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A Guide For Professionals

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CDKL5 Disorder
A Guide for Professionals
Giving hope through research
and support to those living with
a CDKL5 Disorder
Registered Charity No. 1149099. CDKL5 UK
Foreword by Professor John Christodoulou AM
- What is CDKL5
- How can CDKL5 be recognised?
- How do you diagnose CDKL5
- Referral to appropriate specialists
Clinical Symptoms A-Z
Seizure Treatments
Therapeutic Interventions
Clinics / Specialists
We would like to thank
Rett UK,
for allowing us to use
information provided in
their National Best Practice
Guidelines 2013 as a basis
for this publication.
This advice has been
reviewed and approved by
Professor Angus Clarke,
and Dr Hayley Archer of
the Institute of Genetics,
University of Wales
Hospital, Cardiff, UK.
CDKL5 UK, 5 Thorne Lane, Yeovil, Somerset, BA21 3LU UK
1 / CDKL5: A Guide for Professionals
In the decade since gene changes in CDKL5 were fi rst linked to
Rett syndrome, much has been learnt about the CDKL5 disorder.
Whilst individuals with CDKL5 mutations share some clinical features
with those with MECP2 mutations causing Rett syndrome, we now
know that they should be considered to be distinct disorders. In
addition to careful clinical delineation of the disorder, laboratory based
research studies, and the development of a mouse model for Cdkl5
defi ciency, will enhance our understanding of the biological processes
contributing to the CDKL5 disorder, and which will hopefully ultimately
lead to targeted therapies.
It is therefore very timely that the key clinical and genetic features of
the CDKL5 disorder should be brought together into this information
booklet, along with the current approaches to the management of the
complications of the disorder, and details of local specialist services
CDKL5 support organisations. We hope you will nd this resource
of value.
Professor John Christodoulou AM
Director, Western Sydney Genetics Program
Head, Discipline of Genetic Medicine,
Sydney Medical School, University of Sydney
CDKL5: A Guide for Professionals / 2
3 / CDKL5: A Guide for Professionals
What is CDKL5?
CDKL5 is a rare genetic condition that
was rst identifi ed in 2004. It is caused by
mutations in the CDKL5 gene that is found
on the X-chromosome and it therefore
affects mainly girls although boys can also be
affected. It typically presents with epileptic
seizures in the rst few weeks or months of
life followed by severe neurodevelopmental
delay. Many children who are now known
to have CDKL5 were previously thought
to have a variation of another genetic
condition called Rett syndrome (atypical
Rett) because there were some similar
characteristics. However, in 2012, the
“CDKL5 disorder” became recognised as a
distinct condition.
How can CDKL5 disorders
be recognised?
The most prominent feature of the
CDKL5 disorder is early onset of seizures.
The onset of seizures can happen within
the fi rst hours, days, weeks or months.
Children have been diagnosed with
CDKL5 with seizures starting as late as 8
months and in some cases up to the age
of two. Some mothers have described
feeling seizures in the pre-natal period.
Seizures manifest as tonic seizures with
myoclonic clusters and tonic / clonic
seizures. They generally happen in sleep
at the onset of seizures, but as time
passes they may appear during waking
hours as well. It is common for these
rst seizures not to be detectable on
EEG, and some children may initially
be diagnosed with Benign Sleep
Myoclonus, or Sandifer Syndrome. It
is important to note that the absence
of seizure activity on EEG does not
necessarily exclude the presence of
CDKL5 related seizure activity.
Children undiagnosed, are often given
an electro-clinical diagnosis of Ohtahara
Syndrome, Lennox Gastaut Syndrome or
West Syndrome, some also may have a
diagnosis of Leigh’s encephalopathy
or other mitochondrial diseases. These
syndromes have many different genetic
causes including CDKL5. The CDKL5
disorder mainly affects girls, however, it
should not be excluded as a diagnosis
in boys as there are a number that have
been diagnosed worldwide.
For additional symptoms please see
the Clinical Symptoms A-Z from page 3
This information leafl et is aimed at
providing information to professionals
who may be involved in the assessment,
diagnosis and treatment of children
with CDKL5.
This is not intended to be a comprehensive
guide, but rather an introduction to the
complex clinical features that children with
a CDKL5 disorder may exhibit. Not all
features described may be present, and as
the condition was only recognised recently,
there may be other clinical manifestations
that become apparent as we learn more.
