Helen presentation for upload

Translating research findings into improved
outcomes for those affected by Rett syndrome:
where are we in this journey?
Professor Helen Leonard
Telethon Institute for Child Health Research
Perth, Western Australia
Sunshine Coast March 2014
Dedicated to Dr Athel Hockey

A Progressive Syndrome of Autism, Dementia,
Ataxia, and Loss of Purposeful Hand Use in
Girls: Rett’s Syndrome: Report of 35 Cases
Bengt Hagberg, MD, Jean Aicardi MD,Karin Dias, MD, and Ovidio Ramos MD
Thirty-five patients, exclusively girls, from three countries had a uniform and striking progressive encephalopathy. After
normal general and psychomotor development up to the age of 7 to 18 months, developmental stagnation occurred,
followed by rapid deterioration of higher brain functions. Within one-and-a-half years this deterioration led to severe
dementia, autism, loss of purposeful use of the hands, jerky truncal ataxia, and acquired microcephaly. The destructive
stage was followed by apparent stability lasting through decades. Additional insidious neurological abnormalities
supervened, mainly spastic parapareses, vasomotor disturbances of the lower limbs, and epilepsy. Prior extensive
laboratory investigations have not revealed the cause. The condition is similar to a virtually overlooked syndrome
described by Rett in the German literature. The exclusive involvement of females, correlated with findings in family data
analyses, suggests a dominant mutation on one X chromosome that results in affected girls and nonviable male
hemizygous conceptuses.
Hagberg B, Aicardi J, Dias K, Ramos 0: A progressive syndrome of autism, dementia, ataxia, and loss of
purposeful hand use in girls: Rett’s syndrome: report of 35 cases. Ann Neurol 14:471-479, 1983

The pathway for a child with
Rett syndrome in 2014
• When a girl today in 2014 develops the tell-tale symptoms
articulated by Hagberg in 1983
• What will the pathway be for this child?
• What will be the influence of the Rett research journey on
the future pathway for this child and her family?

What do families want to know?
What is the cause?
What do we do now?
What is her future?
Will she walk?
Will she talk?
What is the best therapy?
Will she get epilepsy?
Which specialists should
we see?
What is the best sort of
school?
How can we best use
functional abilities in daily
life?
Is there a suitable respite
available?
How can we support our
teenager making
friendships?
How can we plan for her
future day activity and
medical care needs?
What are the ingredients for a good
quality of life?
How can we support her physical
wellbeing and social contacts?
How can we support independent
living?

What are other important questions
for families and clinicians?
• What determines why girls and women with
Rett syndrome, although sharing many
symptoms, can be very different from one
other?
• How can we modify/improve the clinical course
by making changes to the environment or by
implementing medical treatments and
interventions?

And so what has changed over
these 40 years in terms of:
Cause
Diagnosis
Understanding variability
Clinical course
Management
Quality of life
Life expectancy

Model of Research
Translation
Researchers &
Knowledge
Users
Knowledge
exchange
Creation of
Questions &
Methods
Consultation
with
stakeholders
Partnerships
formed with
collaborators and
stakeholders
Literature
Research forums
Research
Process
Continued
engagement/
relationship
management
Ongoing
reporting to
stakeholders
Feedback
processes
Knowledge
from
research
findings
Dissemination of
knowledge
Publications &
Conference
Presentations
Public
seminars/
Info sessions
Social &
other media
Plain
language
summaries
Stakeholder
feedback
Impacts
Influencing
subsequent
rounds of
research
Communicating
the impacts of
our research
Evaluation of research
implementation
Implementation
of knowledge
Apply the
knowledge
we gain to
tackle health
challenges
Patents
Guidelines
Clinical practice
New drugs
Service provision
Policy
Implications of
knowledge
Determine how this
knowledge could
make a difference
Work with stakeholders
to determine Contextual
relevance of knowledge

