NORD gratefully acknowledges Dr. Helen Leonard, Telethon Kids 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.
Seizures are prominent in genetically confirmed CDKL5 patients, and are usually severe, and include infantile spasms, myoclonic seizures, tonic-clonic seizures, and most particularly epileptic encephalopathy.
Clinical syndromes where CDKL5 mutations should be considered include:
– infantile onset seizures with poor neurocognitive development (epileptic encephalopathy)
– infantile spasms in females and males
– atypical Rett syndrome (Hanefeld variant)
Bahi-Buisson and colleagues (2008) reported on the natural history of epilepsy in 12 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. (2010) developed clinical criteria for what they coined “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 outlined 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 commented 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:
– Low muscle tone
– Hand wringing movements or mouthing of the hands
– Marked developmental delay
– Limited or absent speech
– 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
– Sleep difficulties
– Characteristics such as a sideways glance, and habit of crossing leg
In 2012 Fehr and colleagues capitalized on available data from an international data collection to describe the clinical profile of the CDKL5 disorder and compare it with Rett syndrome. Information on individuals with CDKL5 mutations (n=86) and females with MECP2 mutations (n=920) was sourced from the InterRett database. Most individuals with CDKL5 mutations had severe developmental delay and onset of seizures before the age of three months. Less than one quarter actually met the criteria for the early-onset seizure atypical form of Rett syndrome. Seizures and sleep disturbances were more common than in those with MECP2 mutations while features of regression and spinal curvature or scoliosis were less common.
A shared physical resemblance was also observed between females with the CDKL5 disorder, with the most consistent features being a prominent/broad forehead, deep-set but ‘large-appearing’ eyes, full lips and tapered fingers. Males were more likely to have an unusual facial appearance, with distinctly anteverted nares (upturned tip of the nose), and several males also had a short philtrum (the vertical groove between the nose and upper lip) and everted upper lip. Previous studies of the CDKL5 disorder have also reported features such as large deep-set eyes, strabismus, high forehead, full lips, wide mouth, widely spaced teeth and a high palate.
The International CDKL5 Disorder Database was established in September 2012 and is continuing to collect data from families with a child with confirmed CDKL5 disorder throughout the world. This database provides the capacity to collect important information which will help us better understand this disorder and the associated comorbidities. The first output from the database has examined developmental milestones in 127 children with the CDKL5 disorder. 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. About a quarter of girls had learned to walk independently by the age of four and a half years. Overall males had more impaired development and more delayed milestones. Relationships with genotype (ie type of mutation) were also explored but difficult to determine because of the large number of unique mutations and the few that are shared by more than one individual.
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, rare families in which multiple siblings were affected with the same mutation, have been reported.
CDKL5 mutations have been identified in many ethnic groups, with more females than males being reported with an approximate ratio of 5:1, but with males usually being more severely affected.
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 the CDKL5 disorder 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.
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. 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 comorbidities in this disorder, there is little available literature on prevalence or natural hitory. Bracing may be suggested for 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. 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.
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, potential treatments will first need to be tested using animal models.
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).
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] 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/
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