What is CDKL5 Deficiency Disorder?

 CDKL5 deficiency disorder (CDD) is a rare developmental epileptic encephalopathy (DEE) caused by changes (mutations) in the CDKL5 gene. CDD has been classified as a DEE because the genetic change causes both epileptic activities as well as severe impairment of development. Previously known as serine/threonine-protein kinase 9 (STK9), CDKL5 stands for cyclin-dependent kinase-like 5, and mutations in this gene were first identified as disease-causing in 2004.

The hallmarks of CDD are the onset of seizures at a very early age, (usually about 3 months but can be as early as the first week of life) and severe neurodevelopmental delay impacting cognitive, motor, speech, and visual function. CDD can manifest in a broad range of clinical severity and is often associated with other symptoms such as gastrointestinal and sleep disturbances.

The core symptoms of CDD include epileptic seizures starting early in life, epileptic spasms often occurring without hypsarrhythmia, multiple different types of seizures, limited ability to walk, limited hand skills, lack of eye contact, constipation, sleep difficulties, intellectual disability, etc.

CDKL5 Deficiency Disorder (CDD), a rare genetic disease, has been designated with a new disease code in the International Classification of Diseases (ICD), the medical classification list from the World Health Organization (WHO). The CDKL5 Deficiency Disorder diagnostic code will be incorporated in the October 1, 2020 classification revision. The unique ICD-10 code will facilitate clinical and epidemiological research and improve patient care.

Diagnosis is initially suspected based on clinical presentation and confirmed by molecular genetic testing for CDKL5 mutations or multigene panel testing for early-onset epilepsy.

CDKL5 deficiency disorder (CDD) is a complex of clinical symptoms whose clinical understanding remains limited, with most information being derived from small patient groups seen at individual centers. CDD 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. Besides, CDD is one of the most common monogenic pediatric epilepsies, with several thousand patients estimated in the US and Europe alone.

The biology of the CDKL5 protein and its deficiency is so poorly understood at present that there are currently significantly less investigational therapies being studied. The identification of causative mutations within the CDKL5 gene on the X chromosome has led to the proposal of several therapeutic strategies to treat and eventually cure the disorder.

First, therapies to replace the mutated gene or protein with a functional version are being developed; this is an approach which has proven successful for certain diseases associated with the mutation of a single gene.

Second, targeted genome editing to correct the mutation in affected cells has also been proposed, based on transformational technologies such as CRISPR-mediated site-directed DNA modification.

Third, strategies are being investigated to target, in girls, the reactivation of the unmutated CDKL5 gene on the silenced X chromosome in a process called X reactivation. Finally, drug repurposing efforts are underway using bioinformatics and systems biology approaches to identify drugs developed for other diseases which might be effective against one or more of the symptoms of CDKL5 deficiency. Currently, no curative or specific therapies are available for individuals with the Cyclin-Dependent Kinase-Like 5 Deficiency Disorder, so medical management is symptomatic and supportive.

Several medications (anticonvulsant monotherapy) are recommended to control the symptoms of CDKL5, and in non-effectiveness of the medication, surgical therapies are performed. In many cases, the physical symptoms of CDKL5 can be alleviated and managed with a robust regimen of therapies such as occupational therapy, speech therapy, and vision therapy.

One of the most common features of CDKL5 Deficiency Disorder is seizures that are typically challenging and are often the most difficult health issue to manage. No one anticonvulsant has been found to be uniformly effective, and often multiple anticonvulsants are needed. If seizures are refractory (not responding to the usual medications), then other treatments such as steroids and/or Intravenous Immunoglobulin (IVIG) are suggested. If medications are not effective, other treatment options include Implantation of a Vagus Nerve Stimulator (VNS) and Corpus Callosotomy.

Dietary modifications, such as the ketogenic diet, have shown variable improvement in some individuals having some autistic-like tendencies. However, these rigid dietary changes must only be implemented under close medical supervision and can be demanding on families. Physiotherapy/physical therapy is also of benefit in improving overall muscle tone, trunk stability, strengthening, balance, and prevention of foot deformities, maintaining foot alignment and keeping heel cords lengthened.

The full spectrum or extent of CDKL5 disorder is not known at this time. Recent research suggests that there is a functional interaction between CDKL5 and MECP2, and it may be that therapies currently being trialed in MECP2 mutation-positive Rett syndrome patients may have a therapeutic role in individuals with CDKL5 mutations.

There is still much to learn about CDKL5 deficiency disorder, including why it occurs, what causes its symptoms, and the best way to treat it. With continued research and awareness of CDKL5, it is expected to build a more comprehensive understanding of this disorder, develop diagnostic, therapeutic and preventative standards of care, and continue the search for effective treatments and a desperately needed cure.

Furthermore, pharmaceutical companies, such as Takeda and Ovid Therapeutics and Marinus Pharmaceuticals, are actively working toward the development of potential therapies in order to fulfill the unmet medical needs of the currently used therapeutics.

Overall, the rise in CDKL5 Deficiency Disorder population increased funding by governmental bodies, and vigorous R&D activities are further expected to propel the CDKL5 Deficiency Disorder market during the forecast period.

Extensive research and development activities of pharmaceutical companies with drugs in clinical trials along with the expected launch TAK-935/OV935 (Takeda and Ovid Therapeutics) and Ganaxolone (Marinus Pharmaceuticals) shall fuel the growth of the market during the forecast period.

The dynamics of CDKL5 Deficiency Disorder (CDD) market is anticipated to change in the coming years owing to the improvement in the diagnosis methodologies, raising awareness of the diseases, incremental healthcare spending across the world, and also expects the launch of emerging therapies.