Discovery
• Pathway populated by many people
• Researchers cannot work in isolation from
each other or the community
• End-point of any research is to bring benefit
to population under study

The Rett Syndrome Journey
Andreas Rett
•First description of 22 girls by Andreas Rett
Presentation in 1980 in Manchester
led to a joint French, Swedish,
Portuguese publication in Annals of
Neurology in 1983
1966
Vienna Criteria
• First Clinical Criteria for Diagnosis of
Rett syndrome
Establishment Hagberg’s of variant the Australian
model
Rett syndrome study
1983 1985 1988 1993 1995

The Rett Syndrome Journey
Establishment InterRett Reversal of Rett syndrome
Identification of the genetic cause of Rett
syndrome
a mutation in the MECP2 gene
Rett Syndrome: Revised Diagnostic
Criteria and Nomenclature
Families in Australia and around the world
participating in research
Children with Rett syndrome being diagnosed earlier
More known about the clinical variation
Better management through the development of
guidelines
in a mouse model
1999 2002 2003 2007 2010 2014

The Australian Rett Syndrome
Database Longitudinal perspective
J.Piek@curtin.edu.au

Understanding the Biological Cause:
Serendipity or not
Kankirawatana P, Leonard H, Ellaway C, Scurlock J, Mansour A, Makris CM, Dure LS,
Friez M, Lane J, Kiraly-Borri C, Fabian V, Davis M, Jackson J, Christodoulou J,
Kaufmann WE, Ravine D, Percy AK. Early progressive encephalopathy in boys
and MECP2 mutations.Neurology. 2006;67(1):164-6.
Zhang J, Bao X, Cao G, Jiang S, Zhu X, Lu H, Jia L, Pan H, Fehr S, Davis M,
Leonard H, Ravine D, Wu X. What does the nature of the MECP2 mutation tell us
about parental origin and recurrence risk in Rett syndrome?
Clinical Genetics. 2012;82(6):526-33.

Understanding the Biological Cause:
What has been achieved?
•
Cheadle JP, Gill H, Fleming N, Maynard J, Kerr A, Leonard H, Krawczak M, Cooper DN, Lynch S, Thomas N, Hughes H, Hulten M, Ravine D,
Sampson JR, Clarke A. Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with
mutation type and location (vol 9, pg 1119, 2000). Human Molecular Genetics. 2000;9(11):1717-.

Implications for families
• We know the cause of Rett syndrome for the
majority
• Most children with Rett syndrome in developed
countries are being diagnosed earlier
• What does that mean for families –depending
on where they live
• US, Europe, Australia, China

Diagnosis:
What do families say?
Delay in diagnosis is a source of stress
• “Because she is atypical we did not get a diagnosis until she was about 6 years old.
This caused anguish for us as parents.”
• Having a diagnosis
• Helped families understand the cause of their child’s illness (even
after the child had died)
• “We now know how to deal with each symptom of the disorder that appears as she grows. If
we didn't have a diagnosis, the constant stereotypes and breath holding would be more
difficult and scary to watch”
• Facilitated access to appropriate services and management
• “Rett syndrome has opened up a number of avenues of support (which is fantastic) including
automatic inclusion into programs such as Very Special Kids. Since diagnosis the level of
respite and case management has improved dramatically.”
Leonard H, Davis MR, Turbett GR, Laing NG, Bower C, Ravine D. Effectiveness of posthumous
molecular diagnosis from a kept baby tooth. Lancet 2005;366(9496):1584-1584.

The Diagnostic Odyssey to Rett Syndrome:
The Experience of an Australian Family
• My daughter was eventually diagnosed with the neurological
disorder Rett syndrome a month after her 3rd birthday. For over a
year prior to diagnosis, she had been tested for a range of genetic and
metabolic disorders that I just knew she didn’t have at considerable cost
to the health system.
• Unfortunately, at the time, specialists we consulted were not up to date with the
variances of clinical symptoms in girls suffering with Rett syndrome
and they were persistent in looking to other disorders for answers.
• Doctors refused to test for Rett syndrome because
• Head growth hadn’t decelerated
• Normal stature
• Physically delayed at 6 months
• Hand mouthing rather than stereotypies
Knott M, Leonard H, Downs J. The diagnostic odyssey to Rett syndrome: The experience of an Australian
family. American Journal of Medical Genetics Part A. 2012;158A(1):10-2.

