CDKL5 deficiency disorder

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

CDKL5 deficiency disorder is characterized by seizures that begin in infancy, followed by significant delays in many aspects of development.

Seizures in CDKL5 deficiency disorder usually begin within the first 3 months of life, and can appear as early as the first week after birth. The types of seizures change with age, and may follow a predictable pattern. The most common types are generalized tonic-clonic seizures, which involve a loss of consciousness, muscle rigidity, and convulsions; tonic seizures, which are characterized by abnormal muscle contractions; and epileptic spasms, which involve short episodes of muscle jerks. Seizures occur daily in most people with CDKL5 deficiency disorder, although they can have periods when they are seizure-free. Seizures in CDKL5 deficiency disorder usually do not get better with treatment.

Development is impaired in children with CDKL5 deficiency disorder. Most have severe intellectual disability and little or no speech. The development of gross motor skills, such as sitting, standing, and walking, is delayed or not achieved. About one-third of affected individuals are able to walk independently. Fine motor skills, such as picking up small objects with the fingers, are also impaired; about half of affected individuals have purposeful use of their hands. Most people with this condition have vision problems (cortical visual impairment).

Other common features of CDKL5 deficiency disorder include repetitive hand movements (stereotypies), such as clapping, hand licking, and hand sucking; teeth grinding (bruxism); disrupted sleep; feeding difficulties; and gastrointestinal problems including constipation and backflow of acidic stomach contents into the esophagus (gastroesophageal reflux). Some affected individuals have episodes of irregular breathing. Distinctive facial features in some people with CDKL5 deficiency disorder include a high and broad forehead, large and deep-set eyes, a well-defined space between the nose and upper lip (philtrum), full lips, widely spaced teeth, and a high roof of the mouth (palate). Other physical differences can also occur, such as an unusually small head size (microcephaly), side-to-side curvature of the spine (scoliosis), and tapered fingers.

CDKL5 deficiency disorder was previously classified as an atypical form of Rett syndrome. These conditions have common features, including seizures, intellectual disability, and other problems with development. However, the signs and symptoms associated with CDKL5 deficiency disorder and its genetic cause are distinct from those of Rett syndrome, and CDKL5 deficiency disorder is now considered a separate condition.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

As its name suggests, CDKL5 deficiency disorder is caused by variants (also known as mutations) in the CDKL5 gene. This gene provides instructions for making a protein that is essential for normal brain development and function.

Variants in the CDKL5 gene reduce the amount of functional CDKL5 protein or alter its activity in nerve cells (neurons). A shortage (deficiency) of CDKL5 or impairment of its function disrupts brain development, but it is unclear how these changes cause the specific features of CDKL5 deficiency disorder.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

This condition is inherited in an X-linked dominant pattern. The CDKL5 gene is located on the X chromosome, which is one of the two sex chromosomes. In females (who have two X chromosomes), a variant in one of the two copies of the CDKL5 gene in each cell causes the disorder. In males (who have only one X chromosome), a variant in the only copy of the gene causes the disorder. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Almost all cases of this condition result from new (de novo) variants in the CDKL5 gene that occur during the formation of reproductive cells (eggs or sperm) or in early embryonic development. These cases occur in people with no history of the disorder in their family.

Researchers suspect that the signs and symptoms of CDKL5 deficiency disorder vary in severity in part because of a process called X-inactivation. Early in embryonic development in females, one of the two X chromosomes is permanently inactivated in somatic cells (cells other than egg and sperm cells). X-inactivation ensures that females, like males, have only one active copy of the X chromosome in each body cell. Usually X-inactivation occurs randomly, such that each X chromosome is active in about half of the body cells. This means that about half of cells have an active X chromosome with a CDKL5 gene variant, and half have an active X chromosome without the variant. However, groups of cells that arise from a single original cell have the same copy of the X chromosome inactivated, so the distribution is not exactly half and half. The proportion of neurons in the brain that have the active X chromosome with the variant helps determine how severe the features of the condition are in a given individual. Females with a higher percentage of neurons with the variant have more severe signs and symptoms than females with a lower percentage of neurons with the variant.

Because males have only one X chromosome in each cell, the altered version of the CDKL5 gene is active in all cells. Affected males have no normal copies of the gene.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

CDKL5 deficiency disorder appears to be a rare condition with an incidence of 1 in 40,000 to 60,000 newborns. About 90 percent of those diagnosed with CDKL5 deficiency disorder are girls.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Generalized tonic seizure · Very frequent (99-80%)

A generalized tonic seizure is a type of generalized motor seizure characterized by bilateral limb stiffening or elevation, often with neck stiffening without a subsequent clonic phase. The tonic activity can be a sustained abnormal posture, either in extension or flexion, sometimes accompanied by tremor of the extremities.

Autistic behavior · Frequent (79-30%)

Persistent deficits in social interaction and communication and interaction as well as a markedly restricted repertoire of activity and interest as well as repetitive patterns of behavior.

Bilateral tonic-clonic seizure · Frequent (79-30%)

A bilateral tonic-clonic seizure is a seizure defined by a tonic (bilateral increased tone, lasting seconds to minutes) and then a clonic (bilateral sustained rhythmic jerking) phase.

Broad forehead · Frequent (79-30%)

Width of the forehead or distance between the frontotemporales is more than two standard deviations above the mean (objective); or apparently increased distance between the two sides of the forehead.

Broad proximal phalanges of the hand · Frequent (79-30%)

Increased width of the proximal phalanges of the finger.

Bruxism · Frequent (79-30%)

Bruxism is characterized by the grinding of the teeth including the clenching of the jaw and typically occur during sleep.

Cerebral visual impairment · Frequent (79-30%)

A form of loss of vision caused by damage to the visual cortex rather than a defect in the eye.

Coldness · Frequent (79-30%)

Relative coldness of a body part to palpitation, often acccompanied by feelings of coldness.

Other findings in the same source

From: Orphanet

Additional reported features include Constipation (Frequent (79-30%)); Deep philtrum (Frequent (79-30%)); Deeply set eye (Frequent (79-30%)); Delayed gross motor development (Frequent (79-30%)); Delayed speech and language development (Frequent (79-30%)); Everted lower lip vermilion (Frequent (79-30%)); Feeding difficulties (Frequent (79-30%)); Focal-onset seizure (Frequent (79-30%)); Gait disturbance (Frequent (79-30%)); Gastroesophageal reflux (Frequent (79-30%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing CDKL5 deficiency disorder is Neurology, with a neurologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Which nervous-system findings help explain the symptoms?
• Would an assessment of walking, communication or daily function be helpful?
• Are rehabilitation or other specialist services relevant?

Treatment discussions and follow-up

Where the source describes treatments, these are an overview of possible care, not a prescription for an individual. Ask which option applies to the confirmed diagnosis, what benefit is expected, what adverse effects to watch for and how progress will be assessed. Availability, approvals and local practice can differ from the country described in the source.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.