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 CasesBengt 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?

Imagine

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

ProcessContinued

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

ImpactsInfluencing

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

knowledgeDetermine 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

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

The Rett Syndrome Journey

1966

Vienna Criteria

• First Clinical Criteria for Diagnosis of Rett syndrome

1983 1985 1988 1993 1995

Establishment of the Australian Rett syndrome study

Hagberg’s variant model

Identification of the genetic cause of Rettsyndromea mutation in the MECP2 gene

The Rett Syndrome Journey

201420102007200320021999

Establishment of InterRettReversal of Rett syndrome in a mouse model

Rett Syndrome: Revised Diagnostic Criteria and Nomenclature

Families in Australia and around the world participating in researchChildren with Rett syndrome being diagnosed earlierMore known about the clinical variationBetter management through the development of guidelines

[email protected]

The Australian Rett Syndrome Database Longitudinal perspective

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 familiesWhat has been achieved?

• 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 neurologicaldisorder Rett syndrome a month after her 3rd birthday. For over ayear prior to diagnosis, she had been tested for a range of genetic andmetabolic disorders that I just knew she didn’t have at considerable costto the health system.

• Unfortunately, at the time, specialists we consulted were not up to date with thevariances of clinical symptoms in girls suffering with Rett syndromeand 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

0

10

20

30

40

50

60

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 variabilityin 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 variabilityWhat has been achieved?

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.

Argen&na

Austria

Canada

China

France

Germany

Greece

Hong6Kong

Ireland

Israel

Mexico

New6Zealand

Other6Countries

Spain

The6Netherlands

UK

USA

Understanding clinical variabilityWhat has not or only partially been achieved?

• Role of X-

inactivation

• Other genetic

modulating factors

• What is the role of

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.

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.

Functional abilities: general gross motorZ 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 s

co

re

Downs et al. Mobility profile in Rett syndrome as determined by video analysis. Neuropediatrics 2008;39(4):205-210.

Mobility by mutation

Functional abilities: hand function by age-group

0.1

1

10


Od

ds r

ati

o

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_purple.gph

Hand use by mutation

Language development by mutation type

Scoliosis

Fracture

Epilepsy

Sleep

Behavioural disturbance

Breathing abnormalities

Poor growth

Medical Issues

Scoliosis: risk of onset by mutation

0.1

1

10

p.R29

4X

p.R30

6C

p.R13

3C

C-ter

min

al d

elet

ions

p.T15

8M

p.R16

8X

p.R25

5X

p.R27

0X

Large

genom

ic d

elet

ions

Haza

rd R

ati

o

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 Syndromein Rett syndrome. Pediatrics 2008 ; 121: 540-546.

Association of fracture rate with mutation type in Rett syndrome

0.1

1

10

100

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

Large deletions

p.R106W

p.R168X

p.R255X

p.T158M

p.R270X

p.R306C

C terminal deletions

p.R294X

Other

p.R133C

Early truncating

Months

Mu

tati

on

sAge 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. Epub2013/02/21.

What happens to seizures with age?

0.1

1

10

100


Se

izu

re r

ate

ra

tio

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?

0.1

1

10

<8 years 8-12 years 13-17 years 18 years and above

Od

ds

rati

o (

loga

rith

mic

sca

le)

Age group

Odds ratio and 95% confidence interval for breathing problemby age group (n=318) (reference category: <8 years)

Breathing abnormalities: What do we know?

0.1

1

10

100

C-terminaldeletions

Earlytruncating

Large deletions p.R106W p.R133C p.R168X p.R255X p.R270X p.R294X p.R306C p.T158M

Od

ds

rati

o (

loga

rith

mic

sca

le)

Mutation type

Adjusted odds ratio and 95% confidence interval for breathing problemby mutation type (n=198) (reference category: p.R133C)

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

Pervasive disorder of growth

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

ProcessContinued

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

ImpactsInfluencing

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

knowledgeDetermine 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.

