CDKL5 deficiency disorder
What is CDKL5 syndrome?
Also known as CDKL5 deficiency disorder, this rare disease is characterised by early-onset, drug-resistant epilepsy and neurodevelopmental impairment (developmental delay). It is caused by a genetic mutation in the CDKL5 gene located on the X chromosome.
Historically considered as a special form of Rett syndrome, this disease was recognised by the WHO as CDKL5 Deficiency Disorder (CDD) and included in the International Classification of Diseases (ICD) in October 2020.
Its incidence is estimated to be between 1/40,000 and 1/60,000.
Symptoms of CDKL5 syndrome
The main symptom of the disease is epilepsy, which manifests itself in the form of seizures. These seizures usually appear at an early age, in children as young as a few months old (within the first 8 months of life). Often, epilepsy gradually becomes resistant to treatment. Seizures can take different forms: epileptic spasms, myoclonic seizures, tonic seizures or tonic-clonic seizures.
Epileptic spasms are very brief seizures characterised by sudden flexion and/or extension, often in the arms.
Myoclonic seizures are characterised by one or more spasms that occur in the whole body or in one arm or leg, during which the patient remains conscious.
Tonic seizures are manifested by a sudden fall, loss of consciousness, sustained tonic contraction of all muscles, apnoea, airway mucus hypersecretion and salivary hypersecretion. Sometimes the affected person may bite the side of their tongue.
Tonic-clonic seizures occur in two phases: the tonic phase and the clonic phase. Loss of consciousness occurs during the tonic phase. The patient becomes stiff and has generalised muscle contractions all over the body for about 20 seconds. The seizure may last a few minutes. At the end of the seizure, the patient relaxes and falls asleep.
The alteration of the CDKL5 gene also impacts brain development. Growth delay is usually observed, which is most often manifested by developmental delays of gross motor skills, such as walking (total absence of walking or walking difficulties), and language and behavioural impairments that provoke screaming, agitation, crying, anxiety, spasms. Patients may also experience sleep disorders, gastrointestinal problems, abnormalities in the functioning of the nervous system leading to certain muscle disorders (pharynx, stomach, heart, liver) and irregular breathing.
Patients may have certain characteristic behaviour, such as looking to the side or crossing their legs.
In some children, a characteristic facial feature may be present: broad forehead, deep-set eyes, prominent philtrum (fold under the nose) and an outwardly curved lower lip. They may also suffer from scoliosis or eye disorders. The use of the hands is also relatively limited. The hands usually remain in a clapping position. Patients may have difficulty swallowing, which makes it hard for them to keep hydrated and to eat.
The symptoms are not the same for all patients, as the disease exists in more and less severe forms.
Causes and risk factors of CDKL5 syndrome
CDKL5 syndrome is caused by genetic changes in the CDKL5 gene located on chromosome X at position 22.
Chromosomes are the carriers of genes. A gene is a small section of a chromosome that codes for a particular characteristic in humans (eye colour, etc.). Genes are made up of nucleotides (the main component of all DNA) which form particular strings. These genes are then translated into strings of amino acids, proteins, which interact to form our bodies.
In the case of CDKL5 syndrome, the amino acid sequence is different or some amino acids are missing, which causes the symptoms. There is no single change in the CDKL5 gene that leads to this syndrome, different alterations in the gene can be the cause.
These changes in the CDKL5 gene can be de novo changes, meaning they do not come from the parents' DNA but have arisen incidentally.
They can also be inherited from a parent. Symptoms can also be due to mosaicism: the altered gene is only present in certain cells.
Diagnosing CDKL5 syndrome
The diagnosis is usually made by a neuro-paediatrician. Characteristic clinical manifestations may suggest the disease. Early diagnosis allows treatment to be initiated as soon as possible to minimise complications associated with epilepsy and multiple disabilities.
A brain MRI may be performed to rule out other causes that could provoke the same symptoms, such as a brain malformation. MRI is usually normal in people with CDKL5 syndrome.
A metabolic work-up can also help rule out other diseases, which respond to biological markers in a way that is different to CDKL5 syndrome.
The diagnosis is made when the CDKL5 gene analysis shows alteration. This is done by using a molecular genetics technique to sequence the gene in question.
Treating CDKL5 syndrome
Currently, there is no specific treatment for this condition. The disease management is based on treating the symptoms. Antiseizure medications, usually used to treat epilepsy, can reduce the symptoms. A ketogenic diet, originally used in treatment-refractory epilepsy, which limits carbohydrate intake (especially pasta, rice, bread) to 50g per day, also helps to regulate symptoms.
Non-drug therapies may be helpful: physiotherapy, psychomotor therapy, occupational therapy (assessment and necessary adaptations for people with motor disabilities), orthoptics (visual rehabilitation) and speech therapy.
Living with the disease
It is very difficult to predict life expectancy of a patient with CDKL5 syndrome. Currently, there are adults who are living with the syndrome. However, due to potential disabling conditions that may develop, life expectancy can be shortened.
Some patients adopt a ketogenic diet which helps to limit seizures.
There also exist certain tips that can help patients and their caregivers in their everyday life:
- Encouraging the child to drink through a straw so that he or she can drink independently
- Using a neck float in the bathtub so that the child can move in the water independently
- Using toys that make noise to attract the child's attention, for example a rainstick or a book made with different materials
Published 6 May 2022 • Updated 31 May 2022