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MD1 Neuroscience > DNA Testing in Diagnosis of Neurological Disorders with Loss of Movement Control > Flashcards

DNA Testing in Diagnosis of Neurological Disorders with Loss of Movement Control Flashcards

1
Q

How can you get a neurodegenerative disorder?

A

Acquired

Inherited

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2
Q

What are unstable repeat expansions?

A

Repeating units of 3+ nucleotides in tandem

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3
Q

What are more common: trinucleotide, or tetranucleotide repeats?

A

Trinucleotide

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4
Q

What is the more common sequence of unstable repeat expansions?

A

CAG

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5
Q

Are repeat expansions present in the normal gene?

A

Yes, with a specific range making up repeat region

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6
Q

What is repeat expansion?

A

When number of repeat units increases above certain threshold, associated with condition

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7
Q

Below the threshold, is the number of repeats stable?

A

Yes, in both gametes and somatic cells

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8
Q

Above the threshold, is the number of repeats stable?

A

No, unstable in gametes, and can also be unstable in somatic cells
- Passed onto subsequent generations

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9
Q

Why are repeat expansions also called dynamic mutations?

A

Size of expansion changes

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10
Q

What is anticipation?

A

Expansion size increases in following generations

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11
Q

Do all unstable repeat expansion diseases have anticipation?

A

No

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12
Q

What is anticipation associated with?

A

Earlier onset

Greater severity of symptoms

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13
Q

Which cells are more likely to undergo repeat expansion?

A

Those undergoing DNA replication

  • Gametes
  • Some somatic cells
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14
Q

What is a possible mechanism of expansion?

A
  1. Starting template strand of DNA
  2. Replicating strand detaches inappropriately during replication
  3. Replicating strand slips from proper alignment by one repeat length > mismatched repeat loops out
  4. Newly synthesised strand contains extra repeat
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15
Q

How do unstable repeat expansion disorders present?

A

Primarily neurological

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16
Q

What is the inheritance pattern of unstable repeat expansion disorders?

A

Variable, but mostly autosomal dominant

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17
Q

What is the nature of a class 1 unstable repeat expansion?

A

Non-coding repeats > loss of protein expression/function

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18
Q

What is the consequence of a class 1 unstable repeat expansion?

A

Impaired transcription of affected gene

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19
Q

What is the nature of a class 2 unstable repeat expansion?

A

Non-coding repeats > confer novel properties on RNA

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20
Q

What is the consequence of a class 2 unstable repeat expansion?

A

RNA with toxic gain-of-function

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21
Q

What is the nature of a class 3 unstable repeat expansion?

A

Repeats in codon > confer novel properties to affected protein

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22
Q

What is the consequence of a class 3 unstable repeat expansion?

A

Production of modified protein > overrides function of normal protein

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23
Q

What are late-onset neurodegenerative disorders caused by repeat expansions characterised by?

A

Loss of movement control

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24
Q

Why is it important to diagnose the particular type of unstable repeat expansion disorder?