The Diagnostic Odyssey to Rett Syndrome:
The Experience of an Australian Family
Key messages
• Families often experience considerable frustration during the process of
reaching the diagnosis
• Clinicians need to be aware of the range of presentations
• Families and clinicians need to be working partners at the time of diagnosis
and beyond
• Family perspectives need to inform clinical pathways
• Achieving a diagnosis can bring benefit to the family in short and long term
“Knowledge is Power”
Knott M, Leonard H, Downs J. The diagnostic odyssey to Rett syndrome: The experience of an Australian family.
American Journal of Medical Genetics Part A. 2012;158A(1):10-2.

What has and has not been achieved?
• The age at diagnosis decreased from a median
of 4.5 years before 1999 to 3.5 years afterward
• There is a small percentage of children in whom a genetic cause
has not been identified
• Children with certain groups of MECP2 mutations may be being
missed and not diagnosed till they are older

Relationship between mutation
type & age when diagnosed
60
50
40
30
20
10
0
Fehr S, Bebbington A, Ellaway C, Rowe P, Leonard H, Downs J. Altered attainment of developmental
milestones influences the age of diagnosis of Rett syndrome.Journal of Child Neurology 2011;26(8):980-7.

And does it matter where
in the world you live?
Lim F, Downs J, Li J, Bao X, Leonard H. Barriers to
diagnosis of a rare neurological disorder in China—Lived
experiences of Rett syndrome families. American Journal
of Medical Genetics Part A. 2012;158A:1-9.

The next three issues
• What determines the variability
in the clinical presentation of
Rett syndrome?
• What are the common medical complications?
• How can we modify/improve the clinical course by
medical, environmental or other interventions?

InterRett-Global approach
• Participation invited from both
families and clinicians
– Online and paper-based options
– Available in a range of languages
• Database currently holds data
submitted on over 2500 cases
• Information includes:
– Early development & regression
– Diagnosis & genetics
– Current function
– Co-morbidities
Clinician questionnaire
Alternative languages
Family questionnaire

What has and is being achieved through
working together collaboratively
•

Understanding clinical variability
Argen&na
Austria
Canada
China
France
Germany
Greece
Hong6Kong
Ireland
Israel
Mexico
New6Zealand
Other6Countries
Spain
The6Netherlands
UK
USA
Louise S, Fyfe S, Bebbington A, Bahi-Buisson N, Anderson A, Pineda M, Percy A, Ben Zeev B, Wu XR, Bao XH,
MacLeod PM, Armstrong J, Leonard H. InterRett, a model for international data collection in a rare genetic
disorder. Research in Autism Spectrum Disorders. 2009;3(3):639-59.

Understanding clinical variability
What has not or only partially been achieved?
• Role of X-inactivation
• Other genetic
modulating factors
• What is the role of
Archer, H.et al(2007) Correlation between clinical severity in patients
with Rett syndrome with a p.R168X or p.T158M MECP2 mutation, and
the direction and degree of skewing of X-chromosome inactivation.
J Med Genet, 44, 148-152.
environment and the
amount and quality
of intervention the
child receives
An increase in clinical severity with
increase in the proportion of active
mutated allele was shown for both
the p.R168X and p.T158M
mutations.
Individuals with
the p.R168X
mutation and
heterozygous for
the BDNF
polymorphism
were at an
increased risk of
seizure onset
compared with
those
homozygous for
the wildtype
BDNF allele.
Ben Zeev,B., Bebbington, A., Ho, G., Leonard, H., De Klerk, N., Gak, E., Vecksler, M. & Christodoulou, J.
(2009) The common BDNF polymorphism may be a modifier of disease severity in Rett syndrome.
Neurology, 72, 1242-1247.

