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WEEK 2 SEM 4 > Genetic determinants of learning disability > Flashcards

Genetic determinants of learning disability Flashcards

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1
Q

What percentage of babies are born with a disability?

A

2-3%

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2
Q

What kind of disabilities can newborn babies have and what are their causes?

A
  • about 50% of childhood deafness has an underlying genetic cause
  • about 50% of childhood blindness has an underlying genetic cause
  • about 50% of childhood deaths have an underlying genetic disability
  • about 50 of children with severe learning difficult have an underlying genetic problem
  • about 30% of childhood hospital admissions are due to an underlying genetic disability
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3
Q

What is a learning disability?

A

significantly reduced ability to understand new of complex information

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4
Q

What is the spectrum of learning disability?

A
  • mildly learning disability= IQ 50-70
  • moderately learning disability= IQ of 35-50
  • severely learning disability= IQ of 20-35
  • profoundly learning disability= IQ of less than 20
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5
Q

What are the causes for learning disability?

A
  • genetics
  • problem during birth/preggo- maternal infection, teratogen, premature, trauma
  • problems after birth- severe childhood illness, head injury, poor nutrition, exposure to toxins
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6
Q

Give an example of a disease that is purely genetic?

A

Duchenne muscular dystrophy = mutated dystrophin gene

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7
Q

Give an example of a disease that is purely environmental?

A

scurvy= lacking vitamin C

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8
Q

Give examples of diseases that are a mixture of genetic and environmental?

A

osteogenesis imperfecta = some mutations associated

but not all children present the same way= not all get fractures

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9
Q

Are learning disorders and autism the same?

A

NO

autism can be associated with learning disability of epilepsy

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10
Q

How many people does autism affect in the UK?

A

1%

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11
Q

What is autism?

A

developmental condition
present at birth
takes about 3-5 years to diagnose

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12
Q

What is autism characterised by?

A
  • impaired social interaction
  • impaired social communication
  • impaired imagination
  • repetitive and stereotyped manerisms
  • rigid patterns of behaviour
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13
Q

What is special education needs?

A

all: autistic spectrum disorders, learning difficulties, and physical impairments

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14
Q

How many children have special education needs in the UK?

A

20%

only 3% have statement (document to say they have SEN and may need help in school)

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15
Q

Why should you diagnose a child with a learning disability?

A
  • helps understand why disease has happened
  • can put support in place
  • discuss genetic aspects of conditions (plan for future kids)
  • think about prognosis for the child
  • think about therapeutics
  • discuss risk of recurrence
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16
Q

How do you make a diagnosis?

A
  1. determine main concern first
  2. observe child
  3. HISTORY
    - family
    - pregnancy
    - neonatal
    - development milestones
    - associated problems- hearing, vision, seizures etc.
  4. physical examination
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17
Q

What is a cytogenic abnormality?

A

large scale chromosome changes

  • aneuploidy
  • translocation
  • duplication
  • deletion
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18
Q

What is an aneuploidy?

A

change in chromosome number
monosomy (e.g. turners)
trisomy (e.g. downs syndrome)

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19
Q

What is translocation?

A

parts of chromosome broken off from one and attached onto another

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20
Q

What are the 2 main types of translocation?

A

robertsonian

reciprocal

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21
Q

What is robertsonian translocation?

A
  • have correct number of chromosomes
  • packed in diff way
  • only occur on acrocentric chromosomes (with short P arm)
  • q arms of the 2 acrocentric chromosomes bind together and the p arms bind together
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22
Q

What is an acrocentric chromosome?

A

has short P arm

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23
Q

What are examples of acrocentric chromosomes?

A

13,14,15,21,22

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24
Q

Are there any abnormalities in people with people who have robertsonian translocations?

A

no genetic abnormalities bc all required genetic material is there

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25
Q

Can robertsonian translocations cause problems during reproduction?

A

yes

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26
Q 
What can happen if  these 2 reproduce:
ONE PARENT (mum) ( with the robertsonian translocation has 1 normal chromosome 21, 1 normal chromosome 14, and 1 abnormally translocated combination of chromosomes 14 and 21 (robertsonian chromosome)

SECOND PARENT(dad) (2 normal copies of chromosome 14, and 2 normal copies of chromosome 21)

A
  1. normal: normal chromosomes 14 and 21 from mum and normal chromosome 14 and and 21 from dad
  2. balanced translocation carrier: 1 robertsonian chromosome (14,21) from mum and normal 14 and 21 from dad
  3. unbalanced trisomy 21: 1
    robertsonian from mum (14,21) and normal 21 from mum
    normal 14 and 21 from dad
  4. unbalanced trisomy 14 (lethal):
    robertsonian chromosome (14 and 21) from mum and normal 14 from mum
    normal 14 and 21 from dad
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27
Q

What is a reciprocal translocation?

