Transcript Genetics and neurology
Genetics and neurology
Aims
• • • • •
be able to construct a family tree and interpret common patterns of inheritance know about the features of common chromosome disorders know what to do when the diagnosis of Downs syndrome is suspected at delivery or on the postnatal wards be able to recognise features suggesting dysmorphic or genetic syndromes and to identify associated anomalies know the processes involved in establishing and presenting the diagnosis to parents
What are the symbols for:
• • • • • • • Male Female Affected male Carrier female Abortion / miscarriage Death Identified case / proband
What is the mode of inheritance and why?
Autosomal dominant
Examples - AD
• • • • • • • • • Achondroplasia Ehlers-Danlos Syndrome Familial hypercholestrolaemia Gilbert’s syndrome Marfan’s syndrome Myotonic dystrophy Neurofibromatosis types 1 and 2 Tuberose sclerosis Von Willebrand’s disease
Hallmarks of AD inheritance
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Usually every affected individual has an affected biological parent. There is no skipping of generations. ( exceptions due to penetrance) M=F The recurrence risk of each child of an affected parent is 1/2.
Normal siblings of affected individuals do not transmit the trait to their offspring.
The defective product of the gene is usually a structural protein, not an enzyme.
What is the mode of inheritance and why?
AutosomalRecessive
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Hall marks of AR
M=F Trait in sibs not parents Increased liklihood if related consanguineous May occur as an isolated event if spontaneous mutation On average, the recurrence risk to the unborn sibling of an affected individual is 1/4.
Examples - AR
• • • • • • • • • • • • • • • Alkaptonuria Ataxia telangiectasia β-Thalassaemia Congenital adrenal hyperplasia Cystic fibrosis Galactosaemia Glucose-6-phosphatase deficiency Glycogen storage diseases Homocystinuria Oculocutaneous albinism Phenylketonuria Sickle cell anaemia Spinal muscular atrophy Tay Sachs disease Wilson’s disease
What is the mode of inheritance and why?
X linked recessive
What is the chance of these girls being is a carrier ?
Hallmarks x linked recessive
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The disease is never passed from father to son.
Males affected All affected males in a family are related through their mothers.
Trait or disease is typically passed from an
affected grandfather, through his carrier daughters, to half of his grandsons.
Examples x linked
• • • • • • • • • • Becker muscular dystrophy Duchene muscular dystrophy Fabry’s disease Fragile X syndrome Haemophilias A and B Hunters syndrome Ocular albinism Red-green colour blindness Testicular feminisation syndrome Wiskott-Aldrich syndrome.
Can you draw
• • • You have been asked to see Jamie as ? Ehlers Danlos. His father has been diagnosed. There seem to be no problems with his mother or younger sister Dad has an older sister, who has 3 children the oldest of her two girls are affect but at the moment there are no difficulties in her son. Dad tells you that looking back on it his mother had similar problems but has died 20 years ago and therefore was never diagnosed. His dad seems well.
What is the mode of inheritance
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Autosomal dominant
• • • • • • You have been asked to see Joseph who has a older sister with homocystinuria. There is also an older sister who is well.
Both of Jacobs parents are well. His mother is an only child. Her parents are well. Her father has a younger sister, who is her husbands mother. His father has 2 younger sisters who are also health. Both sets of grandparents are well. What is the relationship of the parents!
What is the mode of inheritance?
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Autosomal recessive
What factors should you ask and look for to help come to a diagnosis?
5 minutes to talk in your group
History
• • • • Medical Developmental history Behaviour 3-generation family history
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Growth – present and at birth inc OFC Skin / hair Skull
– shape, symmetry – sutures / fontanelle
Face
– Overall – forehead, eyes, midface and oral region – ears – shape and stucture
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Hands and Feet
– shape and size
Joints and Skeleton
– contractures, limb shortening – spine length, straight/curved – neck length, webbing
cardiovascular Genitalia and Anus Examination of other family members
‘Parent information’
• • • • When you get the envelop give to team the picture of the face and written information only When if come to questions only give information on that line – or picture if one available May be more than 1 presenting concern – but this needs to be sought – piece by piece If says nothing on card that answers their question say – no concerns or normal
Case 1
Please see Johnny he sat late and is now 18 months and isn’t walking
Newborn Downs
• • • Examine for features of downs including tone and cardiovascular system examination Say concerned that baby low tone – ask registrar / consultant to see Make sure Dad doesn’t leave – or when Dad is going to be there
• • • • • • • Private place, not interrupted Both parents present Know name of baby and parents Baby present Take a midwife Ask parents any concerns Examine and state your concerns – make you wonder about Downs Syndrome
• • • What do family know about Downs?