Functional abilities: general gross motor
Z scores by age-group
0.8
0.6
0.4
0.2
0
-0.2
-0.4
-0.6
-0.8
<8 years 8<13 years 13<19 years >19 years
Z score
Downs et al. Mobility profile in Rett syndrome as determined by
video analysis. Neuropediatrics 2008;39(4):205-210.

Functional abilities:
hand function by age-group
10
1
0.1
Odds ratio
Downs et al. Level of purposeful hand function as a marker of clinical severity in
Rett syndrome. Developmental Medicine & Child Neurology 2010 ;52(9):817-23.

Hand use by mutation
hand-use_purple.gph

Language development by
mutation type

Medical Issues
Scoliosis
Fracture
Epilepsy
Sleep
Behavioural disturbance
Breathing abnormalities
Poor growth

Scoliosis: risk of onset by mutation
10
1
0.1
p.R294X
p.R306C
p.R133C
C-terminal deletions
p.T158M
p.R168X
p.R255X
p.R270X
Large genomic deletions
Hazard Ratio
Ager et al. Predictors of scoliosis in Rett syndrome.
Journal of Child Neurology, 2006, 21 (9): 809-813.
• Three quarters had
developed scoliosis by 13
years of age
• Median age at onset 9.80
years
• Earlier onset associated
with
a) compromised early
development
b) poor mobility at 10
months
c) never walking
• p.R294X mutation
provided some protective
effect

What do we know, have learned about
fractures in Rett syndrome
84 (ex 236) fractured at least once
32 had more than one fracture (maximum 9)
151 fracture episodes
Fracture Incidence Rates
43.3/1000 py - Rett
11.4/1000 py - General Population
(females <20yrs – Cooley & Jones)
Downs et al. Early Determinants of Fractures in Rett Syndrome
in Rett syndrome. Pediatrics 2008 ; 121: 540-546.

Association of fracture rate with
mutation type in Rett syndrome
100
10
1
0.1
Hazard Ratio
Downs et al. Fractures in Rett syndrome. Pediatrics 2008 ; 121:540-546.
• Fracture risk was
increased
specifically in
cases with
p.R270X and in
cases with
p.R168X
mutations.
• Epilepsy also
increased fracture
risk, even after
adjustment for
genotype.

Bone density
LS BMD means z scores and confidence
intervals in each mutation group
Jefferson AL, Woodhead HJ, Fyfe S et al: Bone mineral content and density in Rett syndrome and their
contributing factors. Pediatric Research 2011; 69: 293-298.

Need for Bone Health Guidelines
in Rett syndrome
• High risk of osteoporosis and 4 times the rate
of fracture
• Risk of fracture increased with
• Presence of epilepsy, the p.R168X or p.R270X
mutation in Rett syndrome
• Prior fracture
• Vitamin D insufficiency, physical inactivity, poor
balance and muscle weakness as in the general
population
• No current intervention studies
Creation of
Questions &
Methods
Consultation
with
stakeholders
Partnerships
formed with
collaborators
and
stakeholders
Literature
Research forums

What are we doing?
• Current longitudinal study of factors affecting bone
mineral density and fracture in Rett syndrome
• Developing guidelines using combination of literature
review, consultations with consumers, findings of ongoing
studies and an expert panel
• Will consider prevention, screening, monitoring and
management

Seizures:
What have we learned?
• Median age of onset of seizures
• Age of onset varies by mutation type

0 20 40 60 80 100 120
Early truncating
p.R133C
Other
p.R294X
C terminal deletions
p.R306C
p.R270X
p.T158M
p.R255X
p.R168X
p.R106W
Large deletions
Months
Mutations
Age of onset of seizures
Bao X, Downs J, Wong K, Williams S, Leonard H. Using a large international sample to investigate
epilepsy in Rett syndrome. Developmental Medicine and Child Neurology. 2013;55(6):553-8. Epub
2013/02/21.