CDKL5: A Guide for Professionals / 4
A to Z
Abdominal Distension
This can be due to aerophagy, which
commonly accompanies the abnormal
breathing. Very severe cases may be helped
by percutaneous gastrostomy, while other
cases may also be helped by medication.
Air swallowing can be signifi cant and can
interfere with eating and full respiratory
Altered Pain Response
Inappropriate pain responses are very
common in people with CDKL5. This
can manifest itself in a number of ways.
Parents report that children and adults
bite themselves , may tolerate blood tests
and lumbar punctures without showing
the pain responses that a child of normal
development might experience. However,
they may cry appropriately when they
take a “bump” for example. Altered
pain response should be an important
consideration when assessing someone
with CDKL5 in a clinical setting, such
as an emergency department, because
although they may appear pain free, this
may not always be the case. It has also
been reported that some children who
have experienced extreme pain, may not
always appropriately respond to high dose
opiates, and that alternative medication
would need to be considered.
Apraxia results from dysfunction of the
cerebral hemispheres, especially the parietal
lobe, and can be present in people with
CDKL5. Apraxia includes limb-kinetic apraxia
(the inability to make fi ne, precise movements
with an arm or leg),
(continued on p. 5)
How do you diagnose
a CDKL5 disorder?
The CDKL5 disorder is now being
diagnosed in children at a relatively early
age. Next generation sequencing is the new
genetic technology that is likely to be used
to diagnose CDKL5 disorder in your patient.
It may be referred to as a “gene panel” and
it is basically a genetic blood test. Instead of
looking for spelling mistakes or deletions/
duplications in one gene, the test would
screen a number of genes for changes that
may be found in people with severe early
epilepsy. It should identify both spelling
mistakes and deletions or duplications
within the genes tested. Those who have
had negative CDKL5 gene sequencing in the
past may need this new test to look for a
deletion or duplication of CDKL5 and to
consider whether the explanation for the
child’s diffi culties lies within one of the other
epilepsy syndrome genes.
Referral to Appropriate
If a child is diagnosed with CDKL5 disorder,
then the family should be offered genetic
counselling,. This would provide the family
with the opportunity to discuss their child’s
conditions and to consider their reproductive
options. The family should also be supported
in obtaining appointments with a paediatric
neurologist and with a consultant paediatrician,
who will coordinate the local therapy team
providing the therapists with advice to help
them in supporting the child. The therapists
who may be involved are likely to come from
physiotherapy, speech & language therapy,
occupational therapy and music therapy.
5 / CDKL5: A Guide for Professionals
Steroid Treatment
Steroid treatments, including the use
of Corticotropin (ACTH) or Methyl-
Prednisolone has shown some effi cacy for
those that have Infantile Spasms as part
of their seizure disorder. Although there
is evidence, that some patients may have
a modifi ed hypsarrhythmia that might also
respond to steroid treatment, as well as
those where non-convulsive status is a
A to Z
Apraxia continued...
ideomotor apraxia (the inability to make
the proper movement in response to a
verbal command), ideational apraxia
(the inability to coordinate activities with
multiple, sequential movements, such
as dressing, eating, and bathing), verbal
apraxia (diffi culty coordinating mouth and
speech movements), constructional apraxia
(the inability to copy, draw, or construct
simple fi gures) and oculomotor apraxia
(diffi culty moving the eyes on command).
Apraxia may be accompanied by aphasia.
Generally, treatment for individuals with
apraxia includes physical, speech, or
occupational therapy.
Aspiration Pneumonia
This is due to poor co-ordination of the
muscles involved in swallowing. The
epiglottis should fold over the trachea, to
prevent the food or fl uid from being inhaled,
but fails to do so. Careful assessment of
swallowing by an experienced speech
therapist is required. Positioning is key to
enhance swallowing, as is the texture of
the food and consistency of fl uid.
Autistic Features
Varying degrees of social interaction,
such as avoidance of eye contact or
perseverating on people or objects.
Repetitive behaviours may occur such
as stereotypies, manic walking and
repeated manipulation of objects occur.
Other features include diffi culty in motor
coordination and attention, and lack of
safety awareness.
Bone Density
Osteoporosis is not common in CDKL5.
However, it should be monitored over time
Anti-Convulsant Medication
Seizures within the CDKL5 disorder
are diffi cult to treat.
It is important to note that some people
do very well on low dose mono-therapy,
whereas some need adjunctive therapy.
It is usual for a child to go through the
whole range of medications. Physicians
should work closely with families to ensure
that appropriate dosing is maintained
to ensure quality of life for not only the
child but also the family and care givers.
