Última actualización:
4/25/2024
Años publicados: 2012, 2015, 2020, 2024
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.
Introduction
CDKL5 deficiency disorder (CDD) is a rare developmental epileptic encephalopathy (DEE) caused by changes (variants) in the CDKL5 gene. CDD has been classified as a DEE because it is thought that the genetic change results in 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. CDD can manifest in a broad range of clinical severity and is often associated with other symptoms such as gastrointestinal and sleep disturbances. Although rare, the occurrence may be between ~1:40,000 and 1:60,000 livebirths, but an Australian population-based study suggested a lower incidence.
Previously known as serine/threonine protein kinase 9 (STK9), CDKL5 stands for cyclin-dependent kinase-like 5 and variants in this gene were first identified as disease-causing in 2004. 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 unless mosaic in which case they may be milder and have better gross motor ability.
Seizures are a major problem for patients with CDD because they are usually severe and difficult to control with medication. 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 with about a quarter of affected females and a lesser proportion of males able to walk independently. 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. About three quarters have been found to have cortical visual impairment. Most individuals have severe intellectual disability and little or no speech.
Core Symptoms
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)
Constipation
Sleep difficulties
Purposeless hand movements (stereotypies)
Teeth-grinding (bruxism)
Poor muscle tone (hypotonia)
Intellectual disability
Other Symptoms
Breathing irregularities (such as hyperventilation)
Respiratory infections
Vomiting
Gastroesophageal reflux
Scoliosis
Characteristics such as a sideways glance and habit of crossing legs
Behavioral 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. The first output from the database examined developmental milestones in 127 children with CDD. 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, except when mosaic.
Lack of response to anti-epileptic medication often necessitates the need for other therapeutic options such as ketogenic diet or vagal nerve stimulation while there is growing interest in a possible role for medical cannabis. Sleep disturbances which have an impact not only on the child but on the whole family can be extreme, affecting over 80% of individuals at some point in their life. 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. 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.
Relationships with genotype (i.e. type of CDKL5 gene variant) have also been explored using data from the International CDKL5 Database, but difficult to determine because of the large number of unique variants. A catalogue of CDKL5 sequence variations, including pathogenic variants, nonpathogenic polymorphisms, and sequence variations of uncertain significance can be found at the RettBASE website (). Further studies have now been undertaken to understand the characteristics of the small number of variants that are shared by more than one individual so that at least for those with these variants, 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 and/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 and are now engaged in a project with researchers from the International CDKL5 Disorder Database in Western Australia to develop outcome measures for clinical trials.
The CDKL5 gene provides instructions for making a protein that is essential for normal brain development. Variants 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 variant in a gene on the X chromosome and occur mostly in females. Females are affected when they have an X chromosome with a variant in the CDKL5 gene. Males with a CDKL5 gene variant are usually more severely affected than females except when mosaic, i.e. the variant affects some but not all cells.
Most of the CDKL5 gene variants 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 variant have been reported.
CDKL5 variants have been identified in many ethnic groups, with more females than males being reported with an approximate ratio of 4:1.
Diagnosis is initially suspected based on clinical presentation (i.e. onset of seizures early in life) and now usually confirmed through a multigene panel testing for early onset epilepsy. As some CDKL5 variants are not disease-causing but benign, to confirm a diagnosis the variant must be considered disease-causing in accordance with recognized guidelines for assessing pathogenicity.
Treatment
Medical management for individuals with CDD is mostly symptomatic and supportive. Guidelines have been developed with input from clinicians but there is no clear evidence base for these. 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 also 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 can 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 prescribed. In 2022, ganaxolone (Ztalmy) was approved to treat seizures associated with CDD in patients 2 years of age and older following a randomized controlled trial. This is the first treatment for seizures associated with CDD and the first treatment specifically for CDD.
Vagal nerve stimulation (VNS) has also been used with improvements in some patients. Dietary modifications such as the ketogenic diet have shown variable improvement in some individuals. 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 conditions associated with in this disorder, 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 options for management of scoliosis in CDD. Increased muscle tone may develop, placing the individual at risk of developing foot deformities and shortened heel cords. It is important to maintain walking 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:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Please visit: https://rett.telethonkids.org.au/about/cdkl5-disorder/ for information about the International CDKL5 Database and associated publications.
