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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
Q

Can you have juvenile onset with unstable repeat expansion disorders?

A

Late onset is most common, but juvenile onset does occur

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26
Q

What is the symptom progression in late-onset neurodegenerative disorders caused by unstable repeat expansions?

A

Worsen over time > death

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27
Q

What is DNA testing useful for in unstable repeat expansion disorders?

A

Differential diagnosis
Predictive testing
- Pre-symptomatic at-risk relatives
- Prenatal testing

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28
Q

What is the inheritance pattern of Huntington’s disease?

A

Autosomal dominant

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29
Q

What is the prevalence of Huntington’s disease?

A

1 in 10 000-20 000

  • Varies from population to population
  • Higher in places with founder effect
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30
Q

What is the age of onset of Huntington’s disease?

A

Mean age = 40-50

5-10% at

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31
Q

Why can you get juvenile onset of Huntington’s disease?

A

Number of repeats much higher

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32
Q

What are the main clinical features of Huntington’s disease?

A

Movement/motor disorder
Cognitive disorder
Psychiatric/emotional disorder
Progressive neurodegeneration

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33
Q

Do the clinical features change as Huntington’s disease progresses?

A

Yes:

  • Early features
  • Middle features
  • Late features
34
Q

Is current treatment for Huntington’s disease disease-modifying?

A

No, mitigates some symptoms

35
Q

What is the nucleotide sequence that is expanded in Huntington’s disease?

A

CAG

36
Q

In what region of DNA does repeat expansion happen in Huntington’s disease?

A

In exon 1 of chromosome 4 of HTT gene

37
Q

What protein does CAG code for?

A

Glutamine

38
Q

What is the protein product of the HTT gene?

A

Huntingtin

39
Q

What are the physiological roles of huntingtin?

A 
Transcription
- Brain-derived neurotrophic factor
IC transport of other molecules
IC signalling and metabolism
Reducing apoptosis
40
Q

What change to the protein structure does the expanded CAG huntingtin product have?

A

PolyQ tail at N-terminal

41
Q

What is the effect of polyQ-huntingtin?

A

Toxic effect in basal ganglia, especially in medium spiny neurons (starts here)

42
Q

What is the pathophysiology of Huntington’s disease?

A

Progressive degeneration and loss of medim spiny neurons in striatum of basal ganglia

43
Q

What do the brain scans of someone with Huntington’s disease show?

A

Loss of brain tissue in basal ganglia, and other areas, including cerebral cortex

44
Q

What is the normal number of repeats to have in the HTT gene?

A

26 or less

45
Q

What is the normal, mutable number of repeats to have in the HTT gene?

A

27-35

46
Q

What does it mean if the number of repeats in the HTT is mutable?

A

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
Q

What is the number of repeats in the HTT if you’re in the zone of reduced penetrance?

A

36-39

48
Q

What is your risk of developing Huntington’s disease if you are in the zone of reduced penetrance?

A

Difficult to predict if you’ll develop disease

49
Q

What is the number of repeats in the HTT to be completely penetrant?

A

40 or more

50
Q

What do CCG interruptions in a sequence of CAG repeats in the HTT gene do?

A

Mitigate effects of CAG repeats

51
Q

What is the molecular pathology of Huntington’s disease?

A

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
Q

What are the outcomes of loss of normal huntingtin function?

A

Excitotoxicity
Oxidative stress
Impaired energy metabolism
Apoptosis

53
Q

How is Huntington’s disease classically tested for?

A

PCR using radioactive nucleotide tagging > gel electrophoresis > autoradiography

54
Q

Why is it difficult to get the exact repeat size when testing for Huntington’s disease?

A

DNA polymerase in PCR makes mistakes > causes expansions, similar to those happening in cells

55
Q

Why do you get a ladder pattern in gel electrophoresis when testing for Huntington’s disease?

A

Stuttering effect of PCR > generates product of more than one size

56
Q

How do you chose the correct band in gel electrophoresis when there is a ladder pattern?

A

Focus on band that is largest and darkest

57
Q

What is the margin of error when testing DNA for repeat expansions? What does it mean for the patient?

A

Results are always plus or minus 1-2

Tricky if person on borderline

58
Q

What is currently used to test for Huntington’s disease?

A

PCR using fluorescent nucleotide tagging > fragment analysis on capillary electrophoresis > fluorescence detection

59
Q

What is the inheritance pattern for spinocerebellar ataxias?

A

Autosomal dominant

60
Q

What is the prevalence of spinocerebellar ataxias?

A

Frequency of different types varies in different populations

61
Q

What is the age of onset of spinocerebellar ataxias?

A

Late onset

62
Q

What are the main clinical features of spinocerebellar ataxias?

A 
Progressive degeneration of
- Cerebellum
- Brainstem
- Spinocerebellar tracts
Affects
- Gait
- Hand coordination
- Speech
- Eye movements
Phenotypic variation
63
Q

Which spinocerebellar ataxias are the most common?

A

SCA 1
SCA 2
SCA 3 = Machado-Joseph disease

64
Q

In which populations is SCA 3/Machado-Joseph disease especially relevant?

A

Portuguese

Indigenous Australians, especially in North Arnhem land

65
Q

Why does SCA 6 have no zone of reduced penetrance?

A

Unstable repeats don’t undergo anticipation

66
Q

What is the inheritance pattern for Friedreich ataxia?

A

Autosomal recessive

67
Q

What is the prevalence of Friedreich ataxia?

A

2-4 in 100 000

68
Q

What is the carrier frequency of Friedreich ataxia?

A

1/60 and 1/100 in Indo-Europeans

69
Q

What is the age of onset of Friedreich ataxia?

A

Mean age 10-15

Usually

70
Q

What are the main clinical features of Friedreich ataxia?

A

Progressive limb and gait ataxia
Cardiomyopathy in 65%
Diabetes mellitus in 30%

71
Q

What is the nucleotide sequence that is repeated in Friedreich ataxia?

A

GAA

72
Q

Where is the repeat expansion in Friedreich ataxia?

A

Intron 1 in FXN gene on chromosome 9

73
Q

What is the normal function of the protein affected in Friedreich ataxia?

A

Binds Fe - important for mitochondrial function

74
Q

What does the repeat expansion cause in the FXN gene in Friedreich ataxia?

A

Abnormal secondary structure - maybe even triple helix, or induces heterochromatin > reduced protein production

75
Q

What does the defect caused by Friedreich ataxia result in within the cell?

A

Accumulation of Fe in mitochondria > oxidative damage

76
Q

What proportion of cases does the expansion mutation account for in Friedreich ataxia?

A

94-98%

77
Q

What accounts for the small proportion of cases that aren’t due to an expansion mutation in Friedreich ataxia?

A

Compound heterozygotes with GAA repeat and other point inactivating mutation(s)

78
Q

What is the protein that is affected in Friedreich’s ataxia?

A

Frataxin

79
Q

What is the normal range of repeats in the FTN gene?

A

5-33

80
Q

What is the affected range of repeats in the FTN gene?

A

66-1700

81
Q

What is the mutable range of repeats in the FTN gene?

A

34-65 uninterrupted

82
Q

What often interrupts alleles longer than 27 GAA repeats in the FTN gene?

A

GAGGAA

Could stabilise allele

MD1 Neuroscience (55 decks)

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