A

Treatment
Prognosis
Risk for other family members

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25
Can you have juvenile onset with unstable repeat expansion disorders?
Late onset is most common, but juvenile onset does occur
26
What is the symptom progression in late-onset neurodegenerative disorders caused by unstable repeat expansions?
Worsen over time > death
27
What is DNA testing useful for in unstable repeat expansion disorders?
Differential diagnosis Predictive testing - Pre-symptomatic at-risk relatives - Prenatal testing
28
What is the inheritance pattern of Huntington's disease?
Autosomal dominant
29
What is the prevalence of Huntington's disease?
1 in 10 000-20 000 - Varies from population to population - Higher in places with founder effect
30
What is the age of onset of Huntington's disease?
Mean age = 40-50 | 5-10% at
31
Why can you get juvenile onset of Huntington's disease?
Number of repeats much higher
32
What are the main clinical features of Huntington's disease?
Movement/motor disorder Cognitive disorder Psychiatric/emotional disorder Progressive neurodegeneration
33
Do the clinical features change as Huntington's disease progresses?
Yes: - Early features - Middle features - Late features
34
Is current treatment for Huntington's disease disease-modifying?
No, mitigates some symptoms
35
What is the nucleotide sequence that is expanded in Huntington's disease?
CAG
36
In what region of DNA does repeat expansion happen in Huntington's disease?
In exon 1 of chromosome 4 of HTT gene
37
What protein does CAG code for?
Glutamine
38
What is the protein product of the HTT gene?
Huntingtin
39
What are the physiological roles of huntingtin?
``` Transcription - Brain-derived neurotrophic factor IC transport of other molecules IC signalling and metabolism Reducing apoptosis ```
40
What change to the protein structure does the expanded CAG huntingtin product have?
PolyQ tail at N-terminal
41
What is the effect of polyQ-huntingtin?
Toxic effect in basal ganglia, especially in medium spiny neurons (starts here)
42
What is the pathophysiology of Huntington's disease?
Progressive degeneration and loss of medim spiny neurons in striatum of basal ganglia
43
What do the brain scans of someone with Huntington's disease show?
Loss of brain tissue in basal ganglia, and other areas, including cerebral cortex
44
What is the normal number of repeats to have in the HTT gene?
26 or less
45
What is the normal, mutable number of repeats to have in the HTT gene?
27-35
46
What does it mean if the number of repeats in the HTT is mutable?
Won't develop Huntington's disease themselves Have intermediate size allele Higher risk of expansion in sperm Paternal transmission > expanded number of repeats in offspring
47
What is the number of repeats in the HTT if you're in the zone of reduced penetrance?
36-39
48
What is your risk of developing Huntington's disease if you are in the zone of reduced penetrance?
Difficult to predict if you'll develop disease
49
What is the number of repeats in the HTT to be completely penetrant?
40 or more
50
What do CCG interruptions in a sequence of CAG repeats in the HTT gene do?
Mitigate effects of CAG repeats
51
What is the molecular pathology of Huntington's disease?
Aberrant mRNA splicing of exon 1 + polyQ-huntingtin cleaved by caspases > N-terminal fragments with altered conformation - toxic Form aggregates and nuclear inclusions - may be partly protective cellular response via sequestration Loss of function of normal HTT + possible toxicity of mRNA
52
What are the outcomes of loss of normal huntingtin function?
Excitotoxicity Oxidative stress Impaired energy metabolism Apoptosis
53
How is Huntington's disease classically tested for?
PCR using radioactive nucleotide tagging > gel electrophoresis > autoradiography
54
Why is it difficult to get the exact repeat size when testing for Huntington's disease?
DNA polymerase in PCR makes mistakes > causes expansions, similar to those happening in cells
55
Why do you get a ladder pattern in gel electrophoresis when testing for Huntington's disease?
Stuttering effect of PCR > generates product of more than one size
56
How do you chose the correct band in gel electrophoresis when there is a ladder pattern?
Focus on band that is largest and darkest
57
What is the margin of error when testing DNA for repeat expansions? What does it mean for the patient?
Results are always plus or minus 1-2 | Tricky if person on borderline
58
What is currently used to test for Huntington's disease?
PCR using fluorescent nucleotide tagging > fragment analysis on capillary electrophoresis > fluorescence detection
59
What is the inheritance pattern for spinocerebellar ataxias?
Autosomal dominant
60
What is the prevalence of spinocerebellar ataxias?
Frequency of different types varies in different populations
61
What is the age of onset of spinocerebellar ataxias?
Late onset
62
What are the main clinical features of spinocerebellar ataxias?
``` Progressive degeneration of - Cerebellum - Brainstem - Spinocerebellar tracts Affects - Gait - Hand coordination - Speech - Eye movements Phenotypic variation ```
63
Which spinocerebellar ataxias are the most common?
SCA 1 SCA 2 SCA 3 = Machado-Joseph disease
64
In which populations is SCA 3/Machado-Joseph disease especially relevant?
Portuguese | Indigenous Australians, especially in North Arnhem land
65
Why does SCA 6 have no zone of reduced penetrance?
Unstable repeats don't undergo anticipation
66
What is the inheritance pattern for Friedreich ataxia?
Autosomal recessive
67
What is the prevalence of Friedreich ataxia?
2-4 in 100 000
68
What is the carrier frequency of Friedreich ataxia?
1/60 and 1/100 in Indo-Europeans
69
What is the age of onset of Friedreich ataxia?
Mean age 10-15 | Usually
70
What are the main clinical features of Friedreich ataxia?
Progressive limb and gait ataxia Cardiomyopathy in 65% Diabetes mellitus in 30%
71
What is the nucleotide sequence that is repeated in Friedreich ataxia?
GAA
72
Where is the repeat expansion in Friedreich ataxia?
Intron 1 in FXN gene on chromosome 9
73
What is the normal function of the protein affected in Friedreich ataxia?
Binds Fe - important for mitochondrial function
74
What does the repeat expansion cause in the FXN gene in Friedreich ataxia?
Abnormal secondary structure - maybe even triple helix, or induces heterochromatin > reduced protein production
75
What does the defect caused by Friedreich ataxia result in within the cell?
Accumulation of Fe in mitochondria > oxidative damage
76
What proportion of cases does the expansion mutation account for in Friedreich ataxia?
94-98%
77
What accounts for the small proportion of cases that aren't due to an expansion mutation in Friedreich ataxia?
Compound heterozygotes with GAA repeat and other point inactivating mutation(s)
78
What is the protein that is affected in Friedreich's ataxia?
Frataxin
79
What is the normal range of repeats in the FTN gene?
5-33
80
What is the affected range of repeats in the FTN gene?
66-1700
81
What is the mutable range of repeats in the FTN gene?
34-65 uninterrupted
82
What often interrupts alleles longer than 27 GAA repeats in the FTN gene?
GAGGAA | Could stabilise allele

MD1 Neuroscience (55 decks)

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