Genetic determinants of learning disability Flashcards
(75 cards)
1
Q
What percentage of babies are born with a disability?
A
2-3%
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
3
Q
What is a learning disability?
A
significantly reduced ability to understand new of complex information
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
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
6
Q
Give an example of a disease that is purely genetic?
A
Duchenne muscular dystrophy = mutated dystrophin gene
7
Q
Give an example of a disease that is purely environmental?
A
scurvy= lacking vitamin C
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
9
Q
Are learning disorders and autism the same?
A
NO
autism can be associated with learning disability of epilepsy
10
Q
How many people does autism affect in the UK?
A
1%
11
Q
What is autism?
A
developmental condition
present at birth
takes about 3-5 years to diagnose
12
Q
What is autism characterised by?
A
- impaired social interaction
- impaired social communication
- impaired imagination
- repetitive and stereotyped manerisms
- rigid patterns of behaviour
13
Q
What is special education needs?
A
all: autistic spectrum disorders, learning difficulties, and physical impairments
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)
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
16
Q
How do you make a diagnosis?
A
- determine main concern first
- observe child
- HISTORY
- family
- pregnancy
- neonatal
- development milestones
- associated problems- hearing, vision, seizures etc. - physical examination
17
Q
What is a cytogenic abnormality?
A
large scale chromosome changes
- aneuploidy
- translocation
- duplication
- deletion
18
Q
What is an aneuploidy?
A
change in chromosome number
monosomy (e.g. turners)
trisomy (e.g. downs syndrome)
19
Q
What is translocation?
A
parts of chromosome broken off from one and attached onto another
20
Q
What are the 2 main types of translocation?
A
robertsonian
reciprocal
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
22
Q
What is an acrocentric chromosome?
A
has short P arm
23
Q
What are examples of acrocentric chromosomes?
A
13,14,15,21,22
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
25
Can robertsonian translocations cause problems during reproduction?
yes
26
```
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)
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
27
What is a reciprocal translocation?
can happen in any chromosome
| bits swap between chromosomes
28
What are microscopic deletions and duplications?
small chromosome chunks
29
Give an example of a microscopic deletion?
Wolf- Hirschhorn
- affects p arm of chromosome 4 (Delete)
- prominent nasal bridge
- abnormal upper lip
- hearing problems
- learning difficulties
- cardiac abnormalities
- epilepsy
30
How can you check for a microscopic deletion or duplication?
karyotype
31
What is a submicroscopic deletion?
cannot be seen under microscope
32
Give an example of a submicroscopic deletion?
DiGeorge's syndrome- 22q11 microdeletion
| William's syndrome- deletion in chromosome 7
33
What problems are seen in Di George's Syndrome
- 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
When does the deletion in DiGeorge's syndrom occur?
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
Because submicroscopic deletions cant be seen under a microscope, what do we use to see them?
FISH
| Microarray/ array CGH
36
What happens in FISH?
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
What is the problem with FISH?
it is targeted so you need to know where the problem is to see what is going on
so use array CGH
38
Why do we use array CGH?
it is untargeted
| can find out if we have no idea what the problem is
39
What happens in array CGH?
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
What is William's Syndrome?
- 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
There are some variations that are completely normal in parents but can cause problems in children. Give an example:
- 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
What is a single gene disorder?
change within gene
43
How do you look for a single gene disorder?
sanger sequencing
| nowadays next generation sequencing, whole exome sequencing, and whole genome sequencing are being done too
44
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)
50/50
45
What is an example of an intellectual disability which is autosomal dominant?
TB
| Neurofibromatosis Type I
46
What do you see in TB and Neurofibromatosis Type I conditions?
- 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
What is the chance of autosomal recessive being passed on to offspring?
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
Give an example of a recessive condition?
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
What are the symptoms of phenylketonuria?
−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
What causes phenyletonuria?
- 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
What does X linked recessive mean?
recessive conditions with mutations on one of the X chromosomes
52
Who is mainly affected by X linked recessive diseases?
men
| bc they only have 1 X
53
What is fragile X syndrome?
- 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
What causes fragile X?
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
How do you test for fragile X?
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
What conditions are associated with triple expansion repeats?
- fragile X syndrome
- spinobulbular muscular atrophy
- myotonic atrophy
- huntington’s disease
57
The triple expansion repeats are unstable. What does this mean?
can increase in size in the next generation
58
Which parent affects triple expansion repeats in which conditions?
- myotinic dystrophy = likely to have expansion if maternally inherited
- huntingtons= likely to have expansion if paternally inherited
59
What is the correlation between triple expansion repeat size and disorder severity?
larger the repeat, more features
| symptoms of disorder get more apparent in the next generations because the triplet expansion repeats have increased
60
What is imprinting?
addition of a methyl group to a gene
61
In terms of methylation, what is normal in maternal and paternal chromosomes?
methylated in the maternal chromosome
non- methylated in paternal chromosomes
(OR VICE VERSA)
62
What happens if a gene is methylated?
it becomes suppressed and this is why you need both genes because one is methylated and the other isnt
63
If imprinting goes wrong what can happen?
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
What is an example of an imprinting disorder?
prader willi syndrome- chromosome 15
| angelman syndrome
65
What causes prader willi syndrome?
- loss of paternally inherited SNRPN gene and genes next to it
66
What problems could there be with the SNRPN gene?
- 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
What is seen with prader willi syndrome?
- congenital hypotonia
- sever feeding difficulties in the neonatal period
- obesity later on
68
What happens in angelman's syndrome?
- defect in same region (as prader willi) on chromosome 15
| - gene is UBE3A
69
What could be wrong with the UBE3A gene?
- 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
What are the symptoms of angelman's syndrome?
- sever seizures in the neonatal period
- ataxia
- no language whatsoever
- happy personality
71
What test is used to look for an imprinting disease?
methylation specific PCR:
| array CGH can be done- picks up deletion but doesnt tell you if on the maternal or paternal chromosome
72
What does methylation specific PCR show?
in angelman there will be too much paternally
inherited DNA,
in prader willi there will be too much maternally inherited DNA
73
What is a common environmental/teratogenic cause of foetal alcohol syndrome?
- causes neurodevelopment phenotype
- autism spectrum features
- behavioural problem
- microcephaly
- characteristic facial problems
74
What are the facial features seen with foetal alcohol syndrome?
- a smooth philtrum: this is the area between the upper lip and nose
- thin upper lip
- small eye width
75
What is Fetal valproate syndrome?
- when women on antiepileptic medication (to control their seizures)
- learning difficulties
- behavioural difficulties
face:
- broad nasal bridge
- thin upper lip
- low set ears
