Transcript What can genetics offer in learning disability and autism?

Angus Clarke,
Institute of Medical Genetics,
Cardiff
Outline
 ‘Problems’ with Genetics
 Potential benefits of DIAGNOSIS
 Digression into Rett syndrome
 Difficult questions that remain
2
‘Problems’ with Genetics
 Focus on labels and biomedical processes can lead
to stigmatisation, disrespect and the neglect of
patient and family experiences ...
3
‘Problems’ with Genetics
 Focus on labels and biomedical processes can lead
to stigmatisation, disrespect and the neglect of
patient and family experiences ...
 ... but these problems do not arise from genetics
 social attitudes to disability and difference are deep-
rooted
4
‘Problems’ with Genetics
 Eugenics, Nazism and ‘race hygiene’ have given
genetics a bad name ...
5
‘Problems’ with Genetics
 Eugenics, Nazism and ‘race hygiene’ have given
genetics a bad name ...
 ... political abuse of genetic concepts in 20th century
(heritability; inbreeding depression vs hybrid vigour;
‘race’)
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‘Problems’ with Genetics
 Genetic determinism ...
7
‘Problems’ with Genetics
 Genetic determinism ... is bad science
 and genetics can outlive these misinterpretations
 Note some other types of inappropriately strong
determinism: Marx, Freud, Skinner ...
8
What is a diagnosis?
9
What is a diagnosis?
 Does ‘neural tube defect’ count as a diagnosis?
 Or cleft lip and palate?
 Or are these physical signs?
 What about ‘autism’? or ADHD?
10
Genetics and Diagnosis
 Genetics aims at an explanatory diagnosis that
accounts for causation as well as phenotype
 This aims to inform prognosis
 And to open up possibilities for therapeutic
intervention
11
Diagnosis and Genetics
 Genetics allows greater sophistication in making
diagnoses, leading to:
 Avoidance of erroneous explanations
 - did I do anything in the pregnancy?
 - it must be his fault, it’s not in our side of the family
12
Diagnosis and Genetics
 Genetics allows greater sophistication in making
diagnoses, leading to:
 More precise natural history and prognosis
13
Digression into Rett Syndrome
• Recognition of “cerebral atrophy with
hyperammonaemia” by Andreas Rett 1966
Rett Syndrome
• Recognition of “cerebral atrophy with
hyperammonaemia” by Andreas Rett 1966
• Changes to the diagnostic landscape
Rett syndrome
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X-linked condition
Almost always affects girls (1 in 12,000)
‘Normal’ early development
Stagnation then regression
– social contact, hand skills, speech, ...
– hand stereotypies
• Stabilisation, regain social contact
• Profound cognitive impairment with motor
and autonomic dysfunctions, and relative
2
microcephaly
Other associated features
•
•
•
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Truncal ataxia
Muscle tone, including spasticity in legs
Ventilatory rhythm
Vasomotor disturbances including cool,
atrophic feet
• Seizures
• Scoliosis
• Impaired growth
– including 4th metatarsal
Gene - Yes; Explanation - No
• Usual cause: de novo MECP2 mutation
• ‘Cure’ of Adrian Bird-Jackie Guy mouse
cre-lox model
3
Brain Pathology
• Normal number of cells
• Reduced size of neurons
• Reduced number and complexity of
dendritic trees and synapses
• ‘Reversal’ of MECP2 mutation leads to
reversal of the Rett pathology (Stuart
Cobb, Glasgow)
• Introduction of mutation in adult life =>
features of typical Rett disorder
4
Rett syndrome is primarily a
CLINICAL diagnosis
with a highly characteristic time course
and evolution,
although some ‘mild’ and some ‘severe’
cases - ‘incomplete’, ‘preserved speech’,
‘congenital’ and ‘early seizure’ variants
Is regression necessary to the
diagnosis?
• Essential to delineation of the syndrome
• Regression may be absent in otherwise
classic cases with MECP2 mutation
– ‘mild’ cases (Zappella, preserved-speech)
– severe and early-onset cases (congenital
Rett; Hanefeld early seizures variant)
• 2010 criteria assert that regression is
necessary even for variant RTT
22
Rett syndrome is (usually) caused
by mutations in MECP2, already
being studied by Adrian Bird
Methyl Binding
Domain
Transcription
Repression Domain
AT hooks
•Methyl-CpG-binding protein 2
•Global transcription repressor
•Locus at Xq28
Amir et al 1999
Large deletions in MECP2
MECP2
SYBL1
Exon 1
~2Mb
Exon 1 & 2 (n=3)
Exon 3 & 4.1 (n=3)
Exon 3 & 4 (n=3)
Exon 3 – 4.3 (n=5)
Exon 4.1 - 4.3 (n=1)
Exon 4 (n=1)
Exon 4.2 (n=1)
Exon 4.2 - 4.3 (n=1)
Exon 4.2 - 4.4 (n=1)
Exon 4.3 (n=1)
Exon 4.3 – IRAK1 (n=1)
Exon 2
~5kb
Exon 3
~60kb
<1kb
IRAK1
Exon 4
1.6kb
L1CAM
~124kb
Mild Rett syndrome
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Walk
Swim
Ride a bike
Talk
Use hands – self-feed, write
Better growth
Greater survival
But significant learning
disability
How do the mutations cause
the disease ?
