.

Other prominent organisations who are dedicated to aiding CDD patients include:

• International CDKL5 Disorder Database – Established in 2012, this association collects data from families throughout the world who have children with CDD, and this data is used worldwide for various laboratory and observational experiments in order to understand the disease better.
• Cure CDKL5 – This UK-based charity was specifically created by parents of children who suffer from CDD. Their purpose is to spread awareness of the disease, fundraise for the disease, and to provide comfort for caregivers of CDD patients.
• CDKL5 Centres of Excellence – There are various UK centres primarily based in Bristol, recognised by the NHS, which provide specialist support and care for CDD patients. These centres include the University Hospitals Bristol and Weston and the Bristol Royal Hospital for Children.

Summary

To summarise, CDD is a rare infantile neurological disorder triggered by mutations in the CDKL5 gene, resulting in abnormal brain development. Symptoms which characterise this disease include severe drug-resistant seizures from birth and significant delays in the development of the child. Although there is no current cure, a wide variety of promising research is taking place all over the world, dedicated to improving the quality of life of CDD patients and finding an effective cure. With such international collaboration, we are hopeful that this disease can be defeated.

FAQs

What is the cause of CDKL5 deficiency disorder?

CDKL5 deficiency disorder (CDD) is defined by changes (termed mutations) in the CDKL5 gene, however the exact cause behind why these mutations occur is unknown. Most mutations in CDD patients occur spontaneously and have not been passed down from parents. However, there are rare cases of the disease where multiple siblings develop CDD due to having the same mutation in their CDKL5 gene, indicating that these siblings developed the disease via inheritance of the CDKL5 mutation through their parents. This suggests that family inheritance can be the cause of some rare CDD cases.

What is the life expectancy of a patient with CDKL5 deficiency disorder?

As the disease was only discovered roughly 20 years ago, there is not enough research regarding the natural history of CDD to know the average life expectancy of a patient. However, the oldest reported patients of CDD are in their 60s.

Where is CDKL5 found?

The CDKL5 gene is found on the X chromosome, and the protein the gene produces is mostly located in the brain. It aids normal brain, neuron and synapse development.

What are the key clinical features used to identify CDKL5 deficiency disorder patients?

Key clinical features used to identify children who are suspected to have CDD include early epileptic fits (in the first 3 months of life) and a severe decrease in muscle tone (hypotonia).