|55 Kenosia Avenue
Danbury, CT 06810
Toll Free: 1.800.999.6673
The National Organization for Rare Disorders (NORD) web site, its databases, and the contents thereof are copyrighted by NORD. No part of the NORD web site, databases, or the contents may be copied in any way, including but not limited to the following: electronically downloading, storing in a retrieval system, or redistributing for any commercial purposes without the express written permission of NORD. Permission is hereby granted to print one hard copy of the information on an individual disease for your personal use, provided that such content is in no way modified, and the credit for the source (NORD) and NORD’s copyright notice are included on the printed copy. Any other electronic reproduction or other printed versions is strictly prohibited.
The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.
NORD is very grateful to Dr. Helen Leonard, Telethon Institute, Perth, Australia; Prof. John Christodoulou, NSW Centre for Rett Syndrome Research, Children's Hospital at Westmead, Sydney, Australia; and Dr. Katheryn Elibri Frame, International Foundation for CDKL5 Research, for assistance in the preparation of this report.
CDKL5 is a rare X-linked genetic disorder that results in early onset, difficult to control seizures, and severe neurodevelopmental impairment. CDKL5 stands for cyclin-dependent kinase-like 5, and is a gene located on the X chromosome.
Most of the children affected by CDKL5 suffer from seizures that begin in the first few months of life. Most cannot walk, talk or feed themselves, and many are confined to a wheelchair. Many also suffer with scoliosis, visual impairment, sensory issues and various gastrointestinal difficulties.
CDKL5 mutations were initially thought to be specifically associated with the Hanefeld variant of Rett syndrome, in which earlier seizures are a prominent feature. However, the characteristics of the disorder (phenotype) have been expanded to include early epileptic seizures and later onset intractable seizure disorders commonly including myoclonus without clinical features of Rett syndrome. More recent studies suggest that the predominant phenotype caused by CDKL5 mutations is the so-called epileptic encephalopathy, the onset of severe seizures in the first six months of life (often within the first 3 months), and poor subsequent neurocognitive development and commonly the presence of repetitive hand movements (stereotypies).
CDKL5 mutations have been found in children diagnosed with infantile spasms, West syndrome, Lennox-Gastaut syndrome, Rett syndrome, and autism. The full spectrum of CDKL5 disorders is unknown at this time. It is likely that there are many people affected by CDKL5 who have mild symptoms and no seizures.
The first report associated with an abnormality of the CDKL5 gene was in a child who had retinoschisis, severe intellectual disability and seizures. This patient had a deletion of the end of the CDKL5 gene, which overlaps with the end of the RS1 gene, the latter being associated with the eye abnormality in this patient. Subsequently, disruption of the CDKL5 gene due to X:autosome translocations disrupting the CDKL5 gene were reported in two patients with X-linked infantile spasm syndrome (ISSX). CDKL5 mutations were then linked with Rett syndrome by two groups. Weaving, et al reported a rare family in which one of identical twin sisters had atypical Rett syndrome with early onset seizures, while the other twin had autism and intellectual disability, but did not have Rett syndrome. They had a brother who had severe neonatal onset epileptic encephalopathy. Another female was reported by this group who had atypical Rett syndrome and early onset seizures and a different CDKL5 mutation, and Tao, et al reported two cases with a similar presentation and different mutations of the CDKL5 gene.
Seizures are prominent in CDKL5 mutation-positive patients, are usually severe, and include infantile spasms, myoclonic seizures, tonic-clonic seizures, and most particularly epileptic encephalopathy.
Clinical syndrome where CDKL5 mutations should be considered include:
- infantile onset seizures with poor neurocognitive development (epileptic encephalopathy)
- infantile spasms in females
- X-linked infantile spasm syndrome in males
- atypical Rett syndrome (Hanefeld variant)
Bahi-Buisson and colleagues have described the natural history of epilepsy in patients with CDKL5 mutations, and proposed a 3-stage model of the epileptic phenotype. This model describes early epilepsy in the first stage (median age of 4 weeks), epileptic encephalopathy in the second stage and tonic seizures and late myoclonic epilepsy in the third.
