Angus Clarke, Institute of Medical Genetics, Cardiff
description
Transcript of Angus Clarke, Institute of Medical Genetics, Cardiff
![Page 1: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/1.jpg)
Angus Clarke,Institute of Medical Genetics,
Cardiff
![Page 2: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/2.jpg)
2
Outline‘Problems’ with GeneticsPotential benefits of DIAGNOSISDigression into Rett syndromeDifficult questions that remain
2
![Page 3: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/3.jpg)
3
‘Problems’ with GeneticsFocus on labels and biomedical processes can
lead to stigmatisation, disrespect and the neglect of patient and family experiences ...
3
![Page 4: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/4.jpg)
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
![Page 5: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/5.jpg)
5
‘Problems’ with GeneticsEugenics, Nazism and ‘race hygiene’ have
given genetics a bad name ...
5
![Page 6: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/6.jpg)
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
![Page 7: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/7.jpg)
7
‘Problems’ with GeneticsGenetic determinism ...
7
![Page 8: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/8.jpg)
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
![Page 9: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/9.jpg)
9
What is a diagnosis?
![Page 10: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/10.jpg)
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
![Page 11: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/11.jpg)
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
![Page 12: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/12.jpg)
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
![Page 13: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/13.jpg)
13
Diagnosis and GeneticsGenetics allows greater sophistication in
making diagnoses, leading to:
More precise natural history and prognosis
13
![Page 14: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/14.jpg)
Digression into Rett Syndrome
• Recognition of “cerebral atrophy with hyperammonaemia” by Andreas Rett 1966
![Page 15: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/15.jpg)
Rett Syndrome
• Recognition of “cerebral atrophy with hyperammonaemia” by Andreas Rett 1966
• Changes to the diagnostic landscape
![Page 16: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/16.jpg)
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
![Page 17: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/17.jpg)
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
![Page 18: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/18.jpg)
3
Gene - Yes; Explanation - No
• Usual cause: de novo MECP2 mutation• ‘Cure’ of Adrian Bird-Jackie Guy mouse
cre-lox model
3
![Page 19: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/19.jpg)
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
![Page 20: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/20.jpg)
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
![Page 21: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/21.jpg)
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
![Page 22: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/22.jpg)
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
![Page 23: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/23.jpg)
![Page 24: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/24.jpg)
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
![Page 25: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/25.jpg)
Mild Rett syndrome• Walk• Swim• Ride a bike• Talk• Use hands – self-feed, write• Better growth• Greater survival• But significant learning
disability
![Page 26: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/26.jpg)
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
![Page 27: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/27.jpg)
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 ?
![Page 28: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/28.jpg)
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
![Page 29: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/29.jpg)
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 ?
![Page 30: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/30.jpg)
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
![Page 31: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/31.jpg)
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
![Page 32: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/32.jpg)
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
![Page 33: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/33.jpg)
Facial similarities noted in congenital Rett syndrome
associated with mutations in FOXG1
![Page 34: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/34.jpg)
![Page 35: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/35.jpg)
35
Diagnosis and GeneticsGenetics allows greater sophistication in
making diagnoses, leading to:
More precise natural history and prognosis
35
![Page 36: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/36.jpg)
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
![Page 37: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/37.jpg)
37
Diagnosis and GeneticsGenetics allows greater sophistication in
making diagnoses, leading to:
Discussion of ‘responsibility’, which has both moral and biological components
37
![Page 38: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/38.jpg)
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
![Page 39: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/39.jpg)
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
![Page 40: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/40.jpg)
40
Diagnosis and GeneticsGenetics allows greater sophistication in
making diagnoses, leading to:
Searches for rational treatment
40
![Page 41: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/41.jpg)
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
![Page 42: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/42.jpg)
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
![Page 43: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/43.jpg)
43
Disease MechanismsBut Beware!
Possible ‘Awakenings’ scenarios from rational treatment in Rett syndrome
43
![Page 44: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/44.jpg)
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
![Page 45: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/45.jpg)
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
![Page 46: Angus Clarke, Institute of Medical Genetics, Cardiff](https://reader033.fdocuments.net/reader033/viewer/2022052913/56815b87550346895dc98a44/html5/thumbnails/46.jpg)
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