NORD gratefully acknowledges Dr. Helen Leonard, Telethon Kids Institute, Perth, Australia, Heidi Grabenstatter, PhD, Science Director, International Foundation for CDKL5 Research and Amanda Jaksha, International Foundation for CDKL5 Research, for assistance in the preparation of this report.
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 the epileptic activity as well as the severe impairment of development. 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.1,2 CDD can manifest in a broad range of clinical severity and is often associated with other symptoms such as gastrointestinal and sleep disturbances.2,3 Although rare, the occurrence could be between ~1:40,000 and 1:60,000 live births,4 although an Australian population-based study suggested a lower incidence.5
Previously known as serine/threonine protein kinase 9 (STK9),6 CDKL5 stands for cyclin-dependent kinase-like 5 and mutations in this gene were first identified as disease-causing in 2004.7,8 The letters are an abbreviation of the scientific name of the gene which describes what it does. The CDKL5 gene provides instructions for making proteins that are essential for normal brain and neuron development.
The CDKL5 gene is located on the X chromosome. The X chromosome is one of the sex chromosomes; females have two X’s and males have one X and one Y chromosome. Although many identified patients are males, because of the location of the gene, this disorder mainly affects females. Affected males may have more severe symptoms than females.
Seizures are a major problem for patients with CDD because they are usually severe and difficult to control with medication.10,11 Multiple different types of seizures occur and include infantile spasms, myoclonic seizures and tonic-clonic seizures. Doctors have described more than 30 different types of seizures, and they are divided into two major categories — focal seizures and generalized seizures although not all seizures fit well into these categories. Some individuals have seizures that begin as focal seizures but then spread to the entire brain. Others may have both types of seizures but with no clear pattern.
Everyday functioning has been shown to be severely impaired in about a quarter of affected females and a lesser proportion of males able to walk independently.12 Fine motor skills, such as the ability to pick up small objects, are also impaired; about half of affected individuals have some purposeful use of their hands.12 About three quarters have been found to have cortical visual impairment.13 Most individuals have severe intellectual disability and little or no speech.12
Epileptic seizures starting early in life
Epileptic spasms often occurring without hypsarrhythmia
Multiple different types of seizures
Limited ability to walk
Inability to speak but may use complex gestures/vocalization
Limited hand skills
Lack of eye contact (cortical visual impairment)
Purposeless hand movements (stereotypies)
Poor muscle tone (hypotonia)
Breathing irregularities (such as hyperventilation)
Characteristics such as a sideways glance and habit of crossing legs
Behavioural symptoms such as anxiety and social avoidance
The International CDKL5 Disorder Database was established in September 2012 and is continuing to collect data from families with a child with CDD throughout the world. This database provides the capacity to collect important information which will help to better understand this disorder and the associated medical problems.2,3,5,10,12,14-19 The first output from the database examined developmental milestones in 127 children with CDD.14 Overall attainment of milestones was extremely delayed. For example, the median age of independent sitting for girls was 36 months and by five years only three quarters had learned to sit independently. Males generally have more delayed milestones and more impaired development than females. 12,14
Lack of response to anti-epileptic medication 10 often necessitates the need for other therapeutic options such as ketogenic diet19 or vagal nerve stimulation 15 while there is growing interest in a possible role for medical cannabis.2,20 Sleep disturbances which have an impact not only on the child but on the whole family can be extreme2, affecting over 80% of individuals at some point in their life course.3 Gastrointestinal problems such as constipation and reflux are common as is compromised nutrition with nearly a quarter of females and almost half of males having a gastrostomy tube inserted by the age of 7.5 years.3 A proportion of individuals experience frequent respiratory infections often leading to multiple hospital admissions with over a third of families reporting that lower respiratory tract infections were a problem in the first five years of their child’s life.3
Relationships with genotype (i.e. type of CDKL5 gene mutation) have also been explored using data from the International CDKL5 Database, but difficult to determine because of the large number of unique mutations. A catalogue of CDKL5 sequence variations, including pathogenic mutations, nonpathogenic polymorphisms, and sequence variations of uncertain significance can be found at the RettBASE website (http://mecp2.chw.edu.au). Further studies are currently underway to understand the characteristics of the small number of mutations that are shared by more than one individual so that at least for those with these mutations, doctors will be able to provide some information to families about the predicted clinical course for their child.