Note that to date CDKL5 mutations have only rarely been found to be associated with autism and intellectual disability in the absence of seizures, and have not been described in patients with classical Rett syndrome.
Artuso et al. have recently developed clinical criteria for what they coin "the early onset seizure variant of Rett syndrome" caused by mutations in CDKL5. Consistent with previous research but only based on a series of nine cases, they outline the cardinal features of this variant as irritability in the perinatal period, early epilepsy, hand stereotypies, severely impaired psychomotor development and severe hypotonia. In contrast to classical Rett syndrome they also comment on the absence of a classic regression period, the poor eye contact, generally normal head circumference and other growth parameters and relative absence of autonomic dysfunction.
Other symptoms of a CDKL5 disorder often include:
- A small head (microcephaly) in about 50%
- Low muscle tone
- Hand wringing movements or mouthing of the hands
- Marked developmental delay
- Limited or absent speech
- Hypersensitivity to touch, for example dislike of hair brushing
- Lack of eye contact or poor eye contact
- Gastroesophageal reflux
- Small, cold feet
- Breathing irregularities such as hyperventilation
- Grinding of the teeth
- Episodes of laughing or crying for no reason
- Low/Poor muscle tone
- Very limited hand skills
- Some autistic-like tendencies
- Cortical Visual Impairment (CVI), aka "cortical blindness"
- Eating/drinking challenges
- Interruptive sleep
- Characteristics such as a sideways glance, and habit of crossing leg
The CDKL5 gene provides instructions for making a protein that is essential for normal brain development. Although little is known about the protein's function, it may play a role in regulating the activity of other genes, including the MECP2 gene associated with Rett syndrome. 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.
Most of the CDKL5 gene mutations are "de novo", meaning that they occur spontaneously, and are not passed down through families. However, there is one known family in which multiple siblings were affected with the same mutation, but neither parent was found to be a carrier.
CDKL5 mutations have been identified in many ethnic groups, with the majority of affected individuals to date being female, although some males have been described, usually more severely affected.
Symptoms of the following disorders may be similar to those of CDKL5. Comparisons may be useful for a differential diagnosis:
Rett syndrome is a rare neurodevelopmental disorder that appears to occur almost exclusively in females but can occur rarely in males. Infants and children with the disorder typically develop normally until about 7 to 18 months of age, when they may begin to lose previously acquired skills (developmental regression), such as purposeful hand movements and the ability to communicate. Additional abnormalities typically include slowing of head growth (acquired microcephaly); development of distinctive, uncontrolled (stereotypic) hand movements, such as hand clapping or rubbing, and impaired control of voluntary movements required for coordination of walking (gait apraxia). Affected children also typically develop autistic-like behaviors, breathing irregularities, feeding and swallowing difficulties, growth retardation, and seizures. Rett syndrome is caused by mutations in the MECP2 gene on the X chromosome and can present with a wide range of disability ranging from mild to severe. The course and severity of Rett syndrome is determined by the location, type and severity of the MECP2 mutation and X-inactivation. Therefore, two girls of the same age with the same mutation can appear quite different. (For more information about this condition, choose "Rett" as your search term in the Rare Disease Database.)
West syndrome is a type of epilepsy characterized by spasms, abnormal brain wave patterns called hypsarrhythmia and sometimes intellectual disability. The spasms that occur may range from violent jackknife or "salaam" movements where the whole body bends in half, or they may be no more than a mild twitching of the shoulder or eye changes. These spasms usually begin in the early months after birth and can sometimes be helped with medication. There are many different causes of West syndrome and if a specific cause can be identified, a diagnosis of symptomatic West syndrome can be made. If a cause cannot be determined, a diagnosis of cryptogenic West syndrome is made. A specific cause for West syndrome can be identified in approximately 70-75% of those affected. X-linked West syndrome (X-linked infantile spasm syndrome or ISSX) can be caused by a mutation in the CDKL5gene or the ARX gene on the X chromosome. (For more information about this condition, choose "West" as your search term in the Rare Disease Database.)