What happens to seizures
with age?
100
10
1
0.1
Seizure rate ratio
Jian et al. Seizures in Rett syndrome: an overview from a one-year
calendar study. European Journal of Paediatric Neurology 2007;11(5):310-7.

Are seizures related to
mutation type?

Bao X, Downs J, Wong K, Williams S, Leonard H. Using a large international sample to
investigate epilepsy in Rett syndrome. Developmental Medicine and Child Neurology.
2013;55(6):553-8. Epub 2013/02/21.

Breathing abnormalities:
What do we know?
10
1
0.1
Odds ratio and 95% confidence interval for breathing problem
by age group (n=318) (reference category: <8 years)
<8 years 8-12 years 13-17 years 18 years and above
Odds ratio (logarithmic scale)
Age group

Breathing abnormalities:
What do we know?
100
10
1
0.1
C-terminal
deletions
Adjusted odds ratio and 95% confidence interval for breathing problem
Early
truncating
by mutation type (n=198) (reference category: p.R133C)
Large deletions p.R106W p.R133C p.R168X p.R255X p.R270X p.R294X p.R306C p.T158M
Odds ratio (logarithmic scale)
Mutation type

Improved life expectancy
over time
Freilinger M, Bebbington A, Lanator I, De Klerk N,
Dunkler D, Seidl R, Leonard H, Ronen GM. Survival
with Rett syndrome: comparing Rett's original sample
with data from the Australian Rett syndrome
Database. Developmental Medicine and Child
Neurology. 2010;52(10):962-5.

Pervasive disorder of growth
Contributing factors
• Feeding difficulties
• Oromotor dysfunction
• Other digestive tract disorders
• Additional neurological complexities
• Increased energy requirements

Feeding difficulties
and poor growth
• Difficulty in maintaining growth is one of the core features of Rett
syndrome

Concern about food intake
by age group

Concern about food intake
according to mutation type

Enteral (Peg) feeding as an option
• Progressive decline in height, weight and
body mass index (BMI) z- scores in Rett
syndrome
• Likely influenced by mutation type (e.g. C-terminal
deletions were more likely to have a
normal weight.)
• Gastrostomy is therefore a clear option
• Approximately one quarter of subjects in the
Australian cohort are receiving enteral
nutritional support
Oddy WH, Webb KG, Baikie G, Thompson SM, Reilly S, Fyfe SD, Young D, Anderson AM, Leonard H. Feeding experiences and growth status in
a Rett syndrome population. Journal of Pediatric Gastroenterology and Nutrition. 2007;45(5):582-90.
Bebbington A, Percy A, Christodoulou J, Ravine D, Ho G, Jacoby P, Anderson A, Pineda M, Ben Zeev B, Bahi-Buisson N, Smeets E, Leonard H.
Updating the profile of C-terminal MECP2 deletions in Rett syndrome. Journal of Medical Genetics. 2010;47(4):242-8.
Tarquinio D, Motil K, Hou W, Lee H, Glaze D, Skinner S, Neul J, Annese F, McNair L, Barrish J, Geerts S, Lane J, Percy A. Reference growth
standards in Rett syndrome. Neurology. 2012 79(16):1653-61.