The International Foundation for CDKL5 Research (IFCR) CDKL5 Centers of Excellence deliver multidisciplinary clinical care and collect clinical or research data on patients with CDD in the USA. The first site was established in 2013 and the network has grown to eight sites located at world class institutions. These sites have allowed the development of a CDD specific multicenter clinical research network structure to support clinical research goals.2,13,22
The CDKL5 gene provides instructions for making a protein that is essential for normal brain development. Mutations in the CDKL5 gene reduce the amount of functional CDKL5 protein or alter its activity in 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 CDD. The CDKL5 protein acts as a kinase, which is an enzyme that changes the activity of other proteins by adding oxygen and phosphate atoms (a phosphate group) at specific positions. Researchers have not yet determined which proteins are targeted by the CDKL5 protein.
CDD is an X-linked dominant disorder. X-linked dominant disorders are caused by a mutation in a gene on the X chromosome and occur mostly in females. Females are affected when they have an X chromosome with the CDKL5 gene mutation. Males with a CDKL5 gene mutation are more severely affected than females.
Most of the CDKL5 gene mutations are “de novo”, meaning that they occur spontaneously, and are not passed down through families. However, rare families in which multiple siblings were affected with the same mutation have been reported.8
CDKL5 mutations have been identified in many ethnic groups, with more females than males being reported with an approximate ratio of 4:1. Affected males appear to be more severely affected than females unless they have evidence of two or more populations of cells with different genotypes (mosaicism).12,14
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.24 As some CDKL5 mutations/variants are not disease-causing but benign, to confirm a diagnosis the mutation has to be considered disease-causing in accordance with recognized guidelines for assessing pathogenicity.25
Currently no curative or specific therapies are available for individuals with CDD so medical management is symptomatic and supportive. A multidisciplinary team approach is the most effective way to deliver necessary treatments aimed at maximizing the individual’s abilities and facilitating any skills that may be emerging. An emphasis should be placed on early intervention therapies such as physical therapy, occupational therapy, and speech and augmentative communication therapy. Important aspects of management include psychosocial support for the family, development of an appropriate education plan, and assessment of available community resources.
It is important to have the involvement of a dietitian with expertise in the management of individuals with severe intellectual disability, so that optimal nutritional status can be maintained. Some affected individuals are able to feed orally, however many require the assistance of enteral nutritional support
Most individuals with CDD do not develop verbal expressive language, and so other forms of communication should be considered, including communication boards, technical devices and switch activated systems to facilitate choice making and environmental access.
Seizure control is challenging and is often the most difficult health issue to manage. No one anticonvulsant has been found to be uniformly effective, and often multiple anticonvulsants are needed. Vagal nerve stimulation (VNS) has also been used with improvements in some patients.15 Dietary modifications such as the ketogenic diet have shown variable improvement in some individuals.19 However, these rigid dietary changes must only be implemented under close medical supervision and can be demanding on families.
Many affected individuals develop scoliosis, although as with many comorbidities in this disorder,3 there is limited literature on prevalence or natural history. Bracing may be suggested for some, while others will need to have surgical intervention. Guidelines developed for Rett syndrome may be helpful in providing management options in CDD.26 Increased muscle tone may develop, placing the individual at risk of developing foot deformities and shortened heel cords. It is important to maintain ambulation as much as possible in those who have learned to walk, and ankle orthoses may prove beneficial to prevent these orthopedic problems from developing.
Physiotherapy/physical therapy is also of benefit in improving overall muscle tone, trunk stability, strengthening, balance, prevention of foot deformities, maintaining foot alignment and keeping heel cords lengthened.
Genetic counseling is recommended for families with an affected child.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Please visit: https://rett.telethonkids.org.au/about/cdkl5-disorder/ for information about the International CDKL5 Database and associated publications.
1. Fehr S, Wilson M, Downs J, et al. The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy. Eur J Hum Genet. 2013;21(3):266-273.
2. Olson HE, Demarest ST, Pestana-Knight EM, et al. Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder: clinical review. Pediatr Neurol. 2019;97:18-25.
3. Mangatt M, Wong K, Anderson B, et al. Prevalence and onset of comorbidities in the CDKL5 disorder differ from Rett syndrome. Orphanet J Rare Dis. 2016;11(39):39.
4. Symonds JD, Zuberi SM, Stewart K, et al. Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort. Brain. 2019;142(8):2303-2318.