Lovely baby, always make progress with development, but slower than other children Vast majority go to main stream primary school
• • • • Urgent Karyotype- 48 hours Feeding – can be poor Skin – can be dry Routine hearing screen • • • • Set up meeting both parents around 72 hours –( talk to lab ) Down’s syndrome associate information Re examine heart and arrange cardiology appointment Refer to community paediatrics
• Increase – Secretory otitis media – Myopia • • • Managing these these are key to enabling development Therapy input – low tone Additional educational support More rarely – hypothyroidism, cervical spine instability, coeliac, leukaemia – and almost anything else you can name!
Genetics
98% spontaneous trisomy 2% translocation – risk of recurrence
Antenatal testing – Downs
• Triple testing 15 to 20 weeks – gives risk – maternal age, AFP, hCG, uE3 (better results if also inhibin)– 5% false positive rate • Ultrasound - Nuchal fold –10-15 weeks with serum PAPP-A, b-hCG, maternal agedetection rate of – 62% for a 5% false-positive rate.
• • Chroionic villus sampling ( 12 weeks) 1% foetal loss Amniocentisis (15 weeks) 1% foetal loss NB research blood test – look for trisomy in maternal blood. Currently costs around£500
Case 2
Please see Michael aged 8 years he is stuggling at school
Foetal Alcohol
Microcephaly Behaviour Short attention span Learning difficulties
Case 3
Boys
Fragile X
• • expansion of a single trinucleotide gene sequence (CGG) on the X chromosome Failure to express the protein coded by the FMR1 gene - which is required for normal neural development.
• Normal (29–31 CGG repeats) • Premutation (55–200 CGG repeats)(not affected by the syndrome) – can be carrier mother or father • Full Mutation (more than 200 CGG
Case 4
Prader Willi
Case 5
• • • • • 100% Developmental delay – functionally severe (sit 12/12, crawl 18 -24/12, walk 4) Significant speech impairment (Better comprehension than expressive) Movt – ataxic, tremulous limb movt Behaviour- laughter, smiling, hand flapping, poor attention
• •
Angelmans Syndrome
80% – microcephaly by 2 years (OFC normal at birth) – seizures by 3 years – abnormal EEG large amplitude spike waves on eye closure 20% – flat occiput – protruding / thrusting tongue – feeding disorders – wide mouth / widely spaced teeth – prominent chin, deep set eyes – Drooling – Attraction / fascination with water – thoracic scoliosis
Uniparental disomy
• • child inherits both copies of a chromosome from one parent and none from the other.
due to a loss of function of imprinted genes ie depending on which parent you get it from one bit gets switched off
– an error in meiosis. – Two chromosomes in either the egg or sperm cell fail to separate and both get passed to the fetus. – fetus inherits three chromosomes (trisomy) rather than two. In relatively rare situations, one of the three chromosomes is lost (termed trisomy rescue), resulting in a 'normal' two chromosome state (disomic) after fertilization.
Case 5
William’s Syndrome
• • • • Growth -along 3 rd or below Heart - Aortic Stenosis Behaviour – Hyperactive and talkative – Behavioural problems – Poor sleep – Dislike loud noises Metabolic - hypercalaemia
• • • deletion of q11.23 of chromosome 7.
Around 25 genes Includes ELN gene which codes for the elastin hence the the connective-tissue abnormalities and cardiovascular disease
Case 6
• • • • • 100% Developmental delay – functionally severe (sit 12/12, crawl 18 -24/12, walk 4) Significant speech impairment (Better comprehension than expressive) Movt – ataxic, tremulous limb movt Behaviour- laughter, smiling, hand flapping, poor attention
• •
Angelmans Syndrome
80% – microcephaly by 2 years (OFC normal at birth) – seizures by 3 years – abnormal EEG large amplitude spike waves on eye closure 20% – flat occiput – protruding / thrusting tongue – feeding disorders – wide mouth / widely spaced teeth – prominent chin, deep set eyes – Drooling – Attraction / fascination with water – thoracic scoliosis
Case 6
William’s Syndrome
• • • • Growth -along 3 rd or below Heart - Aortic Stenosis Behaviour – Hyperactive and talkative – Behavioural problems – Poor sleep – Dislike loud noises Metabolic - hypercalaemia
• • • deletion of q11.23 of chromosome 7.
Around 25 genes Includes ELN gene which codes for the elastin hence the the connective-tissue abnormalities and cardiovascular disease
MLPA
• • • • Multiplex ligation-dependent probe amplification (MLPA) Variation on polymerase chain reaction Multiple targets to be amplified with only a single primer pair Use probes of two oligonucleotides which recognise adjacent target sites on the DNA – screen DNA for around 20 conditions associated with learning difficulties.
Summary
• • • • • • • • • Medical developemental Behaviour 3-generation family history Think about growth esp OFC
Growth – present and at birth inc OFC Skin / hair / face
Cardiovascular Hands / feet / joints