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• 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• 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• 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

• 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

• 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 trisomy2% 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 lossNB 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

BehaviourShort attention spanLearning 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

• 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

Uniparental disomy

–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 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– thoracic scoliosis

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

• 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!