Type of feeding
by mutation type

Model of Research
Translation
Researchers &
Knowledge Users
Knowledge
exchange
Creation of
Questions &
Methods
Consultation
with
stakeholders
Partnerships
formed with
collaborators and
stakeholders
Literature
Research forums
Research
Process
Continued
engagement/
relationship
management
Ongoing
reporting to
stakeholders
Feedback
processes
Knowledge
from
research
findings
Dissemination of
knowledge
Publications &
Conference
Presentations
Public
seminars/
Info sessions
Social & other
media
Plain language
summaries
Stakeholder
feedback
Impacts
Influencing
subsequent
rounds of
research
Communicating
the impacts of
our research
Evaluation of research
implementation
Implementation
of knowledge
Apply the
knowledge
we gain to
tackle health
challenges
Patents
Guidelines
Clinical practice
New drugs
Service provision
Policy
Implications of
knowledge
Determine how this
knowledge could make
a difference
Work with stakeholders to
determine Contextual
relevance of knowledge

GI guideline project –
initial groundwork
• Literature review
• Search and key words included combinations of Rett syndrome,
cerebral palsy, developmental disability, intellectual disability, co-morbidity,
gastrointestinal, growth and feeding.
• Limited to full papers in English from 1986 to 2011.
• Statements relevant to the clinical assessment and management of
poor growth in Rett syndrome were extracted from the full text.
• Parent-reported information
• Rettnet, an online email information interchange for parents/persons
with a Rett syndrome interest, was used to collect parent and
caregiver perspectives on poor growth and contributing factors such
as calorie intake and feeding difficulties.
• Postings from January 2008 to March 2009 were extracted and
reviewed.
Creation of
Questions &
Methods
Research
Process
Continued
engagement/
relationship
management
Ongoing
reporting to
stakeholders
Feedback
processes
Consultation
with
stakeholders
Partnerships
formed with
collaborators
and
stakeholders
Literature
Research forums

Recruitment
•We contacted 57 clinicians from across the world
• 38 recruited, from USA, Australia, UK, Sweden, Austria, Belgium, Canada, Israel
• Of the 38, 27 provided data
Profession Number
Child neurologist 7
Gastroenterologist 6
Clinical geneticist 4
Paediatrician 3
Physiotherapist/ occupational therapist 2
Speech pathologist 2
Others 3

Multistage review process
• The initial guideline draft had 47 statements and 35
questions and included sections on
– assessment of calorie intake
– feeding difficulties
– anthropometric measures and other clinical assessments
– ways of increasing calorie intake
– address feeding difficulties
– use of gastrostomy
• The final guidelines document comprised 45 separate
statements

Benefits of gastrostomy
Item Median
response
n/N (%)
1. Benefits of gastrostomy include the following32,42:
Decreased number of feeding times Agree 19/25 (76.0)
Shorter duration of mealtimes Agree 24/25 (96.0)
Reduced vomiting and reflux Neither
agree or
disagree
22/25 (88.0)
Reduced chest infection Agree 24/25 (96.0)
Reduced constipation and pain Neither
agree or
disagree
23/24 (95.8)
Gastrostomy should be considered in children with:
Failure to thrive despite efforts to increase the calorie intake Strongly
agree
20/20 (100)
Oromotor dysfunction causing unsafe swallow Strongly
agree
20/20 (100)
Unusually long feeding time with resultant stress to the carer and
the child
Agree 19/20 (95.0)
2. Gastrostomy may also be associated with improved quality of life
of caregivers32
Agree 24/25 (96.0)

Recommendations now published
Dissemination of
knowledge
Publications &
Conference
Presentations
Public
seminars/
Info sessions
Social &
other media
Plain
language
summaries
Stakeholder
feedback

Dissemination of
knowledge
Publications &
Conference
Presentations
Public
seminars/
Info sessions
Social &
other media
Plain
language
summaries
Stakeholder
feedback
Leonard H, Ravikumara M, Baikie G, Naseem N, Ellaway C, Percy A, Abraham S, Geerts S, Lane J, Jones M,
Bathgate K, Downs J. Assessment and management of nutrition and growth in Rett syndrome. Journal of
Pediatric Gastroenterology and Nutrition. 2013;57: 451–460.

