angus clarke, institute of medical genetics, cardiff
Post on 08-Feb-2016
73 Views
Preview:
DESCRIPTION
TRANSCRIPT
Angus Clarke,Institute of Medical Genetics,
Cardiff
2
Outline‘Problems’ with GeneticsPotential benefits of DIAGNOSISDigression into Rett syndromeDifficult questions that remain
2
3
‘Problems’ with GeneticsFocus on labels and biomedical processes can
lead to stigmatisation, disrespect and the neglect of patient and family experiences ...
3
4
‘Problems’ with GeneticsFocus 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
5
‘Problems’ with GeneticsEugenics, Nazism and ‘race hygiene’ have
given genetics a bad name ...
5
6
‘Problems’ with GeneticsEugenics, 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’)
6
7
‘Problems’ with GeneticsGenetic determinism ...
7
8
‘Problems’ with GeneticsGenetic determinism ... is bad science
and genetics can outlive these misinterpretations
Note some other types of inappropriately strong determinism: Marx, Freud, Skinner ...
8
9
What is a diagnosis?
10
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
11
Genetics and DiagnosisGenetics 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
12
Diagnosis and GeneticsGenetics 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
13
Diagnosis and GeneticsGenetics 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
2
Rett syndrome• 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 microcephaly
2
Other associated features• Truncal ataxia• Muscle tone, including spasticity in legs• Ventilatory rhythm• Vasomotor disturbances including cool,
atrophic feet• Seizures• Scoliosis• Impaired growth
– including 4th metatarsal
3
Gene - Yes; Explanation - No
• Usual cause: de novo MECP2 mutation• ‘Cure’ of Adrian Bird-Jackie Guy mouse
cre-lox model
3
4
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 courseand evolution,
although some ‘mild’ and some ‘severe’ cases - ‘incomplete’, ‘preserved speech’, ‘congenital’ and ‘early seizure’ variants
22
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-CpG-binding protein 2•Global transcription repressor•Locus at Xq28
Methyl Binding Domain
AT hooks
Transcription Repression Domain
Amir et al 1999
Large deletions in MECP2
Exon 4.2 - 4.3 (n=1)
Exon 1 & 2 (n=3)Exon 3 & 4.1 (n=3)
Exon 3 – 4.3 (n=5)Exon 4.1 - 4.3 (n=1)
Exon 4.3 – IRAK1 (n=1)
Exon 3 & 4 (n=3)
Exon 4.2 (n=1)
Exon 4.2 - 4.4 (n=1)Exon 4.3 (n=1)
Exon 4 (n=1)
MECP2
Exon 1 Exon 2 Exon 3 Exon 4
~2Mb ~5kb ~60kb <1kb 1.6kb ~124kb
IRAK1 L1CAMSYBL1
Mild Rett syndrome• 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 explanationsPattern 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 ?
48
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 TestClinical assessment
Test Positive: mutation found
Test Negative: mutation 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
32
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 ....32
Facial similarities noted in congenital Rett syndrome
associated with mutations in FOXG1
35
Diagnosis and GeneticsGenetics allows greater sophistication in
making diagnoses, leading to:
More precise natural history and prognosis
35
36
Diagnosis and GeneticsGenetics 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
37
Diagnosis and GeneticsGenetics allows greater sophistication in
making diagnoses, leading to:
Discussion of ‘responsibility’, which has both moral and biological components
37
38
Diagnosis and GeneticsGenetics allows greater sophistication in
making diagnoses, leading to:
Access to support:disease association/family support grouphealth care servicessocial services and benefitseducational support
38
39
Diagnosis and GeneticsGenetics 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
39
40
Diagnosis and GeneticsGenetics allows greater sophistication in
making diagnoses, leading to:
Searches for rational treatment
40
41
Disease MechanismsFor 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
42
Disease MechanismsAdrian 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
43
Disease MechanismsBut Beware!
Possible ‘Awakenings’ scenarios from rational treatment in Rett syndrome
43
44
Disease MechanismsCauses of autism include CNVs and de novo
point mutationsmany different ‘causes’ with variety of
‘triggers’
Metabolic or neural pathways of related diseases (Ras pathway; pathways revealed by pattern of CNVs in autism/schizophrenia)
44
45
Difficult QuestionsDifficult questions remain ...
BUT we all accept population screening for PKU and congenital hypothyroidism
Will newborn screening for fragile X syndrome become equally acceptable?
45
46
Difficult QuestionsDecisions 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
top related