5. Hector RD, Kalscheuer V, Hennig F, et al. CDKL5 variants: improving our understanding of a rare neurological disorder. Neurology: Genetics. 2017;3(6).
6. Scala E, Ariani F, Mari F, et al. CDKL5/STK9 is mutated in Rett syndrome variant with infantile spasms. J Med Genet. 2005;42(2):103-107.
7. Tao J, Van Esch H, Hagedorn-Greiwe M, et al. Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene are associated with severe neurodevelopmental retardation. Am J Hum Genet. 2004;75(6):1149-1154.
8. Weaving LS, Christodoulou J, Williamson SL, et al. Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation. Am J Hum Genet. 2004;75(6):1079-1093.
9. Bertani I, Rusconi L, Bolognese F, et al. Functional consequences of mutations in CDKL5, an X-linked gene involved in infantile spasms and mental retardation. J Biol Chem. 2006;281(42):32048-32056.
10. Fehr S, Wong K, Chin R, et al. Seizure variables and their relationship to genotype and functional abilities in the CDKL5 disorder. Neurology. 2016;87(21):2206-2213.
11. Müller A, Helbig I, Jansen C, et al. Retrospective evaluation of low long-term efficacy of antiepileptic drugs and ketogenic diet in 39 patients with CDKL5-related epilepsy. Eur J Paediatr Neurol 2016;20(1):147-151.
12. Fehr S, Downs J, Ho G, et al. Functional abilities in children and adults with the CDKL5 disorder. Am J Med Genet A. 2016;170(11):2860-2869.
13. Demarest ST, Olson HE, Moss A, et al. CDKL5 deficiency disorder: Relationship between genotype, epilepsy, cortical visual impairment, and development. Epilepsia. 2019;60(8):1733-1742.
14. Fehr S, Leonard H, Ho G, et al. There is variability in the attainment of developmental milestones in the CDKL5 disorder. J Neurodev Disord. 2015;7(1):2.
15. Lim Z, Wong K, Downs J, Bebbington K, Demarest S, Leonard H. Vagus nerve stimulation for the treatment of refractory epilepsy in the CDKL5 Deficiency Disorder. Epilepsy Res. 2018;146:36-40.
16. MacKay CI, Bick D, Prokop JW, et al. Expanding the phenotype of the CDKL5 deficiency disorder: Are seizures mandatory? American Journal of Medical Genetics Part A.n/a(n/a).
17. Mori Y, Downs J, Wong K, Anderson B, Epstein A, Leonard H. Impacts of caring for a child with the CDKL5 disorder on parental wellbeing and family quality of life. Orphanet J Rare Dis. 2017;12(1):16.
18. Mori Y, Downs J, Wong K, Heyworth J, Leonard H. Comparing Parental Well-Being and Its Determinants Across Three Different Genetic Disorders Causing Intellectual Disability. J Autism Dev Disord. 2017;48(5):1651-1665.
19. Lim Z, Wong K, Olson HE, Bergin AM, Downs J, Leonard H. Use of the ketogenic diet to manage refractory epilepsy in CDKL5 disorder: Experience of >100 patients. Epilepsia. 2017;58(8):1415-1422.
20. Dale T, Downs J, Olson H, Bergin AM, Smith S, Leonard H. Cannabis for refractory epilepsy in children: A review focusing on CDKL5 Deficiency Disorder. Epilepsy Res. 2019;151:31-39.
21. Bruni O, Ottaviano S, Guidetti V, et al. The Sleep Disturbance Scale for Children (SDSC). Construction and validation of an instrument to evaluate sleep disturbances in childhood and adolescence. J Sleep Res. 1996;5(4):251-261.
22. Demarest S, Knight EP, Olson H, et al. Severity Assessment in CDKL5 Deficiency Disorder. Pediatr Neurol. 2019;97:38-42.
23. Neul JL, Kaufmann WE, Glaze DG, et al. Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol. 2010;68(6):944-950.
24. Lindy AS, Stosser MB, Butler E, et al. Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders. Epilepsia. 2018;59(5):1062-1071.
25. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424.
26. Downs J, Bergman A, Carter P, et al. Guidelines for management of scoliosis in Rett syndrome patients based on expert consensus and clinical evidence. Spine (Phila Pa 1976). 2009;34(17):E607-617.
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