Long-term use can affect bone density and
this should be a consideration as the child
gets older, appropriate testing and measures
for monitoring bone density should be
CDKL5: A Guide for Professionals / 6
A to Z
Bone Density continued...
by an endocrinologist especially if there
is a suggestion of precocious puberty.
Osteoporosis should be considered
particularly in those who have never walked
or who have sustained a fracture. Bone
density is also affected by anti-convulsants.
A DEXA bone density scan should be
undertaken in the event of a fracture or to
provide a baseline for future assessments.
Breathing Irregularities /
Some people with CDKL5 experience
varying degrees of breathing irregularities
and these can occur during wakefulness
and sleep. Central and obstructive apnoea
can also occur.
Tooth grinding can be severe and can also
occur during sleep. Involving a specialist
dentist is important to prevent tooth decay
and enamel problems.
Cardiac Problems
Some people have experienced Long
QT syndrome, which is more commonly
associated with Rett Syndrome, abnormalities
in heart rate such as tachycardia, and
non-specifi c changes relating to T waves.
It should be best practice to ensure that
individuals with CDKL5 disorder have
regular ECG’s and echocardiograms.
Treat vigorously and actively with a view
towards prevention. Bowel habits can
change over time and can be a source of
pain and discomfort. Even if dietary fi bre is
adequate, check the daily free water intake,
which may be low.
Ketogenic Diet
The ketogenic diet has been particularly
successful for some people. Many families
report an increase in awareness and
alertness, as well as a decrease in seizure
frequency. The ketogenic diet is a viable
option for both people that feed orally,
through a naso-gastric tube, or G Tube.
Vagal Nerve Stimulation (VNS)
VNS is increasing in popularity. It has been
particular effective in treating CDKL5
related seizures. The settings vary with
some people doing particularly well with
rapid settings whilst others do well on
lower settings.
Neurosurgery can occasionally offer a
method of seizure control when various
other treatments have failed. In CDKL5
disorder the epilepsy rarely has a focus. If a
seizure focus can be identifi ed and is limited
to one hemisphere of the brain it may be
possible to provide surgical treatment.
Eligibility for surgery can be determined by
a PET scan or a SPECT scan to determine
whether there is a focus.
7 / CDKL5: A Guide for Professionals
Hydrotherapy is one of the most essential
of the physical therapies for this group of
profoundly disabled people. There are several
reasons for the importance of this form of
therapy, each of which relates to the nature of
the disorder: CDKL5 produces a movement
disorder which deprives the individual of the
freedom to plan and carry out voluntary
movement. This means that walking, if
achieved, can be impaired. The diffi culties
which lead to the movement problem
include fear which seems to be induced by
perceptual diffi culties. Although CDKL5 is
not a progressive disease there is a liability
to lose muscle bulk, strength and exibility
because of lack of use and the inability of the
brain to coordinate the pathways involved.
A to Z
Cortical Vision Impairment (CVI)
CVI is a form of visual impairment which
is related to the brain rather than the eyes.
For some people with CDKL5 disorder this
can be severe, though for some it does
seem to improve over time. It is important
to diagnose and to allow for therapeutic
input from the appropriate specialists.
Children with CDKL5 disorder tend to have
a distinctive sideways glance.
Epileptic Seizures
Seizures are almost always seen in CDKL5.
Studies have suggested that children
with a CDKL5 disorder exhibit 3 stages of
epilepsy. Stage I is early epilepsy (onset
1-10 weeks) with a normal EEG despite
frequent seizures. Stage II involves the
development of epileptic encephalopathy
(developmental epilepsy) with infantile
spasms and hypsarrhythmia, being seen
in about 50% of cases. Stage III appears
as late, multifocal and myoclonic epilepsy,
although this may not always be the case.
Seizures are often diffi cult to control while
puberty can bring about changes in seizure
pattern and activity. Some become seizure
free, though the neurodevelopmental
issues remain profound.