Research

ProcessContinued

engagement/

relationship

management

Ongoing

reporting to

stakeholders

Feedback

processes

Creation of

Questions &

Methods

Consultation

with

stakeholders

Partnerships

formed with

collaborators

and

stakeholders

Literature

Research forums

Recruitment

Profession Number

Child neurologist 7

Gastroenterologist 6

Clinical geneticist 4

Paediatrician 3

Physiotherapist/ occupational therapist 2

Speech pathologist 2

Others 3

• 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

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 Medianresponse

n/N(%)

1.Benefitsofgastrostomyincludethefollowing32,42

:

Decreasednumberoffeedingtimes Agree 19/25(76.0)

Shorterdurationofmealtimes Agree 24/25(96.0)

Reducedvomitingandreflux Neitheragreeordisagree

22/25(88.0)

Reducedchestinfection Agree 24/25(96.0)

Reducedconstipationandpain Neitheragreeordisagree

23/24(95.8)

Gastrostomyshouldbeconsideredinchildrenwith:

Failuretothrivedespiteeffortstoincreasethecalorieintake Stronglyagree

20/20(100)

Oromotordysfunctioncausingunsafeswallow Stronglyagree

20/20(100)

Unusuallylongfeedingtimewithresultantstresstothecarerandthechild

Agree 19/20(95.0)

2.Gastrostomymayalsobeassociatedwithimprovedqualityoflifeofcaregivers

32

Agree 24/25(96.0)

Recommendations now publishedWhat has been achieved?

Dissemination of

knowledgePublications &

Conference

Presentations

Public

seminars/

Info sessions

Social &

other media

Plain

language

summaries

Stakeholder

feedback


Dissemination of


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.


Dissemination of

knowledge

Publications &

Conference

Presentations

Public

seminars/

Info sessions

Social &

other media

Plain

language

summaries

Stakeholder

feedback

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 cholecystitis

25

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 gallstones

25

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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Stakeholder

feedback

Prevalence of gall bladder disease in

Rett syndrome approximately 2%

Why is gall bladder disease more

common than expected-possibly

related to cholesterol metabolism

Gallbladder disease in Rett syndrome

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

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

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

Publications &

Conference

Presentations

Public

seminars/

Info sessions

Social & other

media

Plain

language

summaries

Stakeholder

feedback

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?

Enteral tube feeding


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 knowledgePublications &

Conference

Presentations

Public

seminars/

Info

sessions

Social &

other media

Plain

language

summaries

Stakeholder

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 behavioursmay be treated

• We probably need a better measure of quality of life

Behaviour: What do we know?

2

4

6

8

10

12

RSB

Q s

core

Mutation type

56789

101112

RS

BQ

sc

ore

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 2000-2002 Australian Rett Syndrome Database n=201

Data from 2011 Australian Rett Syndrome Database n=227

Quality of life by mutation group

-15

-10

-5

0

5

10

15

20

25

30

p.R294X p.R133C Cterminal

p.R168X p.T158M p.R306C Largedeletion

p.R270X p.R255X p.R106W

Psych

oso

cia

l su

mm

ary

sco

re

Lane JB, Lee HS, Smith LW, Cheng P, Percy AK, Glaze DG, Neul JL, Motil KJ, Barrish JO, Skinner SA, AnneseF, 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+ Years0

0.2

0.4

0.6

0.8

1

Age group

Fit

ted

Pro

ba

bil

ity

Any sleep problem


0.2

0.4

0.6

0.8

1

Age group

Fit

ted

Pro

ba

bil

ity

Night laughing

Presence

Persistent


0.2

0.4

0.6

0.8

1

Age group

Fit

ted

Pro

ba

bil

ity

Night screaming

Presence

Persistent


0.2

0.4

0.6

0.8

1

Age group

Fit

ted

Pro

ba

bil

ity

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

Ab

so

lute

Ris

k C

ha

ng

e

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.

Translation

•

Ongoing challenge of maintaining the rage about Rett syndrome

Dissemination of


Conference

Presentations

Public

seminars/

Info sessions

Social &

other media

Plain

language

summaries

Stakeholder

feedback

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

Individual function factors

• bone health

• control of scoliosis

• growth and maintenance of weight

• control of epilepsy

• manageable behaviour

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

The whole picture: the complexity of Rett syndrome goes beyond the biology

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

helen presentation for upload

Education