A

can happen in any chromosome

bits swap between chromosomes

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28
Q

What are microscopic deletions and duplications?

A

small chromosome chunks

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29
Q

Give an example of a microscopic deletion?

A

Wolf- Hirschhorn

  • affects p arm of chromosome 4 (Delete)
  • prominent nasal bridge
  • abnormal upper lip
  • hearing problems
  • learning difficulties
  • cardiac abnormalities
  • epilepsy
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30
Q

How can you check for a microscopic deletion or duplication?

A

karyotype

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31
Q

What is a submicroscopic deletion?

A

cannot be seen under microscope

32
Q

Give an example of a submicroscopic deletion?

A

DiGeorge’s syndrome- 22q11 microdeletion

William’s syndrome- deletion in chromosome 7

33
Q

What problems are seen in Di George’s Syndrome

A
  • antenatally detected ventricular septal defect (can repair at birth)
  • significance speech and language difficulties
  • nasal speech
  • mild-moderate learning difficulties
  • CHD
  • hypocalcaemia
  • renal abnormalities
34
Q

When does the deletion in DiGeorge’s syndrom occur?

A

90% of children with DiGeorge syndrome have had the deletion occur in 22q11 at the time of conception, and so 90% of cases are de novo and have no family history

35
Q

Because submicroscopic deletions cant be seen under a microscope, what do we use to see them?

A

FISH

Microarray/ array CGH

36
Q

What happens in FISH?

A
  1. attach molecular (FLUORESCENT) probe so specific region of chromosome (so 22 for DiGeorge’s syndrome)
  2. 2 molecular probes are used - 1 to locate chromosome and 1 to check abnormalities
37
Q

What is the problem with FISH?

A

it is targeted so you need to know where the problem is to see what is going on
so use array CGH

38
Q

Why do we use array CGH?

A

it is untargeted

can find out if we have no idea what the problem is

39
Q

What happens in array CGH?

A
  1. cut reference DNA and test DNA into chunks
  2. hybridize into slides which have probes in them on specific regions
  3. reference DNA = green
    test DNA= red
  4. look under microscope
  5. if too much RED= duplication
  6. If too much green= DELETION
  7. COMPUTE ANALYSIS
40
Q

What is William’s Syndrome?

A
  • deletion in chromosome 7
  • in short arm in region 11.23

-this causes supervalvular aortic stenosis, learning disabilities, often children have a typical personality trait (talk a lot, helping, very friendly), can develop hypercalcemia

41
Q

There are some variations that are completely normal in parents but can cause problems in children. Give an example:

A
  • 15q11.2 microdeletion (located near the prader willi syndrome microdeletion region)
  • often inherited from parents who are completely normal
  • no specific dysmorphic features that help to get to the diagnosis-there is a very variable phenotype

-in general, they cause mild to moderate learning disabilities, autistic spectrum disorders, susceptibility to adult mental health problems like schizophrenia, and seizure

42
Q

What is a single gene disorder?

A

change within gene

43
Q

How do you look for a single gene disorder?

A

sanger sequencing

nowadays next generation sequencing, whole exome sequencing, and whole genome sequencing are being done too

44
Q

In autosomal dominant conditions, what is the chance of the offspring inheriting the condition? (if one parent is autosomal dominant and the other one is normal)

A

50/50

45
Q

What is an example of an intellectual disability which is autosomal dominant?

A

TB

Neurofibromatosis Type I

46
Q

What do you see in TB and Neurofibromatosis Type I conditions?

A
  • skin changes called adenoma sebaceum, shagreen patches and ungal fibromas in the nails
  • specific brain changes like nodules in the brains, and susceptibility to giant cell astrocytomas
  • kidney problems due to overgrowths in the kidneys
  • there could be problems in the lungs in women
  • sometimes, the patient will only present with learning difficulties and none of the other symptoms (has variable penetrance)
47
Q

What is the chance of autosomal recessive being passed on to offspring?

A

children who inherit both the copies of the faulty gene (from both parents) will be affected by this condition

  • 25% chance affected
  • 50% chance carrier
  • 75% chance unaffected (carrier+unaffected)
48
Q

Give an example of a recessive condition?

A

Phenylketonuria

  • seen at birth at neonatal blood spot (blood taken from baby 5 days after birth)
  • used to be a significant cause of learning difficulty
  • treatable through diet
49
Q

What are the symptoms of phenylketonuria?

A

−developmental delay −behavioral or social problems −seizures−hyperactivity −growth retardation−eczema −microcephaly −a musty odor in the child’s breath, skin or urine−fair skin and blue eyes

50
Q

What causes phenyletonuria?