– contentious
– probably involves loss of fine tuning of gene
expression
– but ‘explanation’ of RTT phenotype (how
genetic change causes RTT) is still unclear
Explanation
• Descriptive explanations
Pattern recognition
=> natural history
• Mechanistic / Linear explanations
A => B => C => D; upstream and target loci
=> science
• ‘Complex System’ explanation
– Complex web of molecular and pathway
interactions
=> despair ?
Lessons for other diseases
• Charting the pathogenic mutations is just
the beginning ...
• The ‘explanation’ for the phenotype may
lie at a ‘higher‘ level of biological function,
e.g. development and function of the CNS
48
Diagnostic Applications of
MECP2 testing
• Classical Rett Syndrome
=~95% mutations
• ‘Atypical’ Rett syndrome
50% mutations
• Early seizure variant
<10% mutations, nil (so far) with infantile spasms
• Is the mutation pathogenic ?
– de novo ? synonymous ? conserved ?
– present in healthy male ?
Diagnostic Test => 2 x 2 Table
Mutation
Test
Clinical
assessment
Test Positive: Test Negative:
mutation
mutation
found
NOT found
Clinical diagnosis:
typical or ‘atypical’
case of RTT
expected
! New and
anomalous
Clinical diagnosis:
NOT
typical of RTT
! New and
anomalous
expected
Family Consequences of
Mutation Testing for RTT
• Confirmation of diagnosis
– Reproductive confidence in face of mosaicism
– But still an emotional kick
• “Disconfirmation” of diagnosis
– An anomalous category
– A different emotional kick
• “Disconfirmation of normality” when MECP2
mutation found in absence of RTT
New categories emerge
• congenital Rett syndrome (FOXG1)
• early onset of seizures group (CDKL5)
• Zappella variant (‘preserved speech’)
(some of the girls with R133C mutation in
MECP2)
• group with some features of Rett and
specific physical features (eg Pitt-Hopkins
syndrome = TCF4, Angelman UBE3A, ...)
• others ....
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Facial similarities noted in
congenital Rett syndrome
associated with mutations in
FOXG1
Diagnosis and Genetics
 Genetics allows greater sophistication in making
diagnoses, leading to:
 More precise natural history and prognosis
35
Diagnosis and Genetics
 Genetics allows greater sophistication in making
diagnoses, leading to:
 Answer family questions (why?, when?, how to
manage?, how to prevent recurrence?, who carries
it?)
 Practical decisions - and issues of guilt and blame -
are played out on the basis of facts instead of guesses
36
Diagnosis and Genetics
 Genetics allows greater sophistication in making
diagnoses, leading to:
 Discussion of ‘responsibility’, which has both moral
and biological components
37
Diagnosis and Genetics
 Genetics allows greater sophistication in making
diagnoses, leading to:
 Access to support:
 disease association/family support group
 health care services
 social services and benefits
 educational support
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Diagnosis and Genetics
 Genetics allows greater sophistication in making
diagnoses, leading to:
 Surveillance for complications
 (i) specific features of the diagnosis
 (ii) incidental findings that emerge from genetic
investigation
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Diagnosis and Genetics
 Genetics allows greater sophistication in making
diagnoses, leading to:
 Searches for rational treatment
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Disease Mechanisms
 For Duchenne muscular dystrophy, cystic fibrosis,
ectodermal dysplasia:
 finding the gene => finding the protein => new
insights => treatment (?)
 Tuberous sclerosis
 Rett syndrome: ‘Gene today, gone tomorrow’
41
Disease Mechanisms
 Adrian Bird/Jackie Guy mouse ‘cure’ => hope!
 Focused treatments for the autonomic problems
found in Rett syndrome become possible
 Work on underlying disease processes becomes
possible ....
42
Disease Mechanisms
 But Beware!
 Possible ‘Awakenings’ scenarios from rational
treatment in Rett syndrome
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Disease Mechanisms
 Causes of autism include CNVs and de novo point
mutations
 many different ‘causes’ with variety of ‘triggers’
 Metabolic or neural pathways of related diseases
(Ras pathway; pathways revealed by pattern of
CNVs in autism/schizophrenia)
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Difficult Questions
 Difficult questions remain ...
 BUT we all accept population screening for PKU and
congenital hypothyroidism
 Will newborn screening for fragile X syndrome
become equally acceptable?
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Difficult Questions
 Decisions about reproduction, population screening
and the unconditional acceptance of ‘Being A good
Parent’ or ‘Parental Virtue’
 Rational Treatments and recruitment to therapeutic
trials
 What would it be like to be ‘cured’ of Rett syndrome?
46