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Angus Clarke, Institute of Medical Genetics, Cardiff

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.

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Angus Clarke, Institute of Medical Genetics, Cardiff

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  1. Angus Clarke, Institute of Medical Genetics, Cardiff

  2. Outline • ‘Problems’ with Genetics • Potential benefits of DIAGNOSIS • Digression into Rett syndrome • Difficult questions that remain 2

  3. ‘Problems’ with Genetics • Focus on labels and biomedical processes can lead to stigmatisation, disrespect and the neglect of patient and family experiences ... 3

  4. ‘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

  5. ‘Problems’ with Genetics • Eugenics, Nazism and ‘race hygiene’ have given genetics a bad name ... 5

  6. ‘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’) 6

  7. ‘Problems’ with Genetics • Genetic determinism ... 7

  8. ‘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

  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 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

  12. 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

  13. Diagnosis and Genetics • Genetics allows greater sophistication in making diagnoses, leading to: • More precise natural history and prognosis 13

  14. Digression into Rett Syndrome • Recognition of “cerebral atrophy with hyperammonaemia” by Andreas Rett 1966

  15. Rett Syndrome • Recognition of “cerebral atrophy with hyperammonaemia” by Andreas Rett 1966 • Changes to the diagnostic landscape

  16. 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 2

  17. 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

  18. Gene - Yes; Explanation - No • Usual cause: de novo MECP2 mutation • ‘Cure’ of Adrian Bird-Jackie Guy mouse cre-lox model 3 3

  19. 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 4

  20. 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

  21. 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 22

  22. Methyl Binding Domain Transcription Repression Domain AT hooks 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 Amir et al 1999

  23. Exon 1 & 2 (n=3) MECP2 Exon 3 & 4.1 (n=3) Exon 3 & 4 (n=3) Exon 3 – 4.3 (n=5) Exon 4.1 - 4.3 (n=1) SYBL1 IRAK1 L1CAM Exon 1 Exon 2 Exon 3 Exon 4 Exon 4 (n=1) Exon 4.2 (n=1) ~2Mb ~5kb ~60kb <1kb 1.6kb ~124kb 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) Large deletions in MECP2

  24. Mild Rett syndrome • Walk • Swim • Ride a bike • Talk • Use hands – self-feed, write • Better growth • Greater survival • But significant learning disability

  25. 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

  26. 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 ?

  27. 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 48

  28. 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 ?

  29. Diagnostic Test => 2 x 2 Table

  30. 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

  31. 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

  32. Facial similarities noted in congenital Rett syndrome associated with mutations in FOXG1

  33. Diagnosis and Genetics • Genetics allows greater sophistication in making diagnoses, leading to: • More precise natural history and prognosis 35

  34. 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

  35. Diagnosis and Genetics • Genetics allows greater sophistication in making diagnoses, leading to: • Discussion of ‘responsibility’, which has both moral and biological components 37

  36. 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 38

  37. 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 39

  38. Diagnosis and Genetics • Genetics allows greater sophistication in making diagnoses, leading to: • Searches for rational treatment 40

  39. 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

  40. 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

  41. Disease Mechanisms • But Beware! • Possible ‘Awakenings’ scenarios from rational treatment in Rett syndrome 43

  42. 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) 44

  43. 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? 45

  44. 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

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