Atypical Rett syndrome includes the Hanefeld variant and X-linked infantile spasm syndrome (ISSX). The Hanefeld variant is used to describe females with early-onset epileptic seizures or infantile spasms with Rett-like features.
Lennox-Gastaut Syndrome is a severe form of epilepsy that typically becomes apparent during infancy or early childhood. Affected children experience several different types of seizures most commonly atonic, tonic and atypical absence seizures. Children with Lennox-Gastaut syndrome may also develop cognitive dysfunction, delays in reaching developmental milestones and behavioral problems. Lennox-Gastaut syndrome can be caused by a variety of underlying conditions, but in some cases no cause can be identified. Lennox-Gastaut syndrome can be difficult to treat because it is resistant (refractory) to many kinds of antiseizure medications. (For more information about this condition, choose "Lennox-Gastaut" as your search term in the Rare Disease Database.)
Autism and autism spectrum disorders (ASDs) are a group of severe neurodevelopmental disorders in which individuals show deficits in social interaction, impaired communication, repetitive behavior and restricted interests and activities. (For more information about this condition, choose "autism" as your search term in the Rare Disease Database.)
Diagnosis is initially suspected based on symptoms, history and physical exam. CDKL5 is confirmed by molecular genetic testing for CDKL5 mutations.
Currently no curative or specific therapies are available for individuals with a CDKL5 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 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 CDKL5 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. Individuals typically have apraxia of speech.
Absence of seizure control is seen in virtually all affected individuals, 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 in some affected individuals with variable success. Dietary modifications, including the ketogenic diet, have shown variable improvement in some individuals, however, these rigid dietary changes must only be implemented under close medical supervision.
Many affected individuals develop scoliosis, although the precise number is not known at this time. Bracing may be required in some, while others will need to have surgical intervention. 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. Physiotherpay/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.
There is still much to be learned about how CDKL5 mutations affect brain function. Because the biology of the CDKL5 protein and its deficiency is so poorly understood at present, there are currently no investigational therapies being studied. 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. However, it must be stressed that this is completely speculative, and will not be able to be tested until a CDKL5-deficient animal model has been developed.
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).
(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at email@example.com.)
Artuso R, Mencarelli MA, Polli R, Sartori S, Ariani F, Pollazzon M, et al. Early-onset seizure variant of Rett syndrome: Definition of the clinical diagnostic criteria. Brain Dev. 2010 Apr 9;32(1):17-24. http://www.ncbi.nlm.nih.gov/pubmed/19362436
White R, Ho G, Schmidt S, Scheffer IE, Fischer A, Yendle SC, et al. Cyclin-Dependent Kinase-Like 5 (CDKL5) Mutation Screening in Rett Syndrome and Related Disorders. Twin Res Hum Genet. 2010 Apr;13(2):168-78. http://www.ncbi.nlm.nih.gov/pubmed/20397747
Psoni S, Willems PJ, Kanavakis E, Mavrou A, Frissyra H, Traeger-Synodinos J, et al. A novel p.Arg970X mutation in the last exon of the CDKL5 gene resulting in late-onset seizure disorder. Eur J Paediatr Neurol. 2010 Mar;14(2):188-91.
Mei D, Marini C, Novara F, Bernardina BD, Granata T, Fontana E, et al. Xp22.3 Genomic deletions involving the CDKL5 gene in girls with early onset epileptic encephalopathy. Epilepsia. 2010 Apr;51(4):647-54.