Feeding Diffi culties
Dysphagia is common in CDKL5. Affected
individuals may have diffi culty with chewing,
tongue movement, and swallowing. This
may impair adequate nutrition or contribute
to respiratory symptoms (aspiration,
coughing, or choking during feeding). This
may worsen with time with many affected
individuals giving up eating altogether. Poor
weight gain and episodes of aspiration
require fl uoroscopic examination and
pH studies. In severe cases percutaneous
Hippotherapy / Equine Therapy
The term “hippotherapy” means “treatment
with the help of the horse”. Hippotherapy
is a physical, occupational, and speech and
language therapy treatment strategy that
utilizes equine movement as part of an
integrated intervention program to achieve
functional outcomes. The movement
provided by the horse is a multidimensional
movement, which is variable, rhythmic and
repetitive and is stimulating for the person
living with CDKL5. Hippotherapy is an
excellent tool for increasing trunk strength
and control, balance, building overall postural
strength and endurance, addressing weight
bearing, and motor planning. This type of
therapy may use a mechanical horse.
CDKL5: A Guide for Professionals / 8
A to Z
Feeding Diffi culties continued...
gastrostomy (PEG) should be considered.
Persistent refl ux may need medication or
surgical correction.
Constipation, diarrhoea, intestinal gas and
gastric refl ux are all common problems.
Constipation may not always be palpable,
and should not be excluded until a bowel
x-ray or ultrasound has been performed. Low
gut motility, as well as slow gastric emptying,
can also be evident with a child with CDKL5.
There is anecdotal evidence that individuals
with CDKL5 may be more susceptible to
volvulus, and intussusception. Therefore
with a rapid clinical deterioration with no
apparent cause, there should be a high index
of suspicion.
Impaired Sleep
This includes night terrors, inappropriate
laughing and jerking. Once awake, children
with CDKL5 can take a long time to fall
asleep again due to irregular breathing
patterns, seizure activity and general
restlessness. Many people with CDKL5
disorder will have signifi cant impairment
of sleep; they have days and nights with
no sleep, but can also go for a couple
of days where they sleep continuously.
Many families use medication in order
to aid sleep in the form or melatonin or
There is a wide range of ability; some
affected patients will never walk, whilst
others walk. Some have almost no
hand skills while others perform some
purposeful actions. Hypotonia is seen
almost universally.
(continued on p. 9)
Music Therapy
Music therapy has enormous value in
aiding communication skills, improving
gross and ne motor skills, helping with
attention and general motivation and
emotional well-being. It can also reduce
stereotypies and functional use of hands
can be developed. Music can also be used
to help relax and calm.
Occupational Therapy
We strongly recommend that the
individual’s overall 24 hour postural
management should be considered
carefully and reassessed at regular
intervals. Individuals should be fully
assessed for each piece of equipment
that will promote functional hand use
and sensory input encouraged to improve
overall quality of life.
This is important in ensuring good postural
management to infl uence scoliosis and joint
deformities, develop or maintain transitional
skills, increase motor ability, stimulate hand
use, improve body awareness, reduce muscle
pain and increase protective responses.
Intensive physiotherapy programmes have
also been used to good effect: Spider
Therapy; TheraSuit Therapy; Universal
Cage Therapy; and neuro-developmental
Treatment (NDT Bobath).
9 / CDKL5: A Guide for Professionals
Vision Therapy
Vision Therapy is an individualized program
designed to correct visual-motor and
perceptual-cognitive defi ciencies. Children
affected by CDKL5 disorder show a range
of characteristics and thus vision teaching
strategies need to be assessed considering
the uniqueness of each child. Vision
Therapy offers comprehensive procedures
designed to enhance the brain’s ability to
control hand-eye coordination problems
and improve visual perceptual diffi culties,
such as:
eye alignment,
eye tracking and eye teaming,
eye focusing abilities,
eye movements,
visual processing
A to Z
Mobility continued...
It is important for the child to be seen
regularly by orthopaedic specialists and
physiotherapy. They need assessments for
scoliosis, hip alignment and joint laxity.
Mood Lability / Involuntary
Many families report inconsolable crying,
laughing and erratic behaviour for no
apparent reason. Although as the child
gets older the families are able to interpret
the crying as being related to pain,
gelastic seizures, or sub-clinical seizure
activity. A person reporting to medical
services with severe crying should receive
full work-up to exclude illness or possible
gastrointestinal obstruction. Mood lability
has been reported by parents, as going on
for days with extreme shifts in the mood
from elation to depression within the
same day.
Range of Motion
Contractures develop over time. Check for
full passive range of motion. Reduction in
Occupational and Physiotherapy services
over time can lead to lack of awareness of
this complication.
The Spine: Scoliosis /
Kyphosis / Lordosis
The chance of developing scoliosis
increases with age, although statistics are
not yet available as to the precise risk.
There should be close monitoring of the
spine for the development of a deformity. If
detected then referral to a spinal surgeon
is recommended.