Wong K, Davies G, Leonard H, Downs J, Junaid M, Amin S. Growth patterns in individuals with CDKL5 deficiency disorder. Dev Med Child Neurol. 2023.
Wong K, Junaid M, Demarest S, Saldaris J, Benke TA, Marsh ED, et al. Factors influencing the attainment of major motor milestones in CDKL5 deficiency disorder. Eur J Hum Genet. 2023;31(2):169-78.
Amin S, Monaghan M, Aledo-Serrano A, Bahi-Buisson N, Chin RF, Clarke AJ, et al. International Consensus Recommendations for the Assessment and Management of Individuals With CDKL5 Deficiency Disorder. Front Neurol. 2022;13:874695.
Downs J, Jacoby P, Saldaris J, Leonard H, Benke T, Marsh E, et al. Negative impact of insomnia and daytime sleepiness on quality of life in individuals with the cyclin-dependent kinase-like 5 deficiency disorder. JOURNAL OF SLEEP RESEARCH. 2022;31(5).
Hong W, Haviland I, Pestana-Knight E, Weisenberg JL, Demarest S, Marsh ED, et al. CDKL5 Deficiency Disorder-Related Epilepsy: A Review of Current and Emerging Treatment. CNS Drugs. 2022;36(6):591-604.
Leonard H, Downs J, Benke TA, Swanson L, Olson H, Demarest S. CDKL5 deficiency disorder: clinical features, diagnosis, and management. Lancet Neurol. 2022;21(6):563-76.
Saldaris J, Leonard H, Jacoby P, Marsh ED, Benke TA, Demarest S, et al. Initial Validation and Reliability of the CDKL5 Deficiency Disorder Hand Function Scale (CDD-Hand). J Child Neurol. 2022;37(6):541-7.
Dale T, Downs J, Wong K, Leonard H. The perceived effects of cannabis products in the management of seizures in CDKL5 Deficiency Disorder. Epilepsy Behav. 2021:108152.
MacKay CI, Wong KS, Demarest ST, Benke TA, Downs J, Leonard H. Exploring genotype-phenotype relationships in the CDKL5 deficiency disorder using an international dataset. Clinical Genetics. 2021;99(1):157-65.
Olson HE, Daniels CI, Haviland I, Swanson LC, Greene CA, Denny AMM, et al. Current neurologic treatment and emerging therapies in CDKL5 deficiency disorder. J Neurodev Disord. 2021;13(1):40.
Saldaris J, Weisenberg J, Pestana-Knight E, Marsh ED, Suter B, Rajaraman R, et al. Content Validation of Clinician-Reported Items for a Severity Measure for CDKL5 Deficiency Disorder. Journal of Child Neurology. 2021;36(11):998-1006.
MacKay CI, Bick D, Prokop JW, et al. Expanding the phenotype of the CDKL5 deficiency disorder: Are seizures mandatory?. Am J Med Genet A. 2020;182(5):1217-1222. doi:10.1002/ajmg.a.61504
Pestana-Knight E, Amin S, Benke T, Fleming T, Cross JH, Olson H, et al. Ganaxolone Significantly Reduces Major Motor Seizures Associated with CDKL5 Deficiency Disorder: A Randomized, Double-blind, Placebo-Controlled Phase 3 Study (Marigold Study). American Epilepsy Society 2020.
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.
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.
Demarest S, Knight EP, Olson H, et al. Severity Assessment in CDKL5 Deficiency Disorder. Pediatr Neurol. 2019;97:38-42.
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.
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.
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.
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.
Hector RD, Kalscheuer V, Hennig F, et al. CDKL5 variants: improving our understanding of a rare neurological disorder. Neurology: Genetics. 2017;3(6).
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.
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.
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.
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.
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.
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.
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.
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.
Hagebeuk EE, Marcelis CL, Alders M, Kaspers A, de Weerd AW. Two Siblings With a CDKL5 Mutation: Genotype and Phenotype Evaluation. J Child Neurol. 2015;30(11):1515-9.
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.
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.
Neul JL, Kaufmann WE, Glaze DG, et al. Rett syndrome: revised diagnostic criteria 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. and nomenclature. Ann Neurol. 2010;68(6):944-950.
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.
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.
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.
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.
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.
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