CDKL5 deficiency disorder: everything there is to know!

What is CDKL5 deficiency disorder? 

Also known as CDKL5 syndrome, CDKL5 deficiency disorder is a rare disease that develops in early childhood. It currently affects between 1/40,000 and 1/60,000 children worldwide.

It is characterized by early-onset epilepsy that becomes resistant to treatment over time. Delays in brain development are also characteristic of the disease.

The condition was recognized as a separate disease by the WHO in October 2020. At present, little is known about it.

What are the causes of CDKL5 deficiency disorder? 

It is an X-linked disorder: alterations in the CDKL5 gene on the X chromosome lead to a deficiency of the CDKL5 protein. Different types of gene alterations can be found in patients affected by the syndrome. The CDKL5 protein plays an important role in brain development during the post-natal period. Its absence or altered function is what causes the symptoms of the disease.

What are the symptoms? 

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 (within the first 8 months of life). Epilepsy often becomes progressively resistant to treatment. Seizures can take different forms: 

• Epileptic spasms: very brief seizures characterized by sudden flexion and/or extension, often in the arms,
  
• Myoclonic seizures: one or more spasms that may occur in the whole body or in one arm or leg, the patient remains conscious,
  
• Tonic seizures: manifested by a sudden fall, loss of consciousness, sustained tonic contraction of all muscles, apnea and bronchial and salivary hypersecretion,
  
• Tonic-clonic seizures: these seizures have two phases: the tonic phase (generalized muscle contraction with loss of consciousness) and the clonic phase (muscle relaxation) 
  

The alteration of the CDKL5 gene also affects brain development. Growth retardation is usually observed, with impaired gross motor skills (total absence of walking or difficulty walking) and language and behavioral disorders such as screaming, agitation, crying, anxiety, spasms. Patients may also experience sleep disturbances (sleepwalking, sleep apnea), gastrointestinal disorders, abnormalities in the functioning of the nervous system leading to low muscle tone (pharynx, stomach, heart, liver) or respiratory irregularities. 

Patients may also display characteristic behavior such as looking to the side or crossing their legs. 

In some children, a characteristic facial feature may be present: a broad forehead, deep-set eyes, a prominent philtrum (fold under the nose) and an outwardly curved lower lip. They may also suffer from scoliosis or visual impairments. The use of the hands may also be relatively limited. Patients may have difficulty swallowing, which makes drinking and eating difficult. 

Symptoms may vary from patient to patient. The disease can also have more or less severe forms. 

How is CDKL5 deficiency disorder diagnosed? 

The diagnosis is usually made by a neuropediatrician. Characteristic clinical manifestations may suggest the disease. Early diagnosis allows treatment to be initiated as soon as possible in order to minimize complications associated with epilepsy and multiple disabilities. 

A brain MRI may be performed to rule out other conditions that could cause the same symptoms, such as a brain malformation. MRI is usually normal in people with CDKL5 syndrome.

A metabolic work-up can also rule out other diseases, which may respond to biological markers in a different way than CDKL5 syndrome does. 

The diagnosis is made when the CDKL5 gene analysis shows alteration. This is done by using a molecular genetic technique to sequence the X chromosome and the gene in question.

In what way is CDKL5 deficiency disorder similar to other conditions? 

CDKL5 syndrome has recently been identified as an independent disease. It was discovered accidentally in patients initially diagnosed with Rett syndrome. These patients had the typical symptoms of Rett syndrome, which is characterized by early onset epilepsy, just like CDKL5 deficiency disorder, and by developmental delays. However, no alteration of the gene involved in Rett syndrome (the MEPC2 gene) was detected in these patients. Furthermore, patients with Rett syndrome may show a regression of acquired abilities (motor skills), which does not seem to be the case in CDKL5 syndrome.

Because of the similarity of symptoms, such as developmental delays and the presence of epilepsy in both diseases, they used to be confused in the past and their similarity may still lead to misdiagnosis. Genetic sequencing allows the precise qualification of the type of genetic alterations the patient suffers from.