A
  • bc of interruption of pathway that metabolizes phenyl alanine to tyrosine
  • there is build up of phenyl alanine
  • cause health problems
  • phenylalanine is found in certain meats, and thus preventing eating these items can help alleviate this problem
51
Q

What does X linked recessive mean?

A

recessive conditions with mutations on one of the X chromosomes

52
Q

Who is mainly affected by X linked recessive diseases?

A

men

bc they only have 1 X

53
Q

What is fragile X syndrome?

A
  • accounts for 5% of all males with learning disabilities
  • causes dysmorphic changes−high forehead, long ears, long face, prominent jaw, macro-orchidism (abnormally large testes)
54
Q

What causes fragile X?

A

triple repeat expansion in the fragile X gene

in fragile X if there are more than 200 repeats of CGG, then the person has fragile X syndrome

55
Q

How do you test for fragile X?

A

cant pick up on array CGH or sangar bc multiple repeats confuse the technology
USE triplet primed PCR test = counts number of repeats within a specific region of the gene

56
Q

What conditions are associated with triple expansion repeats?

A
  • fragile X syndrome
  • spinobulbular muscular atrophy
  • myotonic atrophy
  • huntington’s disease
57
Q

The triple expansion repeats are unstable. What does this mean?

A

can increase in size in the next generation

58
Q

Which parent affects triple expansion repeats in which conditions?

A
  • myotinic dystrophy = likely to have expansion if maternally inherited
  • huntingtons= likely to have expansion if paternally inherited
59
Q

What is the correlation between triple expansion repeat size and disorder severity?

A

larger the repeat, more features

symptoms of disorder get more apparent in the next generations because the triplet expansion repeats have increased

60
Q

What is imprinting?

A

addition of a methyl group to a gene

61
Q

In terms of methylation, what is normal in maternal and paternal chromosomes?

A

methylated in the maternal chromosome
non- methylated in paternal chromosomes
(OR VICE VERSA)

62
Q

What happens if a gene is methylated?

A

it becomes suppressed and this is why you need both genes because one is methylated and the other isnt

63
Q

If imprinting goes wrong what can happen?

A

a) if embryo doesnt have a paternal gene because of deletion or methylation (so now you have methylated mother gene and lack of paternal gene so the embryo will have disease

b) uniparental disomy
- during gametogenesis and embryogenesis, there is a trisomic zygote (zygote with a trisomy)

  • zygote realizes this problem and removes one of the chromosomes in to make chromosome number normal
  • but removes the chromosome with the active gene
  • causing disease
64
Q

What is an example of an imprinting disorder?

A

prader willi syndrome- chromosome 15

angelman syndrome

65
Q

What causes prader willi syndrome?

A
  • loss of paternally inherited SNRPN gene and genes next to it
66
Q

What problems could there be with the SNRPN gene?

A
  • deletion of paternal gene
  • due to maternal uniparental disomy 15 (2 copies of maternal 15)
  • methylation abnormality in the imprinting region in paternal copy of chromosome 15
67
Q

What is seen with prader willi syndrome?

A
  • congenital hypotonia
  • sever feeding difficulties in the neonatal period
  • obesity later on
68
Q

What happens in angelman’s syndrome?

A
  • defect in same region (as prader willi) on chromosome 15

- gene is UBE3A

69
Q

What could be wrong with the UBE3A gene?

A
  • microdeletion in the maternally inherited copy of the UBE3A gene
  • paternal uniparental disomy (2 copies of paternal
    chromosome 15)
  • mutation in the UBE3A gene
  • methylation abnormality in the imprinting region in the
    maternal copy of chromosome 15
70
Q

What are the symptoms of angelman’s syndrome?

A
  • sever seizures in the neonatal period
  • ataxia
  • no language whatsoever
  • happy personality
71
Q

What test is used to look for an imprinting disease?

A

methylation specific PCR:

array CGH can be done- picks up deletion but doesnt tell you if on the maternal or paternal chromosome

72
Q

What does methylation specific PCR show?

A

in angelman there will be too much paternally
inherited DNA,
in prader willi there will be too much maternally inherited DNA

73
Q

What is a common environmental/teratogenic cause of foetal alcohol syndrome?

A
  • causes neurodevelopment phenotype
  • autism spectrum features
  • behavioural problem
  • microcephaly
  • characteristic facial problems
74
Q

What are the facial features seen with foetal alcohol syndrome?

A
  • a smooth philtrum: this is the area between the upper lip and nose
  • thin upper lip
  • small eye width
75
Q

What is Fetal valproate syndrome?

A
  • when women on antiepileptic medication (to control their seizures)
  • learning difficulties
  • behavioural difficulties
    face:
  • broad nasal bridge
  • thin upper lip
  • low set ears

WEEK 2 SEM 4 (6 decks)

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