A challenge for many children with CDKL5
Speech & Language
Supporting communication skills for people
with CDKL5 is vital to improve concentration
and develop effective communication
methods. Speech and language therapists
also have a responsibility to identify eating
diffi culties and provide advice about the
texture of food and drink, adapted utensils,
altering the pace of eating as dysphagia
and aspiration pneumonia are common
problems. The role of interactive eye gaze
technology in facilitating communication for
people with CDKL5 is uncertain but looks
promising for some affected individuals. This
may also prove useful in the assessment of
cognitive function.
CDKL5: A Guide for Professionals / 10
A to Z
Stereotypies continued...
is repetitive and restricted behaviours
(RRB). Some examples are continuously
mouthing objects and hands, rocking, head
swaying, hand fl apping and clapping, also
common in autism and Rett Syndrome.
Similar to obsessive compulsive disorder
(OCD), repetitive behaviour appears
to represent a need for sameness and
a resistance to novelty in which some
children with CDKL5 may resist obstruction
or interruption of their rituals. No one
really knows why they happen and there
is little consensus about treatment.
However, most professionals label RRBs as
purposeless and maladaptive. Alternative
views consider the person may be seeking
sensory (self-) integration or pleasurable
sensations, or creating distraction from
stress, or that the repetitive behaviour is
being triggered by a possible underlying
biomedical cause such as neurological
dysfunction. Hand stereotypies within
CDKL5 are very common. These manifest
as fi nger tapping, hand mouthing, nger
sucking and hand wringing. People with
CDKL5 may hand mouth during feeding
therefore, arm splints may be useful to
enable effective feeding.
Many people with the disorder have non-
functional hand use. However, therapy
should be provided to encourage hand use.
Vasomotor Disturbances
Sympathetic tone is high, due to poor
autonomic restraint. Treat the skin gently,
encourage activities using the whole body,
and ensure that hands and feet are kept
warm even in the summer. Even with warm
clothing the person with CDKL5 may still
have cold extremities.
Health & Social Care
The spectrum of disability and health needs
vary widely with people with CDKL5.
However, they are almost always exclusively
classifi ed by health, social and education
specialists as having Profound and Multiple
Learning Disabilities (PMLD). CDKL5 is a
life shortening condition, due to the nature
of the complications of the seizure disorder,
orthopaedic considerations and autonomic
dysfunction. Therefore the family should be
supported to access the appropriate health
and social care package to meet the family’s
needs. Some people with CDKL5 will access
Continuing Health Care services, and some
will meet the criteria for Hospice Care.
Families requesting Hospice care for respite
should be fully supported to access this.
Throughout their life-time, a person living with
CDKL5 may need the help of many medical
specialists. If a child presents and is diagnosed
early, then a complete clinical work-up should
be adopted. Medical and Allied Health
specialists currently involved with individuals
who have a CDKL5 disorder include:
Paediatrician Paediatric Neurologist
Geneticist Gastroenterologist
Spinal Surgeon Orthopaedic Surgeon
Endocrinologist Cardiologist
Neurosurgeon General Surgeon
Community Children’s Nurse
Neuropsychologist Educational Psychologist
Physiotherapist Occupational Therapist
Dietician Social Worker
Speech and Language Therapist
Testing in United Kingdom
Genetics Laboratory
Institute of Medical Genetics
University Hospital of Wales
Heath Park, Cardiff CF14 4XW
West of Scotland Genetic Services
Level 2B, Laboratory Medicine
Southern General Hospital
Govan Road, Glasgow G51 4TF
Tel: 0141 354 9330
Clinicians with a specialist interest
Dr Hayley Archer / Professor Angus Clarke
Institute of Medical Genetics
University Hospital of Wales
Heath Park, Cardiff CF14 4XW
Ass Prof Sameer Zuberi / Dr John Tolmie
Epilepsy Genetics Clinic
Fraser of Allander Neurosciences Unit
Royal Hospital for Sick Children
Glasgow G3 8SJ
Contact us on email at:
Access to clinics
People with CDKL5 need a well
coordinated local team that meet their
needs. Occasionally, parents / carers may
nd it helpful to access a specialist clinic
for advice. The question being asked will
determine which clinic would be most
appropriate to refer to.
Dr Hayley Archer and Professor Angus
Clarke often see families for information
and advice, but cannot usually offer
regular follow-up to NHS patients from
outside Wales; in that case, they liaise with
local services and suggest appropriate
investigations and other referrals for the
management of specifi c complications.