Nemos C, Lambert L, Giuliano F, Doray B, Roubertie A, Goldenberg A, et al. Mutational spectrum of CDKL5 in early-onset encephalopathies: a study of a large collection of French patients and review of the literature. Clin Genet. 2009 Oct;76(4):357-71. http://www.ncbi.nlm.nih.gov/pubmed/19793311
Bahi-Buisson N, Kaminska A, Boddaert N, Rio M, Afenjar A, Gerard M, et al. The three stages of epilepsy in patients with CDKL5 mutations. Epilepsia. 2008 Feb 7;49(6):1027-37. http://l2c2.isc.cnrs.fr/publications/files/bahi.pdf
Elia M, Falco M, Ferri R, Spalletta A, Bottitta M, Calabrese G, et al. CDKL5 mutations in boys with severe encephalopathy and early-onset intractable epilepsy. Neurology. 2008 Sep 23;71(13):997-9. http://www.ncbi.nlm.nih.gov/pubmed/18809835
Bahi-Buisson N, Nectoux J, Rosas-Vargas H, Milh M, Boddaert N, Girard B, et al. Key clinical features to identify girls with CDKL5 mutations. Brain. 2008 Oct;131(Pt 10):2647-61. http://www.ncbi.nlm.nih.gov/pubmed/18790821
Bertani I, Rusconi L, Bolognese F, Forlani G, Conca B, De Monte L, et al. Functional consequences of mutations in CDKL5, an X-linked gene involved in infantile spasms and mental retardation. J Biol Chem. 2006 Aug 24;281(42):32048-56. http://www.ncbi.nlm.nih.gov/pubmed/16935860
Buoni S, Zannolli R, Colamaria V, Macucci F, di Bartolo RM, Corbini L, et al. Myoclonic encephalopathy in the CDKL5 gene mutation. Clin Neurophysiol. 2006 Jan;117(1):223-7. http://www.ncbi.nlm.nih.gov/pubmed/16326141
Archer HL, Evans J, Edwards S, Colley J, Newbury-Ecob R, O'Callaghan F, et al. CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients. J Med Genet. 2006 Sep;43(9):729-34. http://www.ncbi.nlm.nih.gov/pubmed/16611748
Lin C, Franco B, Rosner MR. CDKL5/Stk9 kinase inactivation is associated with neuronal developmental disorders. Hum Mol Genet. 2005 Dec 15;14(24):3775-86. http://hmg.oxfordjournals.org/content/14/24/3775.full.pdf
Scala E, Ariani F, Mari F, Caselli R, Pescucci C, Longo I, et al. CDKL5/STK9 is mutated in Rett syndrome variant with infantile spasms. J Med Genet. 2005 Feb;42(2):103-7. http://www.ncbi.nlm.nih.gov/pubmed/15689447
Mari F, Azimonti S, Bertani I, Bolognese F, Colombo E, Caselli R, et al. CDKL5 belongs to the same molecular pathway of MeCP2 and it is responsible for the early seizure variant of Rett syndrome. Hum Mol Genet. 2005 May 25;14(14):1935-46. http://www.ncbi.nlm.nih.gov/pubmed/15917271
Evans JC, Archer HL, Colley JP, Ravn K, Nielsen JB, Kerr A, et al. Early onset seizures and Rett-like features associated with mutations in CDKL5. Eur J Hum Genet. 2005 Oct;13(10):1113-20. http://www.nature.com/ejhg/journal/v13/n10/full/5201451a.html
Weaving LS, Christodoulou J, Williamson SL, Friend KL, McKenzie OL, Archer H, et al. Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation. Am J Hum Genet. 2004 Dec;75(6):1079-93. http://www.ncbi.nlm.nih.gov/pubmed/15492925
Tao J, Van Esch H, Hagedorn-Greiwe M, Hoffmann K, Moser B, Raynaud 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 Dec;75(6):1149-54. http://www.ncbi.nlm.nih.gov/pubmed/15499549
Kalscheuer VM, Tao J, Donnelly A, Hollway G, Schwinger E, Kubart S, et al. Disruption of the serine/threonine kinase 9 gene causes severe X-linked infantile spasms and mental retardation. Am J Hum Genet. 2003 Jun;72(6):1401-11. http://www.ncbi.nlm.nih.gov/pubmed/12736870
Huopaniemi L, Tyynismaa H, Rantala A, Rosenberg T, Alitalo T. Characterization of two unusual RS1 gene deletions segregating in Danish retinoschisis families. Hum Mutat. 2000 Oct;16(4):307-14. http://www.ncbi.nlm.nih.gov/pubmed/11013441
Report last updated: 2012/01/17 00:00:00 GMT+0