Gallbladder disease in
Rett syndrome
Item Level of
evidencea
Median
response
n/N b
(%)
Assessment
1. Screaming or apparent abdominal pain is suggestive of gall
bladder dysfunction24
4 Agree 15/16
(93.8)
2. The triad of apparent pain, vomiting and fever is the usual
mode of presentation of cholecystitis25
3 Agree 16/16
(100)
3. Exclude GERD as a cause of pain26 3 Agree 15/16
(93.8)
4. An ultrasound scan can be used to identify the presence of
gallstones25
3 Agree 15/16
(93.8)
5. Oral cholecystogram or a CCK or HIDA scan can be used
to confirm biliary dyskinesia25,27,29
3, 3, 3 Agree 13/13
(100)
Treatment
1. Ursodeoxycholic acid may be considered in an
asymptomatic patient with gallstone(s).
Neither agree
or disagree
10/11
(90.9)
2. The treatment of cholecystitis is cholecystectomy Neither agree
or disagree
13/14
(92.9)
3. Cholecystectomy can be considered in cases of cholecystitis
after antibiotic treatment
Agree 14/15
(93.3)
4. Cholecystectomy is advised for all non-symptomatic
patients with sludge or non-calcified stones that have not
resolved in 2 to 3 months40
3 Neither agree
or disagree
10/12
(83.3)
4. The treatment of biliary dyskinesia is cholecystectomy28 3 Agree 11/13
(84.6)
5. The treatment of cholelithiasis is cholecystectomy24 4 Agree 13/14
(92.9)

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Gallbladder disease in
Rett syndrome
Prevalence of gall bladder disease in
Rett syndrome approximately 2%
Why is gall bladder disease more
common than expected-possibly
related to cholesterol metabolism

Common symptoms & treatment
of gall bladder disease
• Screaming or apparent abdominal pain may indicate
gall bladder dysfunction
• Pain, vomiting and fever common presentation
• Ultrasound can be used to diagnose gall stones
• Removal of gallbladder usual treatment

Dissemination
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seminars/
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Dissemination
of knowledge
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How should nutrition
and growth be assessed?
What investigations are
needed?
How can feeding ability be
assessed?
What are the symptoms of
feeding difficulties and how
can they be managed?
All about enteral feeding

Dissemination
of knowledge
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seminars/
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media
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feedback
Enteral tube feeding
When should enteral
tube feeding be
considered?
What are the types of
enteral tube feeding?
How can feeding ability be
assessed?
How should enteral tube feeding
be monitored?

Gastrostomy Satisfaction
Satisfaction with surgery
Recommend for other girls
and women

Easier to care for daughter’s daily care needs
Feel less anxious about
your daughter’s future health

Satisfaction with weight gain
Ease of giving medication

Enhanced health and well-being
Fewer respiratory infections

Dissemination
of knowledge
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Conference
Presentations
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seminars/
Info
sessions
Social &
other media
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language
summaries
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feedback
In this booklet we discuss
• Reflux
• Constipation
• Abdominal bloating
For each symptom
we discuss
• Assessment
• Investigation
• Management

Behaviour & Quality of everyday life :
What do we know and what don’t we know?
• We haven’t been able to measure behaviour very well
and need to develop a better instrument for doing this
• Although some girls and women with Rett syndrome
appear to have challenging behaviours no research has
been carried out to investigate how these behaviours
may be treated
• We probably need a better measure of quality of life

Behaviour: What do we know?
Data from 2000-2002 Australian Rett Syndrome Database n=201
12
10
8
6
4
2
RSBQ score
Mutation type
12
11
10
5 6 7 8 9
RSBQ score
Robertson L, Hall S, Jacoby P, Ellaway C, De Klerk N,
Leonard H. The association between behaviour and
genotype in Rett Syndrome using the Australian Rett
Syndrome Database. American Journal of Medical
Genetics- Part B Neuropsychiatrics. 2006;141(2):177-83.
Data from 2011 Australian Rett Syndrome Database n=227

Quality of life by mutation group
30
25
20
15
10
5
0
-5
-10
-15
p.R294X p.R133C C
terminal
p.R168X p.T158M p.R306C Large
deletion
p.R270X p.R255X p.R106W
Psychosocial summary score
Lane JB, Lee HS, Smith LW, Cheng P, Percy AK, Glaze DG, Neul JL, Motil KJ, Barrish JO, Skinner SA, Annese
F, McNair L, Graham J, Khwaja O, Barnes K, Krischer JP. Clinical severity and quality of life in children and
adolescents with Rett syndrome. Neurology. 2011;77(20):1812-8. Epub 2011/10/21.

