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:
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Male
Female
Affected male
Carrier female
Abortion / miscarriage
Death
Identified case / proband
What is the mode of inheritance and
why?
Autosomal dominant
Examples - AD
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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
• 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
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
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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
• 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
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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
• 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?
• Autosomal recessive
What factors should you ask and
look for to help come to a
diagnosis?
5 minutes to talk in your group
History
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Medical
Developmental history
Behaviour
3-generation family history
• 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
• 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
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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
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' twochromosome state (disomic)
after fertilization.
Case 5
William’s Syndrome
• Growth -along 3rd 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
Case 6
William’s Syndrome
• Growth -along 3rd 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
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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
Ask for help!