Sleep problems:
What do we know?
0-7 Years 8-12 Years 13-17 Years 18+ Years
1
0.8
0.6
0.4
0.2
0
Age group
Fitted Probability
Any sleep problem
1
0.8
0.6
0.4
0.2
0
Age group
Fitted Probability
Night laughing
Presence
Persistent
1
0.8
0.6
0.4
0.2
0
Age group
Fitted Probability
Night screaming
Presence
Persistent
1
0.8
0.6
0.4
0.2
0
Age group
Fitted Probability
Night waking
Presence
Persistent

Sleep problems:
What don’t we know?
2000 2002 2004 2006 2009
0.3
0.2
0.1
0
−0.1
−0.2
−0.3
Questionnaire Year
Absolute Risk Change
Effect of treatment on sleep problem
Average effect
95% CI
We’re not doing well at treating sleep problems

What are some of the
ingredients of quality of life ?
• Involvement in life situations
with meaningful reward
– Physical activity
– Learning new information
– Social relationships
– Going out
• Allows for friendships, fun
and development of self-identity
Andrews J, Leonard H, Hammond G, Girdler S, Rajapaksa R, Bathgate K, Downs J. Community participation for girls and women living with Rett syndrome.
Disability and Rehabilitation. In press.
Walker E, Crawford F Leonard H. Community Participation: Conversations with parent-carers of young women with Rett syndrome. Journal of Intellectual
& Developmental Disability. In press.

Ongoing challenge of maintaining
the rage about Rett syndrome
Dissemination of
knowledge
Publications &
Conference
Presentations
Public
seminars/
Info sessions
Social &
other media
Plain
language
summaries
Stakeholder
feedback

The whole picture: the complexity of
Rett syndrome goes beyond the biology
Individual function factors
• bone health
• control of scoliosis
• growth and maintenance of weight
• control of epilepsy
• manageable behaviour
Participation
• school and/or day placement
• minimal hospital admissions
Genetic presentation
• Type of MECP2 mutation
• X inactivation status
• Other genetic factors
• Sporadic presentation
Developmental course prior to diagnosis eg,
duration of period prior to developmental regression,
learning to walk
Optimal
well-being,
quality and
duration
of life
Environmental factors
• early therapy interventions,
• ongoing therapy,
• medical management (eg monitoring, medications,
orthoses)
• surgical management (eg monitoring, gastrostomy,
spinal surgery)
• respite, home modifications, supportive community,
financial resources
Activity
• mobility
• hand function
• ability to communicate
• adequacy of sleep
Family functioning
• Function, eg physical and mental health of parents and
siblings
• Activity, eg recreation, family holidays
• Participation, eg parental employment, smooth
transitions between life stages
• Personal factors, eg resilience

Thanks go to...
• NIH (2004-2008)
• NHMRC (2004-2008)
• NHMRC (2111-2013)
• International Rett Syndrome
Foundation (InterRett)
• Financial Markets Foundation for
Children (1999)
• Rett Syndrome Association
Research Fund (2002)
• The families and clinicians who have
supported the research so well over 18
years
• Bill Callaghan and the Rett Syndrome
Association of Australia
• Australian Paediatric Surveillance Unit
• Janelle Lillis and family
Recent funding NIH 1 R01 HD043100-01A1, NHMRC #303189 & #100384, IRSF

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